Abstract
Endocrine-disrupting chemicals (EDCs) are man-made compounds interfering with hormone signaling. Omnipresent in the environment, they can cause adverse effects in a wide range of wildlife. Accordingly, Endocrine Disruption is one focal area of ecotoxicology. Because EDCs induce complex response patterns in vivo via a wide range of mechanisms of action, in vitro techniques have been developed to reduce and understand endocrine toxicity. In this review we revisit the evidence for endocrine disruption in diverse species and the underlying molecular mechanisms. Based on this, we examine the battery of in vitro bioassays currently in use in ecotoxicological research and discuss the following key questions. Why do we use in vitro techniques? What endpoints are we looking at? Which applications are we using in vitro bioassays for? How can we put in vitro data into a broader context? And finally, what is the practical relevance of in vitro data? In critically examining these questions, we review the current state-of-the-art of in vitro (eco)toxicology, highlight important limitations and challenges, and discuss emerging trends and future research needs.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsNotes
- 1.
Imposex is defined as the imposition of male reproductive characteristics, for example, penis development, on female individuals.
- 2.
For example, female testosterone levels might be increased by aromatase inhibition. See Fernandes et al. [369] for a comprehensive review on molluskan steroid biosynthesis.
- 3.
Organotin compounds have been shown to be potent agonists of the retinoid receptors RXR and RAR.
- 4.
- 5.
Given the almost universal contamination of freshwater ecosystems with (treated) wastewater, the issue of feminization became the focal point for research on ED in fish and EDCs in wastewater.
- 6.
VTG is an egg yolk protein precursor. Synthesized in the female liver, it is transported via the bloodstream for incorporation into oocytes. Its expression is estrogen-dependent [371]. Naturally only produced by mature females, its prevalence in juvenile or male fish is considered a biomarker of exposure to estrogenic substances.
- 7.
Intersex males had increased VTG and estradiol levels, delayed spermatogenesis, and malformed reproductive ducts as well as reduced milt production, sperm motility, and fertilization rates.
- 8.
- 9.
During the exposure period, VTG levels in male fathead minnow (short life cycle) were three orders of magnitude higher than in the reference. In addition, the testicular and ovarian development was arrested [372]. Similar effects have been observed in pearl dace. While in this longer-lived species a clear impact on population size has not yet been observed, population structure was affected as indicated by the loss of the 1-year-old size class [374]. In another species (rainbow trout), fertility was unaffected [375]. This highlights considerable species differences [376].
- 10.
Polychlorinated biphenyls (PCBs) and p,p-dichlorodiphenyltrichloroethane (DDT).
- 11.
- 12.
Similar effects can be induced by other endocrine disruptors, including 17β-estradiol, atrazine, and Bisphenol A [379].
- 13.
- 14.
Interestingly, in ovo exposure to estrogenic chemicals feminizes the male gonad in birds [381] as it does in rodent models.
- 15.
The exposure scenario was based on the levels of estrogen-like compounds detected in earthworms sampled at wastewater treatment plants. Morphologically, the brain area controlling song complexity was enlarged in exposed compared to control males [109].
- 16.
In a more recent study, growth and immunocompetence was reduced in nestlings exposed similarly to the previous experiment [382].
- 17.
Notably, polar bears contaminated with organohalogens had thyroid gland lesions [383].
- 18.
- 19.
It has been suggested to replace “secondary” by “consequent” [124].
- 20.
This includes intracrine (intracellular), autocrine (targeting the cell itself), juxtacrine (targeting adjacent cells), and paracrine (targeting cells in the vicinity) signaling.
- 21.
Half of the human NRs are ‘orphan receptors’, i.e., its natural ligand is unknown or might not exist [127]. Here, ligand-independent mechanisms might exist.
- 22.
- 23.
AhR does not belong to the NR superfamily but to the basic helix-loop-helix transcription factors. It is included here because of its relevance to endocrine disruption.
- 24.
Aromatase is a cytochrome P450 (CYP) enzyme converting C19 androgens into C18 estrogens.
- 25.
Another example is prostaglandin synthesis. Several EDCs bind to cyclooxygenase enzymes and block the synthesis of prostaglandin precursors [386].
- 26.
- 27.
Here, EGF, ERK, MAPK, or Ras signaling might be involved. For example, short-chain fatty acids enhance ER and PR activity through activation of mitogen-activated protein kinase (MAPK) and inhibition of histone deacetylase [389]. Such compounds are termed ‘hormone sensitizers’.
- 28.
Peroxisome proliferator-activated receptor (PPAR).
- 29.
Thyroid hormone receptor-associated protein.
- 30.
Interestingly, phthalates increased the binding of TRAP to ERα.
- 31.
- 32.
These methods were later standardized by the OECD as Hershberger/Uterotrophic Bioassay in Rats (Guidelines 441 and 440).
- 33.
Kanter et al. and others [391] developed fish assays for pregnancy testing. They proposed to standardize the animal model because “the results became so confusing that it was felt tests could not be conducted along scientific lines until the fish had been standardized.” This is a splendid reminder that the standardization of bioassays has been an issue from the very beginning.
- 34.
A combined chronic toxicity/carcinogenicity study in rats according to the U.S. EPA’s Pesticide Assessment Guidelines costs approximately 2 million dollars and takes approximately 2 years [392].
- 35.
An AOP is a conceptual framework that portrays existing knowledge concerning the linkage between two anchor points – the molecular initiating event, and an adverse outcome, connected by a chain of key events and the relationships between them (adopted from AOP-KB, https://aopkb.org).
- 36.
So far, the cellular processes resulting in feminization are not well understood. VTG induction is here rather used as biomarker for estrogenic effects than causative.
- 37.
With regard to receptor transactivation, one can argue that the interaction of a chemical with a receptor protein is under investigation (as in the case of LBAs). However, because the induction/repression of the receptor-mediated gene expression is studied, the organizational level under investigation is indeed transcription.
- 38.
While this difference is obvious, it is worth stressing. In the experience of the authors, the level of biological organization is often neglected when discussing in vitro “endocrine activity.”
- 39.
- 40.
An ISI Web of Science search for “ligand binding assay” returns 20 hits in the research area Environmental Science/Ecology (October 2, 2015).
- 41.
Receptor dimerization or nuclear localization may precede this event. Hormone response elements are regulatory, palindromic DNA sequences. See Ruff et al. [395] for more details.
- 42.
These included not only endocrine endpoints but also mutagenicity, genotoxicity, stress response, and cytotoxicity.
- 43.
Multiple substrates are available. Often the cleavage of o-nitrophenyl-β-d-galactopyranosid (ONPG) or chlorophenol red-β-d-galactopyranoside (CPRG) is determined colorimetrically. The fluorescent methylumbelliferyl β-d-galactopyranoside (MUG) has also been used as substrate [396].
- 44.
- 45.
Indeed, OHT is a partial agonist inducing a weak estrogenic response in the absence of a full agonist such as 17β-estradiol [173].
- 46.
This assay has been developed by the German Leibniz Institute of Plant Genetics and Crop Plant Research and is now marketed by New Diagnostics (www.new-diagnostics.com).
- 47.
This list is far from comprehensive given that ISI Web of Science lists 13,292 publications under the keywords “yeast” AND “assay” AND “receptor” (on October 22, 2015).
- 48.
http://www.biodetectionsystems.com/products/bioassays/available-assays.html (last accessed October 23, 2015).
- 49.
Mainly, the results of the DR-CALUX are compared to chemical analysis, especially of dioxin-like compounds.
- 50.
BioDetection Systems BV, the company marketing the CALUX assays, is a 2001 spinoff founded by Prof. Abraham Brouwer of the Free University of Amsterdam.
- 51.
According to an ISI Web of Science search (October 5, 2015).
- 52.
Humans possess 48 nuclear receptors, Caenorhabditis elegans 284 [400].
- 53.
A meta-analysis by Dang et al. [401] demonstrated that the EC50s of several EDCs at human and fish ERs correlate and concluded that “transactivation of ERs in one vertebrate species or one subtype of ERs could be extrapolated to other species or subtypes of ERs for the purpose of chemical screening.” However, the EC50s can differ by two orders of magnitude for many EDCs.
- 54.
- 55.
Notably, other mollusk receptors (e.g., RAR) also appear to be constitutively active [404]. If so, the mechanism of action mediating endocrine disruption in mollusks remains unknown.
- 56.
Despite tremendous advances in analytical chemistry, they remain unknown in most cases.
- 57.
In the U.S., the term toxicity identification evaluation (TIE) is used. However, TIE rather refers to in vivo effects [405].
- 58.
For instance, had we attempted to identify DEHF by NMR, we would have needed to extract, fractionate, and test at least 1,000 L of bottled drinking water.
- 59.
Interestingly, ex vivo data were not predictive.
- 60.
This might be because of publication bias.
- 61.
For instance, the total cell concentration or the dose at the molecular target (biologically effective dose).
- 62.
More information at http://www.epa.gov/endocrine-disruption.
- 63.
See COMMISSION REGULATION (EU) No 589/2014 of 2 June 2014 laying down methods of sampling and analysis for the control of levels of dioxins, dioxin-like PCBs, and non-dioxin-like PCBs in certain foodstuffs and repealing Regulation (EU) No 252/2012. Official Journal of the European Union L 164/18.
- 64.
ISO Standards Catalogue. ISO/TC 147 – Water quality. Standards under development (see www.iso.org).
- 65.
Annual-Average Environmental Quality Standards (AA-EQS) for EE2: 0.035 ng/L and for E2 of 0.4 ng/L. These concentrations should not be exceeded in order to protect the aquatic environment and human health.
