Skip to main content

Ovarian Toxicity of Environmental Contaminants: 50 Shades of Grey

  • Chapter
  • First Online:
Translational Toxicology

Abstract

Exposure to environmental contaminants is thought to be important in the development of adverse effects on reproductive health. While the adverse effects of environmental contaminants on semen quality and testicular function have been well studied, effects on ovarian function are less well defined. Epidemiological studies have linked exposure to environmental contaminants with adverse effects on menstrual cycle characteristics, infertility, and earlier age of menopause onset; yet direct evidence of effects on ovarian function is lacking. Environmental contaminant concentrations have been quantified in human ovarian follicular fluid establishing target tissue exposure; however, such data is sporadic and limited to women undergoing assisted reproductive therapies making generalization of results to the broader population of women difficult. We note that the relationship between serum and follicular fluid concentrations can be orders of magnitude different and thus target tissue distribution requires further study. Animal studies revealed effects of environmental contaminants on ovarian follicle dynamics, oocyte maturation, steroidogenesis, and epigenetic changes. Issues of dosing such as concentration of test chemicals used, route of administration, and use of multiple dose groups remain important limitations of the current literature. While animal studies establish a basis for biological plausibility of effects and support conclusions of reproductive hazard, we conclude that exposures in the general human population are too low to present a demonstrable risk to human ovarian function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahn HJ, An BS, Jung EM, Yang H, Choi KC, Jeung EB (2012) Parabens inhibit the early phase of folliculogenesis and steroidogenesis in the ovaries of neonatal rats. Mol Reprod Dev 79:626–636

    Article  PubMed  Google Scholar 

  • Al-Saleh I, Coskun S, Mashhour A, Shinwari N, El-Doush I, Billedo G, Jaroudi K, Al-Shahrani A, Al-Kabra M, El Din Mohamed G (2008) Exposure to heavy metals (lead, cadmium and mercury) and its effect on the outcome of in-vitro fertilization treatment. Int J Hyg Environ Health 211:560–579

    Article  CAS  PubMed  Google Scholar 

  • Alvarez S, Devouche E (2012) First French national survey on lifestyle and toxic factors in infertile couples. Gynecol Obstet Fertil 40:765–771

    Article  CAS  PubMed  Google Scholar 

  • Ambruosi B, Uranio MF, Sardanelli AM, Pocar P, Martino NA, Paternoster MS, Amati F, Dell’Aquila ME (2011) In vitro acute exposure to DEHP affects oocyte meiotic maturation, energy and oxidative stress parameters in a large animal model. PLoS One 6:e27452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Appt SE, Kaplan JR, Clarkson TB, Cline JM, Christian PJ, Hoyer PB (2006) Destruction of primordial ovarian follicles in adult cynomolgus macaques after exposure to 4-vinylcyclohexene diepoxide: a nonhuman primate model of the menopausal transition. Fertil Steril 86(Suppl 4):1210–1216

    Article  CAS  PubMed  Google Scholar 

  • Augood C, Duckitt K, Templeton AA (1998) Smoking and female infertility: a systematic review and meta-analysis. Hum Reprod 13:1532–1539

    Article  CAS  PubMed  Google Scholar 

  • Baerwald AR, Pierson RA (2004) Endometrial development in association with ovarian follicular waves during the menstrual cycle. Ultrasound Obstet Gynecol 24:453–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baerwald AR, Adams GP, Pierson RA (2003a) Characterization of ovarian follicular wave dynamics in women. Biol Reprod 69:1023–1031

    Article  CAS  PubMed  Google Scholar 

  • Baerwald AR, Adams GP, Pierson RA (2003b) A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril 80:116–122

    Article  PubMed  Google Scholar 

  • Baldridge MG, Stahl RL, Gerstenberger SL, Tripoli V, Hutz RJ (2003) Modulation of ovarian follicle maturation in Long-Evans rats exposed to polychlorinated biphenyls (PCBs) in-utero and lactationally. Reprod Toxicol 17:567–573

    Article  CAS  PubMed  Google Scholar 

  • Batariova A, Spevackova V, Benes B, Cejchanova M, Smid J, Cerna M (2006) Blood and urine levels of Pb, Cd and Hg in the general population of the Czech Republic and proposed reference values. Int J Hyg Environ Health 209:359–366

    Article  CAS  PubMed  Google Scholar 

  • Baukloh V, Bohnet HG, Trapp M, Heeschen W, Feichtinger W, Kemeter P (1987) Biocides in human follicular fluid. Ann N Y Acad Sci 442:240–250