References
LaFont R (2000) The endocrinology of invertebrates. Ecotoxicology 9(1–2):41–57
Kortenkamp A, Martin O, Faust M, Evans R, McKinlay R, Orton F, Rosivatz E (2011) State of the art assessment of endocrine disruptors, final report. European Commission, The Directorate-General for the Environment, p 433
Thornton JW (2001) Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc Natl Acad Sci U S A 98(10):5671–5676
Thornton JW, Need E, Crews D (2003) Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Science 301(5640):1714–1717
Edwards TM, Moore BC, Guillette LJ (2006) Reproductive dysgenesis in wildlife: a comparative view. Int J Androl 29(1):109–120
Guillette LJ (2000) Contaminant-induced endocrine disruption in wildlife. Growth Horm IGF Res 10:45–50
Guillette LJ Jr (2006) Endocrine disrupting contaminants: beyond the dogma. Environ Health Perspect 114:9–12
Kloas W, Urbatzka R, Opitz R, Wuertz S, Behrends T, Hermelink B, Hofmann F, Jagnytsch O, Kroupova H, Lorenz C, Neumann N, Pietsch C, Trubiroha A, Van Ballegooy C, Wiedemann C, Lutz I (2009) Endocrine disruption in aquatic vertebrates. Trends Comp Endocrinol Neurobiol 1163:187–200
McLachlan JA (2001) Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocr Rev 22(3):319–341
Milnes MR, Bermudez DS, Bryan TA, Edwards TM, Gunderson MP, Larkin ILV, Moore BC, Guillette LJ (2006) Contaminant-induced feminization and demasculinization of nonmammalian vertebrate males in aquatic environments. Environ Res 100(1):3–17
Oehlmann J, Schulte-Oehlmann U, Kloas W, Jagnytsch O, Lutz I, Kusk KO, Wollenberger L, Santos EM, Paull GC, Van Look KJW, Tyler CR (2009) A critical analysis of the biological impacts of plasticizers on wildlife. Philos Trans R Soc B-Biol Sci 364(1526):2047–2062
Sumpter JP (2005) Endocrine disrupters in the aquatic environment: an overview. Acta Hydrochim Hydrobiol 33(1):9–16
Tyler CR, Jobling S, Sumpter JP (1998) Endocrine disruption in wildlife: a critical review of the evidence. Crit Rev Toxicol 28(4):319–361
Vos JG, Dybing E, Greim HA, Ladefoged O, Lambre C, Tarazona JV, Brandt I, Vethaak AD (2000) Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation. Crit Rev Toxicol 30(1):71–133
Oehlmann J, Di Benedetto P, Tillmann M, Duft M, Oetken M, Schulte-Oehlmann U (2007) Endocrine disruption in prosobranch molluscs: evidence and ecological relevance. Ecotoxicology 16(1):29–43
Mills LJ, Chichester C (2005) Review of evidence: are endocrine-disrupting chemicals in the aquatic environment impacting fish populations? Sci Total Environ 343(1–3):1–34
Hayes TB, Case P, Chui S, Chung D, Haeffele C, Haston K, Lee M, Mai VP, Marjuoa Y, Parker J, Tsui M (2006) Pesticide mixtures, endocrine disruption, and amphibian declines: are we underestimating the impact? Environ Health Perspect 114:40–50
Milnes MR, Guillette LJ Jr (2008) Alligator tales: new lessons about environmental contaminants from a sentinel species. Bioscience 58(11):1027–1036
Ottinger MA, Lauoie E, Thompson N, Barton A, Whitehouse K, Barton M, Abdelnabi M, Quinn M Jr, Panzica G, Viglietti-Panzica C (2008) Neuroendocrine and behavioral effects of embryonic exposure to endocrine disrupting chemicals in birds. Brain Res Rev 57(2):376–385
Iguchi T, Watanabe H, Katsu Y (2006) Application of ecotoxicogenomics for studying endocrine disruption in vertebrates and invertebrates. Environ Health Perspect 114:101–105
Hamlin HJ, Guillette LJ Jr (2011) Embryos as targets of endocrine disrupting contaminants in wildlife. Birth Defects Res C: Embryo Today 93(1):19–33
Rhind SM (2009) Anthropogenic pollutants: a threat to ecosystem sustainability? Philos Trans R Soc B-Biol Sci 364(1534):3391–3401
Acevedo-Whitehouse K, Duffus ALJ (2009) Effects of environmental change on wildlife health. Philos Trans R Soc B-Biol Sci 364(1534):3429–3438
Jenssen BM (2006) Endocrine-disrupting chemicals and climate change: a worst-case combination for arctic marine mammals and seabirds? Environ Health Perspect 114:76–80
Matthiessen P, Gibbs PE (1998) Critical appraisal of the evidence for tributyltin-mediated endocrine disruption in mollusks. Environ Toxicol Chem 17(1):37–43
Blaber SJM (1970) The occurrence of a penis-like out-growth behind the right tentacle in spent females of Nucella lapillus (L.). Proc Malacol Soc Lond 39:231–232
Smith BS (1971) Sexuality in the American mud snail, Nassarius obsoletus SAY. Proc Malacol Soc Lond 39:377–378
Smith BS (1981) Male characteristics on female mud snails caused by antifouling bottom paints. J Appl Toxicol 1(1):22–25
Smith BS (1981) Reproductive anomalies in stenoglossan snails related to pollution from marinas. J Appl Toxicol 1(1):15–21
Titley-O’Neal CP, Munkittrick KR, MacDonald BA (2011) The effects of organotin on female gastropods. J Environ Monit 13(9):2360–2388
Oetken M, Bachmann J, Schulte-Oehlmann U, Oehlmann J (2004) Evidence for endocrine disruption in invertebrates. Int Rev Cytol 236:1–44
Galante-Oliveira S, Oliveira I, Ferreira N, Santos JA, Pacheco M, Barroso C (2011) Nucella lapillus L. imposex levels after legislation prohibiting TBT antifoulants: temporal trends from 2003 to 2008 along the Portuguese coast. J Environ Monit 13(2):304–312
Guomundsdottir LO, Ho KKY, Lam JCW, Svavarsson J, Leung KMY (2011) Long-term temporal trends (1992–2008) of imposex status associated with organotin contamination in the dogwhelk Nucella lapillus along the Icelandic coast. Mar Pollut Bull 63(5–12):500–507
Nicolaus EE, Barry J (2015) Imposex in the dogwhelk (Nucella lapillus): 22-year monitoring around England and Wales. Environ Monit Assess 187(12):736
Santos JA, Galante-Oliveira S, Barroso C (2011) An innovative statistical approach for analysing non-continuous variables in environmental monitoring: assessing temporal trends of TBT pollution. J Environ Monit 13(3):673–680
Titley-O’Neal CP, MacDonald BA, Pelletier E, Saint-Louis R (2011) Using Nucella lapillus (L.) as a bioindicator of tributyltin (TBT) pollution in eastern Canada: a historical perspective. Water Qual Res J Can 46(1):74–86
Sternberg RM, Gooding MP, Hotchkiss AK, LeBlanc GA (2010) Environmental-endocrine control of reproductive maturation in gastropods: implications for the mechanism of tributyltin-induced imposex in prosobranchs. Ecotoxicology 19(1):4–23
Bettin C, Oehlmann J, Stroben E (1996) TBT-induced imposex in marine neogastropods is mediated by an increasing androgen level. Helgoländer Meeresun 50(3):299–317
Oehlmann J, Stroben E, Schulte-Oehlmann U, Bauer B, Fioroni P, Markert B (1996) Tributyltin biomonitoring using prosobranchs as sentinel organisms. Fresenius J Anal Chem 354(5–6):540–545
Spooner N, Gibbs PE, Bryan GW, Goad LJ (1991) The effect of tributyltin upon steroid titers in the female dogwhelk, Nucella lapillus, and the development of imposex. Mar Environ Res 32(1–4):37–49
Schulte-Oehlmann U, Tillmann M, Markert B, Oehlmann J, Watermann B, Scherf S (2000) Effects of endocrine disruptors on prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part II: Triphenyltin as a xeno-androgen. Ecotoxicology 9(6):399–412
Abidli S, Santos MM, Lahbib Y, Costa Castro LF, Reis-Henriques MA, El Menif NT (2012) Tributyltin (TBT) effects on Hexaplex trunculus and Bolinus brandaris (Gastropoda: Muricidae): imposex induction and sex hormone levels insights. Ecol Indic 13(1):13–21
Castro LFC, Lima D, Machado A, Melo C, Hiromori Y, Nishikawa J, Nakanishi T, Reis-Henriques MA, Santos MM (2007) Imposex induction is mediated through the retinoid X receptor signalling pathway in the neogastropod Nucella lapillus. Aquat Toxicol 85(1):57–66
Horiguchi T, Nishikawa T, Ohta Y, Shiraishi H, Morita M (2010) Time course of expression of the retinoid X receptor gene and induction of imposex in the rock shell, Thais clavigera, exposed to triphenyltin chloride. Anal Bioanal Chem 396(2):597–607
Horiguchi T, Ohta Y, Nishikawa T, Shiraishi F, Shiraishi H, Morita M (2008) Exposure to 9-cis retinoic acid induces penis and vas deferens development in the female rock shell, Thais clavigera. Cell Biol Toxicol 24(6):553–562
Nakanishi T (2008) Endocrine disruption induced by organotin compounds; organotins function as a powerful agonist for nuclear receptors rather than an aromatase inhibitor. J Toxicol Sci 33(3):269–276
Nishikawa J (2006) Imposex in marine gastropods may be caused by binding of organotins to retinoid X receptor. Mar Biol 149(1):117–124
Nishikawa J, Mamiya S, Kanayama T, Nishikawa T, Shiraishi F, Horiguchi T (2004) Involvement of the retinoid X receptor in the development of imposex caused by organotins in gastropods. Environ Sci Technol 38(23):6271–6276
Urushitani H, Katsu Y, Ohta Y, Shiraishi H, Iguchi T, Horiguchi T (2011) Cloning and characterization of retinoid X receptor (RXR) isoforms in the rock shell, Thais clavigera. Aquat Toxicol 103(1–2):101–111
Stange D, Sieratowicz A, Oehlmann J (2012) Imposex development in Nucella lapillus: evidence for the involvement of retinoid X receptor and androgen signalling pathways in vivo. Aquat Toxicol 106–107:20–24
Oehlmann J, Schulte-Oehlmann U, Tillmann M, Markert B (2000) Effects of endocrine disruptors on prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part I: Bisphenol A and octylphenol as xeno-estrogens. Ecotoxicology 9(6):383–397
Schulte-Oehlmann U, Tillmann M, Casey D, Duft M, Markert B, Oehlmann J (2001) Östrogenartige Wirkungen von Bisphenol A auf Vorderkiemenschnecken (Mollusca: Gastropoda: Prosobranchia). Umweltwiss Schadst Forsch 13(6):319–333
Staples CA, Woodburn K, Caspers N, Hall AT, Klecka GM (2002) A weight of evidence approach to the aquatic hazard assessment of bisphenol A. Hum Ecol Risk Assess 8(5):1083–1105
Oehlmann J, Schulte-Oehlmann U, Bachmann J, Oetken M, Lutz I, Kloas W, Ternes TA (2006) Bisphenol A induces superfeminization in the ramshorn snail Marisa cornuarietis (Gastropoda: Prosobranchia) at environmentally relevant concentrations. Environ Health Perspect 114:127–133
Forbes VE, Aufderheide J, Warbritton R, van der Hoevene N, Caspers N (2007) Does bisphenol A induce superfeminization in Marisa cornuarietis? Part II: Toxicity test results and requirements for statistical power analyses. Ecotoxicol Environ Saf 66(3):319–325
Forbes VE, Selck H, Palmqvist A, Aufderheide J, Warbritton R, Pounds N, Thompson R, van der Hoeven N, Caspers N (2007) Does bisphenol A induce superfeminization in Marisa cornuarietis? Part I: Intra- and inter-laboratory variability in test endpoints. Ecotoxicol Environ Saf 66(3):309–318
Bortone SA, Davis WP (1994) Fish intersexuality as indicator of environmental-stress. Bioscience 44(3):165–172
Tyler CR, Jobling S (2008) Roach, sex, and gender-bending chemicals: the feminization of wild fish in English rivers. Bioscience 58(11):1051–1059
Purdom CE (1994) Estrogenic effects of effluents from sewage treatment works. Chem Ecol 8:275–285
Desforges J-PW, Peachey BDL, Sanderson PM, White PA, Blais JM (2010) Plasma vitellogenin in male teleost fish from 43 rivers worldwide is correlated with upstream human population size. Environ Pollut 158(10):3279–3284
Jobling S, Beresford N, Nolan M, Rodgers-Gray T, Brighty GC, Sumpter JP, Tyler CR (2002) Altered sexual maturation and gamete production in wild roach (Rutilus rutilus) living in rivers that receive treated sewage effluents. Biol Reprod 66(2):272–281
Jobling S, Coey S, Whitmore JG, Kime DE, Van Look KJW, McAllister BG, Beresford N, Henshaw AC, Brighty G, Tyler CR, Sumpter JP (2002) Wild intersex roach (Rutilus rutilus) have reduced fertility. Biol Reprod 67(2):515–524
Harris CA, Hamilton PB, Runnalls TJ, Vinciotti V, Henshaw A, Hodgson D, Coe TS, Jobling S, Tyler CR, Sumpter JP (2011) The consequences of feminization in breeding groups of wild fish. Environ Health Perspect 119(3):306–311
Lange A, Paull GC, Hamilton PB, Iguchi T, Tyler CR (2011) Implications of persistent exposure to treated wastewater effluent for breeding in wild roach (Rutilus rutilus) populations. Environ Sci Technol 45(4):1673–1679
Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evans RE, Lazorchak JM, Flick RW (2007) Collapse of a fish population after exposure to a synthetic estrogen. Proc Natl Acad Sci U S A 104(21):8897–8901
Blanchfield PJ, Kidd KA, Docker MF, Palace VP, Park BJ, Postma LD (2015) Recovery of a wild fish population from whole-lake additions of a synthetic estrogen. Environ Sci Technol 49(5):3136–3144
Filby AL, Thorpe KL, Maack G, Tyler CR (2007) Gene expression profiles revealing the mechanisms of anti-androgen-and estrogen-induced feminization in fish. Aquat Toxicol 81(2):219–231
Jobling S, Burn RW, Thorpe K, Williams R, Tyler C (2009) Statistical modeling suggests that antiandrogens in effluents from wastewater treatment works contribute to widespread sexual disruption in fish living in English rivers. Environ Health Perspect 117(5):797–802
Hill EM, Evans KL, Horwood J, Rostkowski P, Oladapo FO, Gibson R, Shears JA, Tyler CR (2010) Profiles and some initial identifications of (anti)androgenic compounds in fish exposed to wastewater treatment works effluents. Environ Sci Technol 44(3):1137–1143
Rostkowski P, Horwood J, Shears JA, Lange A, Oladapo FO, Besselink HT, Tyler CR, Hill EM (2011) Bioassay-directed identification of novel antiandrogenic compounds in bile of fish exposed to wastewater effluents. Environ Sci Technol 45(24):10660–10667
Schriks M, van Leerdam JA, van der Linden SC, van der Burg B, van Wezel AP, de Voogt P (2010) High-resolution mass spectrometric identification and quantification of glucocorticoid compounds in various wastewaters in the Netherlands. Environ Sci Technol 44(12):4766–4774
Suzuki G, Tue NM, van der Linden S, Brouwer A, van der Burg B, van Velzen M, Lamoree M, Someya M, Takahashi S, Isobe T, Tajima Y, Yamada TK, Takigami H, Tanabe S (2011) Identification of major dioxin-like compounds and androgen receptor antagonist in acid-treated tissue extracts of high trophic-level animals. Environ Sci Technol 45(23):10203–10211
Thomas KV, Langford K, Petersen K, Smith AJ, Tollefsen KE (2009) Effect-directed identification of naphthenic acids as important in vitro xeno-estrogens and anti-androgens in North sea offshore produced water discharges. Environ Sci Technol 43(21):8066–8071
Weiss JM, Hamers T, Thomas KV, van der Linden S, Leonards PEG, Lamoree MH (2009) Masking effect of anti-androgens on androgenic activity in European river sediment unveiled by effect-directed analysis. Anal Bioanal Chem 394(5):1385–1397
Weiss JM, Simon E, Stroomberg GJ, de Boer R, de Boer J, van der Linden SC, Leonards PEG, Lamoree MH (2011) Identification strategy for unknown pollutants using high-resolution mass spectrometry: androgen-disrupting compounds identified through effect-directed analysis. Anal Bioanal Chem 400(9):3141–3149
Alford RA, Richards SJ (1999) Global amphibian declines: a problem in applied ecology. Annu Rev Ecol Syst 30:133–165
Stuart SN, Chanson JS, Cox NA, Young BE, Rodrigues ASL, Fischman DL, Waller RW (2004) Status and trends of amphibian declines and extinctions worldwide. Science 306(5702):1783–1786
Pounds JA, Bustamante MR, Coloma LA, Consuegra JA, Fogden MPL, Foster PN, La Marca E, Masters KL, Merino-Viteri A, Puschendorf R, Ron SR, Sanchez-Azofeifa GA, Still CJ, Young BE (2006) Widespread amphibian extinctions from epidemic disease driven by global warming. Nature 439(7073):161–167
Sodhi NS, Bickford D, Diesmos AC, Lee TM, Koh LP, Brook BW, Sekercioglu CH, Bradshaw CJA (2008) Measuring the meltdown: drivers of global amphibian extinction and decline. PLoS One 3(2)
Mann RM, Hyne RV, Choung CB, Wilson SP (2009) Amphibians and agricultural chemicals: review of the risks in a complex environment. Environ Pollut 157(11):2903–2927
Reeder AL, Ruiz MO, Pessier A, Brown LE, Levengood JM, Phillips CA, Wheeler MB, Warner RE, Beasley VR (2005) Intersexuality and the cricket frog decline: historic and geographic trends. Environ Health Perspect 113(3):261–265
Hayes TB, Anderson LL, Beasley VR, de Solla SR, Iguchi T, Ingraham H, Kestemont P, Kniewald J, Kniewald Z, Langlois VS, Luque EH, McCoy KA, Munoz-de-Toro M, Oka T, Oliveira CA, Orton F, Ruby S, Suzawa M, Tavera-Mendoza LE, Trudeau VL, Victor-Costa AB, Willingham E (2011) Demasculinization and feminization of male gonads by atrazine: consistent effects across vertebrate classes. J Steroid Biochem Mol Biol 127(1–2):64–73
Hayes TB, Khoury V, Narayan A, Nazir M, Park A, Brown T, Adame L, Chan E, Buchholz D, Stueve T, Gallipeau S (2010) Atrazine induces complete feminization and chemical castration in male African clawed frogs (Xenopus laevis). Proc Natl Acad Sci U S A 107(10):4612–4617
Woodward AR, Percival HF, Jennings ML, Clinton TM (1993) Low clutch viability of American alligators. Fla Sci 56(1):52–63
Guillette LJ, Brock JW, Rooney AA, Woodward AR (1999) Serum concentrations of various environmental contaminants and their relationship to sex steroid concentrations and phallus size in juvenile American alligators. Arch Environ Contam Toxicol 36(4):447–455
Heinz GH, Percival HF, Jennings ML (1991) Contaminants in American alligator eggs from Lake Apopka, Lake Griffin, and Lake Okeechobee, Florida. Environ Monit Assess 16(3):277–285
Rauschenberger RH, Wiebe JJ, Sepulveda MS, Scarborough JE, Gross TS (2007) Parental exposure to pesticides and poor clutch viability in American alligators. Environ Sci Technol 41(15):5559–5563
Guillette LJ, Gross TS, Masson GR, Matter JM, Percival HF, Woodward AR (1994) Developmental abnormalities of the gonad and abnormal sex-hormone concentrations in juvenile alligators from contaminated and control lakes in Florida. Environ Health Perspect 102(8):680–688
Crain DA, Guillette LJ, Pickford DB, Percival HF, Woodward AR (1998) Sex-steroid and thyroid hormone concentrations in juvenile alligators (Alligator mississippiensis) from contaminated and reference lakes in Florida, USA. Environ Toxicol Chem 17(3):446–452
Guillette LJ, Pickford DB, Crain DA, Rooney AA, Percival HF (1996) Reduction in penis size and plasma testosterone concentrations in juvenile alligators living in a contaminated environment. Gen Comp Endocrinol 101(1):32–42
Crain DA, Guillette LJ (1998) Reptiles as models of contaminant-induced endocrine disruption. Anim Reprod Sci 53(1–4):77–86
Guillette LJ Jr, Edwards TM, Moore BC (2007) Alligators, contaminants and steroid hormones. Environ Sci 14(6):331–347
Moore BC, Hamlin HJ, Botteri NL, Guillette LJ Jr (2010) Gonadal mRNA expression levels of TGF beta superfamily signaling factors correspond with post-hatching morphological development in American alligators. Sex Dev 4(1–2):62–72
Moore BC, Milnes MR, Kohno S, Katsu Y, Iguchi T, Woodruff TK, Guillette LJ Jr (2011) Altered gonadal expression of TGF-beta superfamily signaling factors in environmental contaminant-exposed juvenile alligators. J Steroid Biochem Mol Biol 127(1–2):58–63
Ratcliffe DA (1967) Decrease in eggshell weight in certain birds of prey. Nature 215(5097):208–210
Bowerman WW, Giesy JP, Best DA, Kramer VJ (1995) A review of factors affecting productivity of bald eagles in the Great-lakes region - implications for recovery. Environ Health Perspect 103:51–59
Fry DM (1995) Reproductive effects in birds exposed to pesticides and industrial-chemicals. Environ Health Perspect 103:165–171
Ratcliffe DA (1970) Changes attributable to pesticides in egg breakage frequency and eggshell thickness in some British birds. J Appl Ecol 7(1):67–107
Best DA, Elliott KH, Bowerman WW, Shieldcastle M, Postupalsky S, Kubiak TJ, Tillitt DE, Elliott JE (2010) Productivity, embryo and eggshell characteristics, and contaminants in bald eagles from the Great Lakes, USA, 1986 to 2000. Environ Toxicol Chem 29(7):1581–1592
Bruggeman V, Swennen Q, De Ketelaere B, Onagbesan O, Tona K, Decuypere E (2003) Embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in chickens: effects of dose and embryonic stage on hatchability and growth. Comp Biochem Physiol Part C: Toxicol Pharmacol 136(1):17–28
Fernie KJ, Shutt JL, Mayne G, Hoffman D, Letcher RJ, Drouillard KG, Ritchie IJ (2005) Exposure to polybrominated diphenyl ethers (PBDEs): changes in thyroid, vitamin A, glutathione homeostasis, and oxidative stress in American kestrels (Falco sparverius). Toxicol Sci 88(2):375–383
Holm L, Blomqvist A, Brandt I, Brunstrom B, Ridderstrale Y, Berg C (2006) Embryonic exposure to o, p’-DDT causes eggshell thinning and altered shell gland carbonic anhydrase expression in the domestic hen. Environ Toxicol Chem 25(10):2787–2793
Hoogesteijn AL, DeVoogd TJ, Quimby FW, De Caprio T, Kollias GV (2005) Reproductive impairment in zebra finches (Taeniopygia guttata). Environ Toxicol Chem 24(1):219–223
Lundholm CE (1997) DDE-induced eggshell thinning in birds: effects of p, p’-DDE on the calcium and prostaglandin metabolism of the eggshell gland. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 118(2):113–128
Quaglino AE, Craig-Veit CB, Viant MR, Erichsen AL, Fry DM, Millam JR (2002) Oral estrogen masculinizes female zebra finch song system. Horm Behav 41(2):236–241
Rochester JR, Heiblum R, Rozenboim I, Millam JR (2008) Post-hatch oral estrogen exposure reduces oviduct and egg mass and alters nest-building behavior in adult zebra finches (Taeniopygia guttata). Physiol Behav 95(3):370–380
Millam JR, Craig-Veit CB, Quaglino AE, Erichsen AL, Famula TR, Fry DM (2001) Posthatch oral estrogen exposure impairs adult reproductive performance of zebra finch in a sex-specific manner. Horm Behav 40(4):542–549
Rochester JR, Forstmeier W, Millam JR (2010) Post-hatch oral estrogen in zebra finches (Taeniopygia guttata): is infertility due to disrupted testes morphology or reduced copulatory behavior? Physiol Behav 101(1):13–21
Markman S, Leitner S, Catchpole C, Barnsley S, Mueller CT, Pascoe D, Buchanan KL (2008) Pollutants increase song complexity and the volume of the brain area HVC in a songbird. PLoS One 3(2)
Braune BM, Outridge PM, Fisk AT, Muir DCG, Helm PA, Hobbs K, Hoekstra PF, Kuzyk ZA, Kwan M, Letcher RJ, Lockhart WL, Norstrom RJ, Stern GA, Stirling I (2005) Persistent organic pollutants and mercury in marine biota of the Canadian Arctic: an overview of spatial and temporal trends. Sci Total Environ 351:4–56
Letcher RJ, Bustnes JO, Dietz R, Jenssen BM, Jorgensen EH, Sonne C, Verreault J, Vijayan MM, Gabrielsen GW (2010) Exposure and effects assessment of persistent organohalogen contaminants in arctic wildlife and fish. Sci Total Environ 408(15):2995–3043
Tanabe S (2002) Contamination and toxic effects of persistent endocrine disrupters in marine mammals and birds. Mar Pollut Bull 45(1–12):69–77
Buckman AH, Veldhoen N, Ellis G, Ford JKB, Helbing CC, Ross PS (2011) PCB-associated changes in mRNA expression in killer whales (Orcinus orca) from the NE Pacific Ocean. Environ Sci Technol 45(23):10194–10202
Routti H, Arukwe A, Jenssen BM, Letcher RJ, Nyman M, Backman C, Gabrielsen GW (2010) Comparative endocrine disruptive effects of contaminants in ringed seals (Phoca hispida) from Svalbard and the Baltic Sea. Comp Biochem Physiol Part C: Toxicol Pharmacol 152(3):306–312
Schwacke LH, Zolman ES, Balmer BC, De Guise S, George RC, Hoguet J, Hohn AA, Kucklick JR, Lamb S, Levin M, Litz JA, McFee WE, Place NJ, Townsend FI, Wells RS, Rowles TK (2012) Anaemia, hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus). Proc R Soc B Biol Sci 279(1726):48–57
Villanger GD, Lydersen C, Kovacs KM, Lie E, Skaare JU, Jenssen BM (2011) Disruptive effects of persistent organohalogen contaminants on thyroid function in white whales (Delphinapterus leucas) from Svalbard. Sci Total Environ 409(13):2511–2524
Van den Berg KJ, Zurcher C, Brouwer A, Vanbekkum DW (1988) Chronic toxicity of 3,4,3’,4’-tetrachlorobiphenyl in the marmoset monkey (Callithrix jacchus). Toxicology 48(2):209–224
Iguchi T, Katsu Y (2008) Commonality in signaling of endocrine disruption from snail to human. Bioscience 58(11):1061–1067
Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, Lee D-H, Shioda T, Soto AM, vom Saal FS, Welshons WV, Zoeller RT, Myers JP (2012) Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endoc Rev 33(3):378–455
Barouki R, Gluckman PD, Grandjean P, Hanson M, Heindel JJ (2012) Developmental origins of non-communicable disease: implications for research and public health. Environ Health 11:1–9, http://www.ehjournal.net/content/11/1/42
Kortenkamp A (2007) Ten years of mixing cocktails: a review of combination effects of endocrine-disrupting chemicals. Environ Health Perspect 115:98–105
Bern HA, Blair P, Brasseur S, Colborn T, Cunha GR, Davis W, Döhler KD, Fox G, Fry M, Gray LE, Green R, Hines MJKT, McLachlan J, Myers JP, Peterson RW, Reijnders PJH, Soto AM, Van Der Kraak G, vom Saal FS, Whitten P (1992) Statement from the work session on chemically-induced alterations in sexual development: the wildlife/human connection. In: Colborn T, Clement C (eds) Chemically-induced alterations in sexual and functional development: the wildlife/human connection. Advances in modern environmental toxicology, vol. xxi. Princeton Scientific Pub, Princeton, NJ, p 403
Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S, Lucier G, Luster M, Mac MJ, Maczka C, Miller R, Moore J, Rolland R, Scott G, Sheehan DM, Sinks T, Tilson HA (1996) Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environ Health Perspect 104(Suppl 4):715–740
European Commission (1996) Report of Proceedings: European Workshop on the Impact of Endocrine Disrupters on Human Health and Wildlife, Weybridge, UK, EUR 17549, European Commission, Environment and Climate Research Programme of DG XII, 2–4 December 1996
WHO/IPCS (2002) Global assessment of the state-of-the-science of endocrine disruptors. WHO publication no. WHO/PCS/EDC/02.2. International Programme on Chemical Safety, World Health Organisation, Geneva, Switzerland
Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, Woodruff TJ, Vom Saal FS (2012) Endocrine-disrupting chemicals and public health protection: a statement of principles from the Endocrine Society. Endocrinology
Germain P, Staels B, Dacquet C, Spedding M, Laudet V (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58(4):685–704
Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3(11):950–964
Rubin BS (2011) Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol 127(1–2):27–34
Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM (2009) Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev 30(1):75–95
Tabb MM, Blumberg B (2006) New modes of action for endocrine-disrupting chemicals. Mol Endocrinol 20(3):475–482
Masuyama H, Hiramatsu Y, Kunitomi M, Kudo T, MacDonald PN (2000) Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate Pregnane X receptor-mediated transcription. Mol Endocrinol 14(3):421–428
Takeshita A, Igarashi-Migitaka J, Nishiyama K, Takahashi H, Takeuchi Y, Koibuchi N (2011) Acetyl tributyl citrate, the most widely used phthalate substitute plasticizer, induces cytochrome P450 3A through steroid and xenobiotic receptor. Toxicol Sci 123(2):460–470
Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, Ozawa Y (2001) Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol 145(4):513–517
Mendiola J, Jorgensen N, Andersson A-M, Calafat AM, Ye X, Redmon JB, Drobnis EZ, Wang C, Sparks A, Thurston SW, Liu F, Swan SH (2010) Are environmental levels of bisphenol A associated with reproductive function in fertile men? Environ Health Perspect 118(9):1286–1291
Aldad TS, Rahmani N, Leranth C, Taylor HS (2011) Bisphenol-A exposure alters endometrial progesterone receptor expression in the nonhuman primate. Fertil Steril 96(1):175–179
Masuyama H, Hiramatsu Y (2004) Involvement of suppressor for Gal 1 in the ubiquitin/proteasome-mediated degradation of estrogen receptors. J Biol Chem 279(13):12020–12026
Weigel NL, Moore NL (2007) Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol 21(10):2311–2319
Gillesby BE, Zacharewski TR (1998) Exoestrogens: mechanisms of action and strategies for identification and assessment. Environ Toxicol Chem 17(1):3–14
Zsarnovszky A, Le HH, Wang HS, Belcher SM (2005) Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A. Endocrinology 146(12):5388–5396
le Maire A, Grimaldi M, Roecklin D, Dagnino S, Vivat-Hannah V, Balaguer P, Bourguet W (2009) Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors. EMBO Rep 10(4):367–373
Inoshita H, Masuyama H, Hiramatsu Y (2003) The different effects of endocrine-disrupting chemicals on estrogen receptor-mediated transcription through interaction with coactivator TRAP220 in uterine tissue. J Mol Endocrinol 31(3):551–561
Rüegg J, Swedenborg E, Wahlstroem D, Escande A, Balaguer P, Pettersson K, Pongratz I (2008) The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin. Mol Endocrinol 22(2):304–316
Safe S, Wormke M (2003) Inhibitory aryl hydrocarbon receptor-estrogen receptor a cross-talk and mechanisms of action. Chem Res Toxicol 16(7):807–816
Swedenborg E, Ruegg J, Makela S, Pongratz I (2009) Endocrine disruptive chemicals: mechanisms of action and involvement in metabolic disorders. J Mol Endocrinol 43(1–2):1–10
Crews D, Gillette R, Scarpino SV, Manikkam M, Savenkova MI, Skinner MK (2012) Epigenetic transgenerational inheritance of altered stress responses. Proc Natl Acad Sci U S A 109(23):9143–9148
Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK (2013) Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One 8(1):e55387
Bjornstrom L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19(4):833–842
Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M (2000) Multiple actions of steroid hormones: a focus on rapid, nongenomic effects. Pharmacol Rev 52(4):513–555
Watson CS, Jeng Y-J, Guptarak J (2011) Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways. J Steroid Biochem Mol Biol 127(1–2):44–50
Mainini CG (1947) Pregnancy test using the male toad. J Clin Endocrinol Metab 7(9):653–658
Bulbring E, Burn JH (1935) The estimation of oestrin and of male hormone in oily solution. J Physiol-Lond 85(3):320–333
Korenchevsky V (1932) The assay of testicular hormone preparations. Biochem J 26:413–422
Kanter AE, Bauer CP, Klawans AH (1934) A new biologic test for hormones in pregnancy urine: preliminary report. JAMA 103(26):2026–2027
National Research Council (2007) Toxicity testing in the 21st century: a vision and a strategy, vol xvii. National Academies Press, Washington, DC, p 196
Langley G, Austin CP, Balapure AK, Birnbaum LS, Bucher JR, Fentem J, Fitzpatrick SC, Fowle JR III, Kavlock RJ, Kitano H, Lidbury BA, Muotri AR, Peng SQ, Sakharov D, Seidle T, Trez T, Tonevitsky A, van de Stolpe A, Whelan M, Willett C (2015) Lessons from toxicology: developing a 21st-century paradigm for medical research. Environ Health Perspect 123:A268–A272
Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL, Schmieder PK, Serrrano JA, Tietge JE, Villeneuve DL (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29(3):730–741
Hultman MT, Rundberget JT, Tollefsen KE (2015) Evaluation of the sensitivity, responsiveness and reproducibility of primary rainbow trout hepatocyte vitellogenin expression as a screening assay for estrogen mimics. Aquat Toxicol 159:233–244
Scrimshaw MD, Lester JN (2004) In-vitro assays for determination of oestrogenic activity. Anal Bioanal Chem 378(3):576–581
Zacharewski T (1997) In vitro bioassays for assessing estrogenic substances. Environ Sci Technol 31(3):613–623
de Jong LAA, Uges DRA, Franke JP, Bischoff R (2005) Receptor-ligand binding assays: technologies and applications. J Chromatogr B Analyt Technol Biomed Life Sci 829(1–2):1–25
Hulme EC, Trevethick MA (2010) Ligand binding assays at equilibrium: validation and interpretation. Br J Pharmacol 161(6):1219–1237
Chae K, Albro PW, Luster MI, Mckinney JD (1984) A screening assay for the tetrachlorodibenzo-para-dioxin receptor using the [iodovaleramide-i-125 derivative of trichlorodibenzo-para-dioxin as the binding ligand. Int J Environ Anal Chem 17(3–4):267–274
Poland A, Glover E, Kende AS (1976) Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-para-dioxin by hepatic cytosol: evidence that binding species is receptor for induction of aryl-hydrocarbon hydroxylase. J Biol Chem 251(16):4936–4946
Yost EE, Pow CL, Hawkins MB, Kullman SW (2014) Bridging the gap from screening assays to estrogenic effects in fish: potential roles of multiple estrogen receptor subtypes. Environ Sci Technol 48(9):5211–5219
Fang ML, Webster TF, Ferguson PL, Stapleton HM (2015) Characterizing the peroxisome proliferator-activated receptor (PPAR gamma) ligand binding potential of several major flame retardants, their metabolites, and chemical mixtures in house dust. Environ Health Perspect 123(2):166–172
Wagner M, Vermeirssen ELM, Buchinger S, Behr M, Magdeburg A, Oehlmann J (2013) Deriving bio-equivalents from in vitro bioassays: assessment of existing uncertainties and strategies to improve accuracy and reporting. Environ Toxicol Chem 32(8):1906–1917
Martin MT, Dix DJ, Judson RS, Kavlock RJ, Reif DM, Richard AM, Rotroff DM, Romanov S, Medvedev A, Poltoratskaya N, Gambarian M, Moeser M, Makarov SS, Houck KA (2010) Impact of environmental chemicals on key transcription regulators and correlation to toxicity end points within EPA’s ToxCast program. Chem Res Toxicol 23(3):578–590
Escher BI, Allinson M, Altenburger R, Bain PA, Balaguer P, Busch W, Crago J, Denslow ND, Dopp E, Hilscherova K, Humpage AR, Kumar A, Grimaldi M, Jayasinghe BS, Jarosova B, Jia A, Makarov S, Maruya KA, Medvedev A, Mehinto AC, Mendez JE, Poulsen A, Prochazka E, Richard J, Schifferli A, Schlenk D, Scholz S, Shiraish F, Snyder S, Su GY, Tang JYM, van der Burg B, van der Linden SC, Werner I, Westerheide SD, Wong CKC, Yang M, Yeung BHY, Zhang XW, Leusch FDL (2014) Benchmarking organic micropollutants in wastewater, recycled water and drinking water with in vitro bioassays. Environ Sci Technol 48(3):1940–1956
Purvis IJ, Chotai D, Dykes CW, Lubahn DB, French FS, Wilson EM, Hobden AN (1991) An androgen-inducible expression system for Saccharomyces cerevisiae. Gene 106(1):35–42
Routledge EJ, Sumpter JP (1996) Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen. Environ Toxicol Chem 15(3):241–248
Sohoni P, Sumpter JP (1998) Several environmental oestrogens are also anti-androgens. J Endocrinol 158(3):327–339
Beresford N, Routledge EJ, Harris CA, Sumpter JP (2000) Issues arising when interpreting results from an in vitro assay for estrogenic activity. Toxicol Appl Pharmacol 162(1):22–33
Dhooge W, Arijs K, D’Haese I, Stuyvaert S, Versonnen B, Janssen C, Verstraete W, Comhaire F (2006) Experimental parameters affecting sensitivity and specificity of a yeast assay for estrogenic compounds: results of an interlaboratory validation exercise. Anal Bioanal Chem 386(5):1419–1428
Murk AJ, Legler J, van Lipzig MMH, Meerman JHN, Belfroid AC, Spenkelink A, van der Burg B, Rijs GBJ, Vethaak D (2002) Detection of estrogenic potency in wastewater and surface water with three in vitro bioassays. Environ Toxicol Chem 21(1):16–23
Wagner M, Oehlmann J (2011) Endocrine disruptors in bottled mineral water: estrogenic activity in the E-Screen. J Steroid Biochem Mol Biol 127(1–2):128–135
Wagner M, Schlusener MP, Ternes TA, Oehlmann J (2013) Identification of putative steroid receptor antagonists in bottled water: combining bioassays and high-resolution mass spectrometry. PLoS One 8(8), e72472
De Boever P, Demare W, Vanderperren E, Cooreman K, Bossier P, Verstraete W (2001) Optimization of a yeast estrogen screen and its applicability to study the release of estrogenic isoflavones from a soygerm powder. Environ Health Perspect 109(7):691–697
Schultis T, Metzger JW (2004) Determination of estrogenic activity by LYES-assay (yeast estrogen screen-assay assisted by enzymatic digestion with lyticase). Chemosphere 57(11):1649–1655