    Article  Google Scholar 

  • Bloom MS, Buck Louis GM, Schisterman EF, Liu A, Kostyniak PJ (2007) Maternal serum polychlorinated biphenyl concentrations across critical windows of human development. Environ Health Perspect 115:1320–1324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bloom MS, Kim D, vom Saal FS, Taylor JA, Cheng G, Lamb JD, Fujimoto VY (2011) Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization. Fertil Steril 96:672–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bloom MS, Fujimoto VY, Steuerwald AJ, Cheng G, Browne RW, Parsons PJ (2012a) Background exposure to toxic metals in women adversely influences pregnancy during in vitro fertilization (IVF). Reprod Toxicol 34:471–481

    Article  CAS  PubMed  Google Scholar 

  • Bloom MS, Kim K, Kruger PC, Parsons PJ, Arnason JG, Steuerwald AJ, Fujimoto VY (2012b) Associations between toxic metals in follicular fluid and in vitro fertilization (IVF) outcomes. J Assist Reprod Genet 29:1369–1379

    Article  PubMed  PubMed Central  Google Scholar 

  • Boivin J, Bunting L, Collins JA, Nygren KG (2007) International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 22:1506–1512

    Article  PubMed  Google Scholar 

  • Borman SM, Christian PJ, Sipes IG, Hoyer PB (2000) Ovotoxicity in female Fischer rats and B6 mice induced by low-dose exposure to three polycyclic aromatic hydrocarbons: comparison through calculation of an ovotoxic index. Toxicol Appl Pharmacol 167:191–198

    Article  CAS  PubMed  Google Scholar 

  • Brieno-Enriquez MA, Reig-Viader R, Cabero L, Toran N, Martinez F, Roig I, Garcia Caldes M (2012) Gene expression is altered after bisphenol A exposure in human fetal oocytes in vitro. Mol Hum Reprod 18:171–183

    Article  CAS  PubMed  Google Scholar 

  • Byskov AGS (1978) Follicle atresia. In: Jones R (ed) The vertebrate ovary. Plenum Press, New York, pp 533–562

    Google Scholar 

  • Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL (2008) Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ Health Perspect 116:39–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casper RF, Quesne M, Rogers IM, Shirota T, Jolivet A, Milgrom E, Savouret JF (1999) Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity. Mol Pharmacol 56:784–790

    CAS  PubMed  Google Scholar 

  • Chandra A, Martinez GM, Mosher WD, Abma JC, Jones J (2005) Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. Vital Health Stat 23:1–160

    Google Scholar 

  • Chedrese PJ, Feyles F (2001) The diverse mechanism of action of dichlorodiphenyldichloroethylene (DDE) and methoxychlor in ovarian cells in vitro. Reprod Toxicol 15:693–698

    Article  CAS  PubMed  Google Scholar 

  • Cohn BA, Cirillo PM, Wolff MS, Schwingl PJ, Cohen RD, Sholtz RI, Ferrara A, Christianson RE, van den Berg BJ, Siiteri PK (2003) DDT and DDE exposure in mothers and time to pregnancy in daughters. Lancet 361:2205–2206

    Article  CAS  PubMed  Google Scholar 

  • Cooper GS, Klebanoff MA, Promislow J, Brock JW, Longnecker MP (2005) Polychlorinated biphenyls and menstrual cycle characteristics. Epidemiology 16:191–200

    Article  PubMed  Google Scholar 

  • Cortvrindt RG, Smitz JE (2002) Follicle culture in reproductive toxicology: a tool for in-vitro testing of ovarian function? Hum Reprod Update 8:243–254

    Article  CAS  PubMed  Google Scholar 

  • Cortvrindt RG, Hu Y, Liu J, Smitz JE (1998) Timed analysis of the nuclear maturation of oocytes in early preantral mouse follicle culture supplemented with recombinant gonadotropin. Fertil Steril 70:1114–1125

    Article  CAS  PubMed  Google Scholar 

  • Davis BJ, Price HC, O’Connor RW, Fernando R, Rowland AS, Morgan DL (2001) Mercury vapor and female reproductive toxicity. Toxicol Sci 59:291–296

    Article  CAS  PubMed  Google Scholar 

  • De FE, Porpora MG, Di DA, Ingelido AM, Cardelli M, Cosmi EV, Donnez J (2004) Dioxin-like compounds and endometriosis: a study on Italian and Belgian women of reproductive age. Toxicol Lett 150:203–209