Routledge EJ, Parker J, Odum J, Ashby J, Sumpter JP (1998) Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicol Appl Pharmacol 153(1):12–19
Lyttle CR, Damianmatsumura P, Juul H, Butt TR (1992) Human estrogen-receptor regulation in a yeast model system and studies on receptor agonists and antagonists. J Steroid Biochem Mol Biol 42(7):677–685
Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, Omalley BW, McGuire WL (1991) Variant human breast-tumor estrogen-receptor with constitutive transcriptional activity. Cancer Res 51(1):105–109
McDonnell DP, Nawaz Z, Densmore C, Weigel NL, Pham TA, Clark JH, Omalley BW (1991) High-level expression of biologically-active estrogen-receptor in Saccharomyces cerevisiae. J Steroid Biochem Mol Biol 39(3):291–297
McDonnell DP, Nawaz Z, Omalley BW (1991) In situ distinction between steroid-receptor binding and transactivation at a target gene. Mol Cell Biol 11(9):4350–4355
Inoue D, Nakama K, Matsui H, Sei K, Ike M (2009) Detection of agonistic activities against five human nuclear receptors in river environments of Japan using a yeast two-hybrid assay. Bull Environ Contam Toxicol 82(4):399–404
Miller CA, Tan XB, Wilson M, Bhattacharyya S, Ludwig S (2010) Single plasmids expressing human steroid hormone receptors and a reporter gene for use in yeast signaling assays. Plasmid 63(2):73–78
Hahn T, Tag K, Riedel K, Uhlig S, Baronian K, Gellissen G, Kunze G (2006) A novel estrogen sensor based on recombinant Arxula adeninivorans cells. Biosens Bioelectron 21(11):2078–2085
Bovee TFH, Helsdingen RJR, Hamers ARM, van Duursen MBM, Nielen MWF, Hoogenboom RLAP (2007) A new highly specific and robust yeast androgen bioassay for the detection of agonists and antagonists. Anal Bioanal Chem 389(5):1549–1558
Kamata R, Shiraishi F, Nakajima D, Takigami H, Shiraishi H (2009) Mono-hydroxylated polychlorinated biphenyls are potent aryl hydrocarbon receptor ligands in recombinant yeast cells. Toxicol in Vitro 23(4):736–743
Lee HJ, Lee YS, Kwon HB, Lee K (2003) Novel yeast bioassay system for detection of androgenic and antiandrogenic compounds. Toxicol in Vitro 17(2):237–244
Leskinen P, Michelini E, Picard D, Karp M, Virta M (2005) Bioluminescent yeast assays for detecting estrogenic and androgenic activity in different matrices. Chemosphere 61(2):259–266
Miller CA (1997) Expression of the human aryl hydrocarbon receptor complex in yeast: activation of transcription by indole compounds. J Biol Chem 272(52):32824–32829
Miller CA, Martinat MA, Hyman LE (1998) Assessment of aryl hydrocarbon receptor complex interactions using pBEVY plasmids: expression vectors with bi-directional promoters for use in Saccharomyces cerevisiae. Nucleic Acids Res 26(15):3577–3583
Bovee TFH, Helsdingen RJR, Hamers ARM, Brouwer BA, Nielen MWF (2011) Recombinant cell bioassays for the detection of (gluco)corticosteroids and endocrine-disrupting potencies of several environmental PCB contaminants. Anal Bioanal Chem 401(3):873–882
Gaido KW, Leonard LS, Lovell S, Gould JC, Babai D, Portier CJ, McDonnell DP (1997) Evaluation of chemicals with endocrine modulating activity in a yeast-based steroid hormone receptor gene transcription assay. Toxicol Appl Pharmacol 143(1):205–212
Garcia-Reyero N, Grau E, Castillo M, De Alda MJL, Barcelo D, Pina B (2001) Monitoring of endocrine disruptors in surface waters by the yeast recombinant assay. Environ Toxicol Chem 20(6):1152–1158
Ito-Harashima S, Shiizaki K, Kawanishi M, Kakiuchi K, Onishi K, Yamaji R, Yagi T (2015) Construction of sensitive reporter assay yeasts for comprehensive detection of ligand activities of human corticosteroid receptors through inactivation of CWP and PDR genes. J Pharmacol Toxicol Methods 74:41–52
Inoue D, Nakama K, Sawada K, Watanabe T, Takagi M, Sei K, Yang M, Hirotsuji J, Hu J, Nishikawa J-I, Nakanishi T, Ike M (2010) Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan. Water Res 44(8):2409–2418
Kamata R, Shiraishi F, Nishikawa J-I, Yonemoto J, Shiraishi H (2008) Screening and detection of the in vitro agonistic activity of xenobiotics on the retinoic acid receptor. Toxicol in Vitro 22(4):1050–1061
Li J, Ma M, Wang ZJ (2008) A two-hybrid yeast assay to quantify the effects of xenobiotics on retinoid X receptor-mediated gene expression. Toxicol Lett 176(3):198–206
Zhen H, Wu X, Hu J, Xiao Y, Yang M, Hirotsuji J, Nishikawa J-I, Nakanishi T, Ike M (2009) Identification of retinoic acid receptor agonists in sewage treatment plants. Environ Sci Technol 43(17):6611–6616
Kitagawa Y, Takatori S, Oda H, Nishikawa J, Nishihara T, Nakazawa H, Hori S (2003) Detection of thyroid hormone receptor-binding activities of chemicals using a yeast two-hybrid assay. J Health Sci 49(2):99–104
Shiraishi F, Okumura T, Nomachi M, Serizawa S, Nishikawa J, Edmonds JS, Shiraishi H, Morita M (2003) Estrogenic and thyroid hormone activity of a series of hydroxy-polychlorinated biphenyls. Chemosphere 52(1):33–42
Rajasarkka J, Hakkila K, Virta M (2011) Developing a compound-specific receptor for bisphenol A by directed evolution of human estrogen receptor alpha. Biotechnol Bioeng 108(11):2526–2534
Rajasarkka J, Virta M (2013) Characterization of a bisphenol A specific yeast bioreporter utilizing the bisphenol A-targeted receptor. Anal Chem 85(21):10067–10074
Rajasarkka J, Koponen J, Airaksinen R, Kiviranta H, Virta M (2014) Monitoring bisphenol A and estrogenic chemicals in thermal paper with yeast-based bioreporter assay. Anal Bioanal Chem 406(23):5695–5702
Murk AJ, Legler J, Denison MS, Giesy JP, van de Guchte C, Brouwer A (1996) Chemical-activated luciferase gene expression (CALUX): a novel in vitro bioassay for Ah receptor active compounds in sediments and pore water. Fundam Appl Toxicol 33(1):149–160
Aarts JMMJG, Denison MS, Cox MA, Schalk MAC, Garrison PM, Tullis K, Dehaan LHJ, Brouwer A (1995) Species-specific antagonism of Ah receptor action by 2,2’,5,5’-tetrachlorobiphenyl and 2,2’,3,3’,4,4’-hexachlorobiphenyl. Eur J Pharmacol Environ Toxicol Pharmacol 293(4):463–474
Garrison PM, Tullis K, Aarts JMMJG, Brouwer A, Giesy JP, Denison MS (1996) Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals. Fundam Appl Toxicol 30(2):194–203
Legler J, van den Brink CE, Brouwer A, Murk AJ, van der Saag PT, Vethaak AD, van der Burg P (1999) Development of a stably transfected estrogen receptor-mediated luciferase reporter gene assay in the human T47D breast cancer cell line. Toxicol Sci 48(1):55–66
Sonneveld E, Jansen HJ, Riteco JAC, Brouwer A, van der Burg B (2005) Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol Sci 83(1):136–148
Gijsbers L, Man H-Y, Kloet SK, de Haan LHJ, Keijer J, Rietjens IMCM, van der Burg B, Aarts JMMJG (2011) Stable reporter cell lines for peroxisome proliferator-activated receptor gamma (PPAR gamma)-mediated modulation of gene expression. Anal Biochem 414(1):77–83
Piersma AH, Bosgra S, van Duursen MBM, Hermsen SAB, Jonker LRA, Kroese ED, van der Linden SC, Man H, Roelofs MJE, Schulpen SHW, Schwarz M, Uibel F, van Vugt-Lussenburg BMA, Westerhout J, Wolterbeek APM, van der Burg B (2013) Evaluation of an alternative in vitro test battery for detecting reproductive toxicants. Reprod Toxicol 38:53–64
van der Burg B, van der Linden S, Man H-Y, Winter R, Jonker L, van Vugt-Lussenburg B, Brouwer A (2013) A panel of quantitative calux® reporter gene assays for reliable high-throughput toxicity screening of chemicals and complex mixtures, p 532
Brennan JC, He G, Tsutsumi T, Zhao J, Wirth E, Fulton MH, Denison MS (2015) Development of species-specific Ah receptor-responsive third generation CALUX cell lines with enhanced responsiveness and improved detection limits. Environ Sci Technol 49(19):11903–11912
Gizzi G, Hoogenboom LAP, Von Holst C, Rose M, Anklam E (2005) Determination of dioxins (PCDDs/PCDFs) and PCBs in food and feed using the DR CALUX (R) bioassay: results of an international validation study. Food Addit Contam 22(5):472–481
He G, Tsutsumi T, Zhao B, Baston DS, Zhao J, Heath-Pagliuso S, Denison MS (2011) Third-generation Ah receptor-responsive luciferase reporter plasmids: amplification of dioxin-responsive elements dramatically increases CALUX bioassay sensitivity and responsiveness. Toxicol Sci 123(2):511–522
Pieterse B, Felzel E, Winter R, van der Burg B, Brouwer A (2013) PAH-CALUX, an optimized bioassay for AhR-mediated hazard identification of polycyclic aromatic hydrocarbons (PAHs) as individual compounds and in complex mixtures. Environ Sci Technol 47(20):11651–11659
van der Burg B, Winter R, Man H-Y, Vangenechten C, Berckmans P, Weimer M, Witters H, van der Linden S (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reproductive Toxicology 30(1):18–24
van der Burg B, Winter R, Weimer M, Berckmans P, Suzuki G, Gijsbers L, Jonas A, van der Linden S, Witters H, Aarts J, Legler J, Kopp-Schneider A, Bremer S (2010) Optimization and prevalidation of the in vitro ER alpha CALUX method to test estrogenic and antiestrogenic activity of compounds. Reprod Toxicol 30(1):73–80
Van Loco J, Van Leeuwen SPJ, Roos P, Carbonnelle S, de Boer J, Goeyens L, Beernaert H (2004) The international validation of bio- and chemical-analytical screening methods for dioxins and dioxin-like PCBs: the DIFFERENCE project rounds 1 and 2. Talanta 63(5):1169–1182
Windal I, Denison MS, Birnbaum LS, Van Wouwe N, Baeyens W, Goeyens L (2005) Chemically activated luciferase gene expression (CALUX) cell bioassay analysis for the estimation of dioxin-like activity: critical parameters of the CALUX procedure that impact assay results. Environ Sci Technol 39(19):7357–7364
Anezaki K, Yamaguchi K, Takeuchi S, Iida M, Jin K, Kojima H (2009) Application of a bioassay using DR-Ecoscreen cells to the determination of dioxins in ambient air: a comparative study with HRGC-HRMS analysis. Environ Sci Technol 43(19):7478–7483
Besselink HT, Schipper C, Klamer H, Leonards P, Verhaar H, Felzel E, Murk AJ, Thain J, Hosoe K, Schoeters G, Legler J, Brouwer B (2004) Intra- and interlaboratory calibration of the DR Calux (R) bioassay for the analysis of dioxins and dioxin-like chemicals in sediments. Environ Toxicol Chem 23(12):2781–2789
Bovee TFH, Heskamp HH, Helsdingen RJR, Hamers ARM, Brouwer BA, Nielen MWF (2013) Validation of a recombinant cell bioassay for the detection of (gluco)corticosteroids in feed. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 30(2):264–271
Bovee TFH, Hoogenboom LAP, Hamers ARM, Traag WA, Zuidema T, Aarts J, Brouwer A, Kuiper HA (1998) Validation and use of the CALUX-bioassay for the determination of dioxins and PCBs in bovine milk. Food Addit Contam 15(8):863–875
Chou IC, Lee W-J, Wang L-C, Chang-Chien G-P, Lee W-S, Lee H (2008) Validation of the CALUX bioassay as a screening and semi-quantitative method for PCDD/F levels in cow’s milk. J Hazard Mater 154(1–3):1166–1172
Sonneveld E, Pieterse B, Schoonen WG, van der Burg B (2011) Validation of in vitro screening models for progestagenic activities: inter-assay comparison and correlation with in vivo activity in rabbits. Toxicol in Vitro 25(2):545–554
Tsutsumi T, Amakura Y, Nakamura M, Brown DJ, Clark GC, Sasaki K, Toyoda M, Maitani T (2003) Validation of the CALUX bioassay for the screening of PCDD/Fs and dioxin-like PCBs in retail fish. Analyst 128(5):486–492
Windal I, Van Wouwe N, Eppe G, Xhrouet C, Debacker V, Baeyens W, De Pauw E, Goeyens L (2005) Validation and interpretation of CALUX as a tool for the estimation of dioxin-like activity in marine biological matrixes. Environ Sci Technol 39(6):1741–1748
Wilson VS, Bobseine K, Gray LE (2004) Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicol Sci 81(1):69–77
Balaguer P, Francois F, Comunale F, Fenet H, Boussioux AM, Pons M, Nicolas JC, Casellas C (1999) Reporter cell lines to study the estrogenic effects of xenoestrogens. Sci Total Environ 233(1–3):47–56
Jugan ML, Oziol L, Bimbot M, Huteau V, Tamisier-Karolak S, Blondeau JP, Levi Y (2009) In vitro assessment of thyroid and estrogenic endocrine disruptors in wastewater treatment plants, rivers and drinking water supplies in the greater Paris area (France). Sci Total Environ 407(11):3579–3587
Wehmas LC, Cavallin JE, Durhan EJ, Kahl MD, Martinovic D, Mayasich J, Tuominen T, Villeneuve DL, Ankley GT (2011) Screening complex effluents for estrogenic activity with the T47D-kbluc cell bioassay: assay optimization and comparison with in vivo responses in fish. Environ Toxicol Chem 30(2):439–445
Grimaldi M, Boulahtouf A, Delfosse V, Thouennon E, Bourguet W, Balaguer P (2015) Reporter cell lines for the characterization of the interactions between human nuclear receptors and endocrine disruptors. Front Endocrinol 6:62–62
Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21(1):102–116
Tian J, Feng Y, Fu H, Xie HQ, Jiang JX, Zhao B (2015) The aryl hydrocarbon receptor: a key bridging molecule of external and internal chemical signals. Environ Sci Technol 49(16):9518–9531
Fritsche E, Schaefer C, Calles C, Bernsmann T, Bernshausen T, Wurm M, Huebenthal U, Cline JE, Hajimiragha H, Schroeder P, Klotz L-O, Rannug A, Fuerst P, Hanenberg H, Abel J, Krutmann J (2007) Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci U S A 104(21):8851–8856
Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203
Beischlag TV, Morales JL, Hollingshead BD, Perdew GH (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18(3):207–250
Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, Pohjanvirta R (2006) Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries. Mol Pharmacol 69(1):140–153
Mandal PK (2005) Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J Comp Physiol B 175(4):221–230
Doolittle DJ, Newton JF, Goodman JI (1983) Quantitative studies on metabolic-activation in vitro employing benzo[a]pyrene as the test compound. Mutat Res 108(1–3):29–44
Doolittle DJ, Goodman JI (1984) Quantitative studies on the in vitro metabolic-activation of dimethylnitrosamine by rat-liver postmitochondrial supernatant. Environ Health Perspect 57(Aug):327–332
Mason G, Farrell K, Keys B, Piskorskapliszczynska J, Safe L, Safe S (1986) Polychlorinated dibenzo-para-dioxins: quantitative in vitro and in vivo structure-activity-relationships. Toxicology 41(1):21–31
Piskorska-Pliszczynska J, Keys B, Safe S, Newman MS (1986) The cytosolic receptor-binding affinities and AHH induction potencies of 29 polynuclear aromatic-hydrocarbons. Toxicol Lett 34(1):67–74
Safe S (1987) Determination of 2,3,7,8-Tcdd toxic equivalent factors (TEFs): support for the use of the in vitro AHH induction assay. Chemosphere 16(4):791–802
Van den Berg M, Birnbaum L, Bosveld ATC, Brunstrom B, Cook P, Feeley M, Giesy JP, Hanberg A, Hasegawa R, Kennedy SW, Kubiak T, Larsen JC, van Leeuwen FXR, Liem AKD, Nolt C, Peterson RE, Poellinger L, Safe S, Schrenk D, Tillitt D, Tysklind M, Younes M, Waern F, Zacharewski T (1998) Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect 106(12):775–792
Van den Berg M, Birnbaum LS, Denison M, De Vito M, Farland W, Feeley M, Fiedler H, Hakansson H, Hanberg A, Haws L, Rose M, Safe S, Schrenk D, Tohyama C, Tritscher A, Tuomisto J, Tysklind M, Walker N, Peterson RE (2006) The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicol Sci 93(2):223–241
Soto AM, Chung KL, Sonnenschein C (1994) The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogen-sensitive cells. Environ Health Perspect 102(4):380–383
Soto AM, Sonnenschein C (1985) The role of estrogens on the proliferation of human breast tumor cells (MCF-7). J Steroid Biochem Mol Biol 23(1):87–94
Soto AM, Sonnenschein C, Chung KL, Fernandez MF, Olea N, Serrano FO (1995) The E-Screen assay as a tool to identify estrogens: an update on estrogenic environmental-pollutants. Environ Health Perspect 103:113–122
Villalobos M, Olea N, Brotons JA, Oleaserrano MF, Dealmodovar JMR, Pedraza V (1995) The E-Screen assay: a comparison of different MCF7 cell stocks. Environ Health Perspect 103(9):844–850
Desaulniers D, Leingartner K, Zacharewski T, Foster WG (1998) Optimization of an MCF7-E3 cell proliferation assay and effects of environmental pollutants and industrial chemicals. Toxicol in Vitro 12(4):409–422
Korner W, Hanf V, Schuller W, Kempter C, Metzger J, Hagenmaier H (1999) Development of a sensitive E-screen assay for quantitative analysis of estrogenic activity in municipal sewage plant effluents. Sci Total Environ 225(1–2):33–48
Rasmussen TH, Nielsen JB (2002) Critical parameters in the MCF-7 cell proliferation bioassay (E-Screen). Biomarkers 7(4):322–336
Vanparys C, Maras M, Lenjou M, Robbens J, Van Bockstaele D, Blust R, De Coen W (2006) Flow cytometric cell cycle analysis allows for rapid screening of estrogenicity in MCF-7 breast cancer cells. Toxicol in Vitro 20(7):1238–1248
Riverso M, Kortenkamp A, Silva E (2014) Non-tumorigenic epithelial cells secrete MCP-1 and other cytokines that promote cell division in breast cancer cells by activating ER alpha via PI3K/Akt/mTOR signaling. Int J Biochem Cell Biol 53:281–294
Gutleb AC, Meerts I, Bergsma JH, Schriks M, Murk AJ (2005) T-Screen as a tool to identify thyroid hormone receptor active compounds. Environ Toxicol Pharmacol 19(2):231–238
Schriks M, Vrabie CM, Gutleb AC, Faassen EJ, Rietjens I, Murk AJ (2006) T-screen to quantify functional potentiating, antagonistic and thyroid hormone-like activities of poly halogenated aromatic hydrocarbons (PHAHs). Toxicol in Vitro 20(4):490–498
Gutleb AC, Mossink L, Schriks M, van den Berg HJH, Murk AJ (2007) Delayed effects of environmentally relevant concentrations of 3,3’,4,4’-tetrachlorobiphenyl (PCB-77) and non-polar sediment extracts detected in the prolonged-FETAX. Sci Total Environ 381(1–3):307–315
Taxvig C, Vinggaard AM, Hass U, Axelstad M, Boberg J, Hansen PR, Frederiksen H, Nellemann C (2008) Do parabens have the ability to interfere with steroidogenesis? Toxicol Sci 106(1):206–213
Ghisari M, Bonefeld-Jorgensen EC (2009) Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol Lett 189(1):67–77
Long M, Kruger T, Ghisari M, Bonefeld-Jorgensen EC (2012) Effects of selected phytoestrogens and their mixtures on the function of the thyroid hormone and the aryl hydrocarbon receptor. Nutr Cancer 64(7):1008–1019
Long M, Ghisari M, Bonefeld-Jorgensen EC (2013) Effects of perfluoroalkyl acids on the function of the thyroid hormone and the aryl hydrocarbon receptor. Environ Sci Pollut Res 20(11):8045–8056
Ghisari M, Long M, Tabbo A, Bonefeld-Jorgensen EC (2015) Effects of currently used pesticides and their mixtures on the function of thyroid hormone and aryl hydrocarbon receptor in cell culture. Toxicol Appl Pharmacol 284(3):292–303
Sanderson JT (2006) The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals. Toxicol Sci 94(1):3–21
Connolly L, Ropstad E, Verhaegen S (2011) In vitro bioassays for the study of endocrine-disrupting food additives and contaminants. TrAC Trends Anal Chem 30(2):227–238
OECD (2011) Test no. 456: H295R steroidogenesis assay. OECD, Paris. doi: 10.1787/9789264122642-en
US EPA (2009) Endocrine disruptor screening program test guidelines. OPPTS 890.1550: steroidogenesis (human cell line – H295R). Office of Prevention, Pesticides and Toxic Substances, United States Environmental Protection Agency
Harvey PW, Everett DJ, Springall CJ (2007) Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis. J Appl Toxicol 27(2):103–115
Zhang XW, Yu RMK, Jones PD, Lam GKW, Newsted JL, Gracia T, Hecker M, Hilscherova K, Sanderson JT, Wu RSS, Giesy JP (2005) Quantitative RT-PCR methods for evaluating toxicant-induced effects on steroidogenesis using the H295R cell line. Environ Sci Technol 39(8):2777–2785
Hecker M, Hollert H, Cooper R, Vinggaard AM, Akahori Y, Murphy M, Nellemann C, Higley E, Newsted J, Laskey J, Buckalew A, Grund S, Maletz S, Giesy J, Timm G (2011) The OECD validation program of the H295R steroidogenesis assay: phase 3. Final inter-laboratory validation study. Environ Sci Pollut Res 18(3):503–515
Hilscherova K, Jones PD, Gracia T, Newsted JL, Zhang XW, Sanderson JT, Yu RMK, Wu RSS, Giesy JP (2004) Assessment of the effects of chemicals on the expression of ten steroidogenic genes in the H295R cell line using real-time PCR. Toxicol Sci 81(1):78–89
Maglich JM, Kuhn M, Chapin RE, Pletcher MT (2014) More than just hormones: H295R cells as predictors of reproductive toxicity. Reprod Toxicol 45:77–86
Antczak P, Jo HJ, Woo S, Scanlan L, Poynton H, Loguinov A, Chan S, Falciani F, Vulpe C (2013) Molecular toxicity identification evaluation (mTIE) approach predicts chemical exposure in Daphnia magna. Environ Sci Technol 47(20):11747–11756
Bundy JG, Davey MP, Viant MR (2009) Environmental metabolomics: a critical review and future perspectives. Metabolomics 5(1):3–21
Iguchi T, Watanabe H, Katsu Y (2007) Toxicogenomics and ecotoxicogenomics for studying endocrine disruption and basic biology. Gen Comp Endocrinol 153(1–3):25–29
Grun F, Blumberg B (2006) Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. Endocrinology 147(6, Suppl. S):S50–S55
Jordao R, Casas J, Fabrias G, Campos B, Pina B, Lemos MFL, Soares AMVM, Tauler R, Barata C (2015) Obesogens beyond vertebrates: lipid perturbation by tributyltin in the crustacean Daphnia magna. Environ Health Perspect 123(8):813–819
Alsop DH, Brown SB, van der Kraak GJ (2004) Dietary retinoic acid induces hindlimb and eye deformities in Xenopus laevis. Environ Sci Technol 38(23):6290–6299
Chen C-H, Chou P-H, Kawanishi M, Yagi T (2014) Occurrence of xenobiotic ligands for retinoid X receptors and thyroid hormone receptors in the aquatic environment of Taiwan. Mar Pollut Bull 85(2):613–618
Inoue D, Nakama K, Sawada K, Watanabe T, Matsui H, Sei K, Nakanishi T, Ike M (2011) Screening of agonistic activities against four nuclear receptors in wastewater treatment plants in Japan using a yeast two-hybrid assay. J Environ Sci (China) 23(1):125–132
Inoue D, Sawada K, Wada Y, Sei K, Ike M (2013) Removal characteristics of retinoic acids and 4-oxo-retinoic acids in wastewater by activated sludge treatment. Water Sci Technol 67(12):2868–2874
Sawada K, Inoue D, Wada Y, Sei K, Nakanishi T, Ike M (2012) Detection of retinoic acid receptor agonistic activity and identification of causative compounds in municipal wastewater treatment plants in Japan. Environ Toxicol Chem 31(2):307–315
Miyagawa S, Lange A, Hirakawa I, Tohyama S, Ogino Y, Mizutani T, Kagami Y, Kusano T, Ihara M, Tanaka H, Tatarazako N, Ohta Y, Katsu Y, Tyler CR, Iguchi T (2014) Differing species responsiveness of estrogenic contaminants in fish is conferred by the ligand binding domain of the estrogen receptor. Environ Sci Technol 48(9):5254–5263
Kunz PY, Fent K (2006) Estrogenic activity of UV filter mixtures. Toxicol Appl Pharmacol 217(1):86–99
Legler J, Zeinstra LM, Schuitemaker F, Lanser PH, Bogerd J, Brouwer A, Vethaak AD, De Voogt P, Murk AJ, Van der Burg B (2002) Comparison of in vivo and in vitro reporter gene assays for short-term screening of estrogenic activity. Environ Sci Technol 36(20):4410–4415
Simmons DB, Marlatt VL, Trudeau VL, Sherry JP, Metcalfe CD (2010) Interaction of Galaxolide(R) with the human and trout estrogen receptor-alpha. Sci Total Environ 408(24):6158–6164
Ihara M, Kitamura T, Kumar V, Park C-B, Ihara MO, Lee S-J, Yamashita N, Miyagawa S, Iguchi T, Okamoto S, Suzuki Y, Tanaka H (2015) Evaluation of estrogenic activity of wastewater: comparison among in vitro er alpha reporter gene assay, in vivo vitellogenin induction, and chemical analysis. Environ Sci Technol 49(10):6319–6326
Kohno S, Katsu Y, Iguchi T, Guillette LJ Jr (2008) Novel approaches for the study of vertebrate steroid hormone receptors. Integr Comp Biol 48(4):527–534
Hultin CL, Hallgren P, Persson A, Hansson MC (2014) Identification of an estrogen receptor gene in the natural freshwater snail Bithynia tentaculata. Gene 540(1):26–31
Katsu Y, Matsubara K, Kohno S, Matsuda Y, Toriba M, Oka K, Guillette LJ Jr, Ohta Y, Iguchi T (2010) Molecular cloning, characterization, and chromosome mapping of reptilian estrogen receptors. Endocrinology 151(12):5710–5720
Kaur S, Jobling S, Jones CS, Noble LR, Routledge EJ, Lockyer AE (2015) The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: implications for developing new model organisms. PLoS One 10(4)
Nagasawa K, Treen N, Kondo R, Otoki Y, Itoh N, Rotchell JM, Osada M (2015) Molecular characterization of an estrogen receptor and estrogen-related receptor and their autoregulatory capabilities in two Mytilus species. Gene 564(2):153–159
Vogeler S, Galloway TS, Lyons BP, Bean TP (2014) The nuclear receptor gene family in the Pacific oyster, Crassostrea gigas, contains a novel subfamily group. BMC Genomics 15
Bannister R, Beresford N, Granger DW, Pounds NA, Rand-Weaver M, White R, Jobling S, Routledge EJ (2013) No substantial changes in estrogen receptor and estrogen-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals. Aquat Toxicol 140:19–26
Bridgham JT, Keay J, Ortlund EA, Thornton JW (2014) Vestigialization of an allosteric switch: genetic and structural mechanisms for the evolution of constitutive activity in a steroid hormone receptor. PLoS Genet 10(1)
Grun F, Watanabe H, Zamanian Z, Maeda L, Arima K, Cubacha R, Gardiner DM, Kanno J, Iguchi T, Blumberg B (2006) Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Mol Endocrinol 20(9):2141–2155
Kanayama T, Kobayashi N, Mamiya S, Nakanishi T, Nishikawa J (2005) Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor gamma/retinoid X receptor pathway. Mol Pharmacol 67(3):766–774
Watson CS, Bulayeva NN, Wozniak AL, Alyea RA (2007) Xenoestrogens are potent activators of nongenomic estrogenic responses. Steroids 72(2):124–134
Rajapakse N, Silva E, Kortenkamp A (2002) Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Environ Health Perspect 110(9):917–921
Silva E, Rajapakse N, Kortenkamp A (2002) Something from “nothing”: eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol 36(8):1751–1756
Kortenkamp A (2014) Low dose mixture effects of endocrine disrupters and their implications for regulatory thresholds in chemical risk assessment. Curr Opin Pharmacol 19:105–111
Christiansen S, Kortenkamp A, Axelstad M, Boberg J, Scholze M, Jacobsen PR, Faust M, Lichtensteiger W, Schlumpf M, Burdorf A, Hass U (2012) Mixtures of endocrine disrupting contaminants modelled on human high end exposures: an exploratory study in rats. Int J Androl 35(3):303–316
Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, Hass U (2009) Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environ Health Perspect 117(12):1839–1846
Hass U, Scholze M, Christiansen S, Dalgaard M, Vinggaard AM, Axelstad M, Metzdorff SB, Kortenkamp A (2007) Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environ Health Perspect 115:122–128
Jarošová B, Erseková A, Hilscherová K, Loos R, Gawlik BM, Giesy JP, Bláha L (2014) Europe-wide survey of estrogenicity in wastewater treatment plant effluents: the need for the effect-based monitoring. Environ Sci Pollut Res 21(18):10970–10982
Behr M, Oehlmann J, Wagner M (2011) Estrogens in the daily diet: in vitro analysis indicates that estrogenic activity is omnipresent in foodstuff and infant formula. Food Chem Toxicol 49(10):2681–2688
Wagner M, Oehlmann J (2009) Endocrine disruptors in bottled mineral water: total estrogenic burden and migration from plastic bottles. Environ Sci Pollut Res 16(3):278–286
Yang CZ, Yaniger SI, Jordan VC, Klein DJ, Bittner GD (2011) Most plastic products release estrogenic chemicals: a potential health problem that can be solved. Environ Health Perspect 119(7):989–996
Brack W (2003) Effect-directed analysis: a promising tool for the identification of organic toxicants in complex mixtures? Anal Bioanal Chem 377(3):397–407
Buchinger S, Spira D, Broder K, Schlusener M, Ternes T, Reifferscheid G (2013) Direct coupling of thin-layer chromatography with a bioassay for the detection of estrogenic compounds: applications for effect-directed analysis. Anal Chem 85(15):7248–7256
Jonker W, Lamoree MH, Houtman CJ, Hamers T, Somsen GW, Kool J (2015) Rapid activity-directed screening of estrogens by parallel coupling of liquid chromatography with a functional gene reporter assay and mass spectrometry. J Chromatogr A 1406:165–174
Reemtsma T (2001) Prospects of toxicity-directed wastewater analysis. Anal Chim Acta 426(2):279–287
Schmitt S, Reifferscheid G, Claus E, Schluesener M, Buchinger S (2012) Effect directed analysis and mixture effects of estrogenic compounds in a sediment of the river Elbe. Environ Sci Pollut Res 19(8):3350–3361
Creusot N, Budzinski H, Balaguer P, Kinani S, Porcher J-M, Ait-Aissa S (2013) Effect-directed analysis of endocrine-disrupting compounds in multi-contaminated sediment: identification of novel ligands of estrogen and pregnane X receptors. Anal Bioanal Chem 405(8):2553–2566
Simon E, van Velzen M, Brandsma SH, Lie E, Loken K, de Boer J, Bytingsvik J, Jenssen BM, Aars J, Hamers T, Lamoree MH (2013) Effect-directed analysis to explore the polar bear exposome: identification of thyroid hormone disrupting compounds in plasma. Environ Sci Technol 47(15):8902–8912
Weiss JM, Andersson PL, Zhang J, Simon E, Leonards PEG, Hamers T, Lamoree MH (2015) Tracing thyroid hormone-disrupting compounds: database compilation and structure-activity evaluation for an effect-directed analysis of sediment. Anal Bioanal Chem 407(19):5625–5634
Alvarez-Munoz D, Indiveri P, Rostkowski P, Horwood J, Greer E, Minier C, Pope N, Langston WJ, Hill EM (2015) Widespread contamination of coastal sediments in the Transmanche Channel with anti-androgenic compounds. Mar Pollut Bull 95(2):590–597
Berger E, Potouridis T, Haeger A, Puettmann W, Wagner M (2015) Effect-directed identification of endocrine disruptors in plastic baby teethers. J Appl Toxicol 35(11):1254–1261
Fang H, Tong W, Perkins R, Soto AM, Prechtl NV, Sheehan DM (2000) Quantitative comparisons of in vitro assays for estrogenic activities. Environ Health Perspect 108(8):723–729
Leusch FD, de Jager C, Levi Y, Lim R, Puijker L, Sacher F, Tremblay LA, Wilson VS, Chapman HF (2010) Comparison of five in vitro bioassays to measure estrogenic activity in environmental waters. Environ Sci Technol 44(10):3853–3860
Dreier DA, Connors KA, Brooks BW (2015) Comparative endpoint sensitivity of in vitro estrogen agonist assays. Regul Toxicol Pharmacol 72(2):185–193
Akahori Y, Nakai M, Yamasaki K, Takatsuki M, Shimohigashi Y, Ohtaki M (2008) Relationship between the results of in vitro receptor binding assay to human estrogen receptor alpha and in vivo uterotrophic assay: comparative study with 65 selected chemicals. Toxicol in Vitro 22(1):225–231
Coldham NG, Dave M, Sivapathasundaram S, McDonnell DP, Connor C, Sauer MJ (1997) Evaluation of a recombinant yeast cell estrogen screening assay. Environ Health Perspect 105(7):734–742
Rotroff DM, Martin MT, Dix DJ, Filer DL, Houck KA, Knudsen TB, Sipes NS, Reif DM, Xia M, Huang R, Judson RS (2014) Predictive endocrine testing in the 21st century using in vitro assays of estrogen receptor signaling responses. Environ Sci Technol 48(15):8706–8716
Rotroff DM, Dix DJ, Houck KA, Knudsen TB, Martin MT, McLaurin KW, Reif DM, Crofton KM, Singh AV, Xia M, Huang R, Judson RS (2013) Using in vitro high throughput screening assays to identify potential endocrine-disrupting chemicals. Environ Health Perspect 121(1):7–14
Blaauboer BJ (2015) The long and winding road of progress in the use of in vitro data for risk assessment purposes: from “carnation test” to integrated testing strategies. Toxicology 332:4–7
Meek ME, Lipscomb JC (2015) Gaining acceptance for the use of in vitro toxicity assays and QIVIVE in regulatory risk assessment. Toxicology 332:112–123
Villeneuve DL, Ankley GT, Makynen EA, Blake LS, Greene KJ, Higley EB, Newsted JL, Giesy JP, Hecker M (2007) Comparison of fathead minnow ovary explant and H295R cell-based steroidogenesis assays for identifying endocrine-active chemicals. Ecotoxicol Environ Saf 68(1):20–32
Puy-Azurmendi E, Olivares A, Vallejo A, Ortiz-Zarragoitia M, Pina B, Zuloaga O, Cajaraville MP (2014) Estrogenic effects of nonylphenol and octylphenol isomers in vitro by recombinant yeast assay (RYA) and in vivo with early life stages of zebrafish. Sci Total Environ 466:1–10
Hornung MW, Kosian PA, Haselman JT, Korte JJ, Challis K, Macherla C, Nevalainen E, Degitz SJ (2015) In vitro, ex vivo, and in vivo determination of thyroid hormone modulating activity of benzothiazoles. Toxicol Sci 146(2):254–264
Leusch FDL, Khan SJ, Gagnon MM, Quayle P, Trinh T, Coleman H, Rawson C, Chapman HF, Blair P, Nice H, Reitsema T (2014) Assessment of wastewater and recycled water quality: a comparison of lines of evidence from in vitro, in vivo and chemical analyses. Water Res 50:420–431
Vermeirssen ELM, Burki R, Joris C, Peter A, Segner H, Suter MJF, Burkhardt-Holm P (2005) Characterization of the estrogenicity of swiss midland rivers using a recombinant yeast bioassay and plasma vitellogenin concentrations in feral male brown trout. Environ Toxicol Chem 24(9):2226–2233
Henneberg A, Bender K, Blaha L, Giebner S, Kuch B, Koehler H-R, Maier D, Oehlmann J, Richter D, Scheurer M, Schulte-Oehlmann U, Sieratowicz A, Ziebart S, Triebskorn R (2014) Are in vitro methods for the detection of endocrine potentials in the aquatic environment predictive for in vivo effects? Outcomes of the projects SchussenAktiv and SchussenAktiv plus in the Lake Constance area, Germany. PLoS One 9(6)
Groothuis FA, Heringa MB, Nicol B, Hermens JL, Blaauboer BJ, Kramer NI (2015) Dose metric considerations in in vitro assays to improve quantitative in vitro-in vivo dose extrapolations. Toxicology 332:30–40
Brinkmann M, Maletz S, Krauss M, Bluhm K, Schiwy S, Kuckelkorn J, Tiehm A, Brack W, Hollert H (2014) Heterocyclic aromatic hydrocarbons show estrogenic activity upon metabolization in a recombinant transactivation assay. Environ Sci Technol 48(10):5892–5901
Louisse J, Bosgra S, Blaauboer BJ, Rietjens IM, Verwei M (2015) Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling. Arch Toxicol 89(7):1135–1148
Yoon M, Campbell JL, Andersen ME, Clewell HJ (2012) Quantitative in vitro to in vivo extrapolation of cell-based toxicity assay results. Crit Rev Toxicol 42(8):633–652
Wetmore BA (2015) Quantitative in vitro-to-in vivo extrapolation in a high-throughput environment. Toxicology 332:94–101
Wilk-Zasadna I, Bernasconi C, Pelkonen O, Coecke S (2015) Biotransformation in vitro: an essential consideration in the quantitative in vitro-to-in vivo extrapolation (QIVIVE) of toxicity data. Toxicology 332:8–19
Burden N, Sewell F, Andersen ME, Boobis A, Chipman JK, Cronin MTD, Hutchinson TH, Kimber I, Whelan M (2015) Adverse outcome pathways can drive non-animal approaches for safety assessment. J Appl Toxicol 35(9):971–975
Lee JW, Won E-J, Raisuddin S, Lee J-S (2015) Significance of adverse outcome pathways in biomarker-based environmental risk assessment in aquatic organisms. J Environ Sci 35:115–127
Plant NJ (2015) An introduction to systems toxicology. Toxicol Res 4(1):9–22
Simmons DBD, Benskin JP, Cosgrove JR, Duncker BP, Ekman DR, Martyniuk CJ, Sherry JP (2015) Omics for aquatic ecotoxicology: control of extraneous variability to enhance the analysis of environmental effects. Environ Toxicol Chem 34(8):1693–1704
Spurgeon DJ, Jones OAH, Dorne J-LCM, Svendsen C, Swain S, Stuerzenbaum SR (2010) Systems toxicology approaches for understanding the joint effects of environmental chemical mixtures. Sci Total Environ 408(18):3725–3734
Waters MD, Fostel JM (2004) Toxicogenomics and systems toxicology: aims and prospects. Nat Rev Genet 5(12):936–948
Yoon K, Kwack SJ, Kim HS, Lee B-M (2014) Estrogenic endocrine-disrupting chemicals: molecular mechanisms of actions on putative human diseases. J Toxicol Environ Health B Crit Rev 17(3):127–174
Escher B, Leusch F (2012) Bioanalytical tools in water quality assessment. International Water Association, London
Kunz PY, Kienle C, Carere M, Homazava N, Kase R (2015) In vitro bioassays to screen for endocrine active pharmaceuticals in surface and waste waters. J Pharm Biomed Anal 106:107–115
Loos R (2012) Analytical methods relevant to the European Commission’s 2012 proposal on priority substances under the water framework directive. Publications Office of the European Union
OECD (2012) OECD Series on Testing and Assessment Number 178. Detailed review paper on the state of the science on novel in vitro and in vivo screening and testing methods and endpoints for evaluating endocrine disruptors. ENV/JM/MONO(2012)23
EU (2008) DIRECTIVE 2008/105/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 2008 on environmental quality standards in the field of water policy, amending and subsequently repealing Council Directives 82/176/EEC, 83/513/EEC, 84/156/EEC, 84/491/EEC, 86/280/EEC and amending Directive 2000/60/EC of the European Parliament and of the Council. Off J Eur Union L 348/84
ANZECC, ARMCANZ (2000) Australian and New Zealand guidelines for fresh and marine water quality. Aquatic ecosystems: Rationale and background information, vol. 2. Australian Water Association, Artarmon, AU
EU Council (2009) Council conclusions on combination effects of chemicals Brussels, Belgium. 2988th Environment Council meeting, Council of the European Union, 22 Dec 2009
Epa U (2002) Guidance on cumulative risk assessment of pesticide chemicals that have a common mechanism of toxicity, federal register. U.S. Environmental Protection Agency. Office of Pesticide Programs, Washington, DC
OSPAR Commission (2007) Practical guidance document on whole effluent assessment, No. 316/2007. OSPAR Commission, London
OECD (2005) OECD Series on Testing and Assessment Number 34. Guidance document on the validation and international acceptance of new or updated test methods for hazard assessment. ENV/JM/MONO(2005)14
Tang JYM, McCarty S, Glenn E, Neale PA, Warne MSJ, Escher BI (2013) Mixture effects of organic micropollutants present in water: towards the development of effect-based water quality trigger values for baseline toxicity. Water Res 47(10):3300–3314
EU (2013) DIRECTIVE 2013/39/EU OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 12 August 2013 amending Directives 2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy. Off J Eur Union L226/1
Brand W, de Jongh CM, van der Linden SC, Mennes W, Puijker LM, van Leeuwen CJ, van Wezel AP, Schriks M, Heringa MB (2013) Trigger values for investigation of hormonal activity in drinking water and its sources using CALUX bioassays. Environ Int 55:109–118
Jarošová B, Bláha L, Giesy JP, Hilscherová K (2014) What level of estrogenic activity determined by in vitro assays in municipal waste waters can be considered as safe? Environ Int 64:98–109
Escher BI, Neale PA, Leusch FDL (2015) Effect-based trigger values for in vitro bioassays: reading across from existing water quality guideline values. Water Res 81:137–148
Langston WJ, Burt GR, Chesman BS (2007) Feminisation of male clams Scrobicularia plana from estuaries in Southwest UK and its induction by endocrine-disrupting chemicals. Mar Ecol Prog Ser 333:173–184
De Solla SR, Martin PA, Fernie KJ, Park BJ, Mayne G (2006) Effects of environmentally relevant concentrations of atrazine on gonadal development of snapping turtles (Chelydra serpentina). Environ Toxicol Chem 25(2):520–526
Mattsson A, Olsson JA, Brunstrom B (2008) Selective estrogen receptor alpha activation disrupts sex organ differentiation and induces expression of vitellogenin II and very low-density apolipoprotein II in Japanese quail embryos. Reproduction 136(2):175–186
Wagner M (2012) Endocrine disruptors in bottled water and foodstuff: a bioassay-based approach. Dr. Phil. Nat., Faculty of Biological Sciences, Goethe University, Frankfurt, p 206
Fernandes D, Loi B, Porte C (2011) Biosynthesis and metabolism of steroids in molluscs. J Steroid Biochem Mol Biol 127(3–5):189–195
Dodds EC, Lawson W (1936) Synthetic oestrogenic agents without the phenanthrene nucleus. Nature 137:996
Vanbohemen CG, Lambert JGD, Goos HJT, Vanoordt P (1982) Estrone and estradiol participation during exogenous vitallogenesis in the female rainbow-trout, Salmo gairdneri. Gen Comp Endocrinol 46(1):81–92
Palace VP, Evans RE, Wautier K, Baron C, Vandenbyllardt L, Vandersteen W, Kidd K (2002) Induction of vitellogenin and histological effects in wild fathead minnows from a lake experimentally treated with the synthetic estrogen, ethynylestradiol. Water Qual Res J Can 37(3):637–650
Park BJ, Kidd K (2005) Effects of the synthetic estrogen ethinylestradiol on early life stages of mink frogs and green frogs in the wild and in situ. Environ Toxicol Chem 24(8):2027–2036
Palace VP, Wautier KG, Evans RE, Blanchfield PJ, Mills KH, Chalanchuk SM, Godard D, McMaster ME, Tetreault GR, Peters LE, Vandenbyllaardt L, Kidd KA (2006) Biochemical and histopathological effects in pearl dace (Margariscus margarita) chronically exposed to a synthetic estrogen in a whole lake experiment. Environ Toxicol Chem 25(4):1114–1125
Werner J, Palace VP, Wautier KG, Mills KH, Chalanchuk SM, Kidd KA (2006) Reproductive fitness of lake trout (Salvelinus namaycush) exposed to environmentally relevant concentrations of the potent estrogen ethynylestradiol (EE2) in a whole lake exposure experiment. Sci Mar 70:59–66
Palace VP, Evans RE, Wautier KG, Mills KH, Blanchfield PJ, Park BJ, Baron CL, Kidd KA (2009) Interspecies differences in biochemical, histopathological, and population responses in four wild fish species exposed to ethynylestradiol added to a whole lake. Can J Fish Aquat Sci 66(11):1920–1935
Milnes MR, Bryan TA, Katsu Y, Kohno S, Moore BC, Iguchi T, Guillette LJ Jr (2008) Increased posthatching mortality and loss of sexually dimorphic gene expression in alligators (Alligator mississippiensis) from a contaminated environment. Biol Reprod 78(5):932–938
Stoker C, Repetti MR, Garcia SR, Zayas MA, Galoppo GH, Beldomenico HR, Loque EH, Munoz-de-Toro M (2011) Organochlorine compound residues in the eggs of broad-snouted caimans (Caiman latirostris) and correlation with measures of reproductive performance. Chemosphere 84(3):311–317
Stoker C, Beldomenico PM, Bosquiazzo VL, Zayas MA, Rey F, Rodriguez H, Munoz-de-Toro M, Luque EH (2008) Developmental exposure to endocrine disruptor chemicals alters follicular dynamics and steroid levels in Caiman latirostris. Gen Comp Endocrinol 156(3):603–612
Rider CV, Hartig PC, Cardon MC, Lambright CR, Bobseine KL, Guillette LJ Jr, Gray LE Jr, Wilson VS (2010) Differences in sensitivity but not selectivity of xenoestrogen binding to alligator versus human estrogen receptor alpha. Environ Toxicol Chem 29(9):2064–2071
Fry DM, Toone CK (1981) DDT-induced feminization of gull embryos. Science 213(4510):922–924
Markman S, Mueller CT, Pascoe D, Dawson A, Buchanan KL (2011) Pollutants affect development in nestling starlings Sturnus vulgaris. J Appl Ecol 48(2):391–397
Sonne C, Iburg T, Leifsson PS, Born EW, Letcher RJ, Dietz R (2011) Thyroid gland lesions in organohalogen contaminated East Greenland polar bears (Ursus maritimus). Toxicol Environ Chem 93(4):789–805
Colborn T, vom Saal FS, Soto AM (1993) Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect 101(5):378–384
Colborn T, Dumanoski D, Myers JP (1996) Our stolen future: are we threatening our fertility, intelligence, and survival? A scientific detective story. Dutton, New York
Kristensen DM, Skalkam ML, Audouze K, Lesne L, Desdoits-Lethimonier C, Frederiksen H, Brunak S, Skakkebaek NE, Jegou B, Hansen JB, Junker S, Leffers H (2011) Many putative endocrine disruptors inhibit prostaglandin synthesis. Environ Health Perspect 119(4):534–541
Masuyama H, Inoshita H, Hiramatsu Y, Kudo T (2002) Ligands have various potential effects on the degradation of pregnane X receptor by proteasome. Endocrinology 143(1):55–61
Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S (2003) The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Mol Cell Biol 23(6):1843–1855
Jansen MS, Nagel SC, Miranda PJ, Lobenhofer EK, Afshari CA, McDonnell DP (2004) Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A 101(18):7199–7204
Brunnberg S, Pettersson K, Rydin E, Matthews J, Hanberg A, Pongratz I (2003) The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription. Proc Natl Acad Sci U S A 100(11):6517–6522
Kleiner IS, Weisman AI, Barowsky H (1935) An investigation of the new biologic test for hormones in pregnancy urine: preliminary report. JAMA 104:1318–1319
Klaassen CD, Casarett LJ, Doull J (2013) Casarett and Doull’s toxicology: the basic science of poisons. McGraw-Hill, New York
Yalow RS, Berson SA (1960) Immunoassay of endogenous plasma insulin in man. J Clin Invest 39(7):1157–1175
Khan MN, Findlay JWA (2010) Ligand-binding assays: development, validation, and implementation in the drug development arena. Wiley, Hoboken, NJ
Ruff M, Gangloff M, Wurtz JM, Moras D (2000) Estrogen receptor transcription and transactivation: structure-function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res 2(5):353–359
Muller MB, Dausend C, Weins C, Frimmel FH (2004) A new bioautographic screening method for the detection of estrogenic compounds. Chromatographia 60(3–4):207–211
Vanderperren E, Demare W, Blust R, Cooreman K, Bossier P (2001) Oestrogenic activity of CPRG (chlorophenol red-beta-D-galactopyranoside), a beta-galactosidase substrate commonly used in recombinant yeast oestrogenic assays. Biomarkers 6(5):375–380
Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS (1986) Phenol red in tissue-culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci U S A 83(8):2496–2500
Welshons WV, Wolf MF, Murphy CS, Jordan VC (1988) Estrogenic activity of phenol red. Mol Cell Endocrinol 57(3):169–178
Antebi A (2006) Nuclear hormone receptors in C. elegans. In: WormBook (ed). The C. elegans Research Community, WormBook. doi:10.1895/wormbook.1.64.1. http://www.wormbook.org
Dang Z, Ru S, Wang W, Rorije E, Hakkert B, Vermeire T (2011) Comparison of chemical-induced transcriptional activation of fish and human estrogen receptors: regulatory implications. Toxicol Lett 201(2):152–175
Scott AP (2012) Do mollusks use vertebrate sex steroids as reproductive hormones? Part I: Critical appraisal of the evidence for the presence, biosynthesis and uptake of steroids. Steroids 77(13):1450–1468
Scott AP (2013) Do mollusks use vertebrate sex steroids as reproductive hormones? II. Critical review of the evidence that steroids have biological effects. Steroids 78(2):268–281
Gutierrez-Mazariegos J, Nadendla EK, Lima D, Pierzchalski K, Jones JW, Kane M, Nishikawa J-I, Hiromori Y, Nakanishi T, Santos MM, Castro LFC, Bourguet W, Schubert M, Laudet V (2014) A mollusk retinoic acid receptor (RAR) ortholog sheds light on the evolution of ligand binding. Endocrinology 155(11):4275–4286
Burgess RM, Ho KT, Brack W, Lamoree M (2013) Effects-directed analysis (EDA) and toxicity identification evaluation (TIE): complementary but different approaches for diagnosing causes of environmental toxicity. Environ Toxicol Chem 32(9):1935–1945
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Wagner, M., Kienle, C., Vermeirssen, E.L.M., Oehlmann, J. (2017). Endocrine Disruption and In Vitro Ecotoxicology: Recent Advances and Approaches. In: Reifferscheid, G., Buchinger, S. (eds) In vitro Environmental Toxicology - Concepts, Application and Assessment. Advances in Biochemical Engineering/Biotechnology, vol 157. Springer, Cham. https://doi.org/10.1007/10_2016_2
Download citation
DOI: https://doi.org/10.1007/10_2016_2
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-45906-6
Online ISBN: 978-3-319-45908-0
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)