    Article  CAS  Google Scholar 

  • De Felip E, di Domenico A, Miniero R, Silvestroni L (2004) Polychlorobiphenyls and other organochlorine compounds in human follicular fluid. Chemosphere 54:1445–1449

    Article  PubMed  CAS  Google Scholar 

  • Dickerson EH, Sathyapalan T, Knight R, Maguiness SM, Killick SR, Robinson J, Atkin SL (2011) Endocrine disruptor & nutritional effects of heavy metals in ovarian hyperstimulation. J Assist Reprod Genet 28:1223–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dvornyk V, Long JR, Liu PY, Zhao LJ, Shen H, Recker RR, Deng HW (2006) Predictive factors for age at menopause in Caucasian females. Maturitas 54:19–26

    Article  PubMed  Google Scholar 

  • Dyer SM, Cattani M, Pisaniello DL, Williams FM, Edwards JW (2001) Peripheral cholinesterase inhibition by occupational chlorpyrifos exposure in Australian termiticide applicators. Toxicology 169:177–185

    Article  CAS  PubMed  Google Scholar 

  • Eladak S, Grisin T, Moison D, Guerquin MJ, N’Tumba-Byn T, Pozzi-Gaudin S, Benachi A, Livera G, Rouiller-Fabre V, Habert R (2015) A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound. Fertil Steril 103:11–21

    Article  CAS  PubMed  Google Scholar 

  • Eskenazi B, Warner M, Marks AR, Samuels S, Gerthoux PM, Vercellini P, Olive DL, Needham L, Patterson D Jr, Mocarelli P (2005) Serum dioxin concentrations and age at menopause. Environ Health Perspect 113:858–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farr SL, Cooper GS, Cai J, Savitz DA, Sandler DP (2004) Pesticide use and menstrual cycle characteristics among premenopausal women in the Agricultural Health Study. Am J Epidemiol 160:1194–1204

    Article  CAS  PubMed  Google Scholar 

  • Foster WG (1992) Reproductive toxicity of chronic Lead exposure in the female cynomolgus monkey. Reprod Toxicol 6:123–131

    Article  CAS  PubMed  Google Scholar 

  • Foster WG (1995) The reproductive toxicity of Great Lakes contaminants. Environ Health Perspect 103(Suppl 9):63–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foster WG (2003) Do environmental contaminants adversely affect human reproductive physiology? J Obstet Gynaecol Can 25:33–44

    PubMed  Google Scholar 

  • Foster WG, McMahon A, Younglai EV, Jarrell JF, Lecavalier P (1995) Alterations in circulating ovarian steroids in hexachlorobenzene-exposed monkeys. Reprod Toxicol 9:541–548

    Article  CAS  PubMed  Google Scholar 

  • Foster WG, McMahon A, Rice DC (1996) Subclinical changes in luteal function in cynomolgus monkeys with moderate blood lead levels. J Appl Toxicol 16:159–163

    Article  CAS  PubMed  Google Scholar 

  • Franczak A, Nynca A, Valdez KE, Mizinga KM, Petroff BK (2006) Effects of acute and chronic exposure to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin on the transition to reproductive senescence in female Sprague-Dawley rats. Biol Reprod 74:125–130

    Article  CAS  PubMed  Google Scholar 

  • Fujimoto VY, Kim D, vom Saal FS, Lamb JD, Taylor JA, Bloom MS (2011) Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization. Fertil Steril 95:1816–1819

    Article  CAS  PubMed  Google Scholar 

  • Fuortes L, Clark M, Kirchner H, Smith E (1997) Association between female infertility and agricultural work history. Am J Ind Med 31:445–451

    Article  CAS  PubMed  Google Scholar 

  • Gallicchio L, Miller S, Greene T, Zacur H, Flaws JA (2009) Premature ovarian failure among hairdressers. Hum Reprod 24:2636–2641

    Article  CAS  PubMed  Google Scholar 

  • Ganesan S, Keating AF (2014) Impact of 7,12-dimethylbenz[a]anthracene exposure on connexin gap junction proteins in cultured rat ovaries. Toxicol Appl Pharmacol 274:209–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganesan S, Keating AF (2015) Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells. Toxicol Appl Pharmacol 282:252–258

    Article  CAS  PubMed  Google Scholar 

  • Ganesan S, Bhattacharya P, Keating AF (2013) 7,12-Dimethylbenz[a]anthracene exposure induces the DNA repair response in neonatal rat ovaries. Toxicol Appl Pharmacol 272:690–696

    Article  CAS  PubMed  Google Scholar 

  • Ganesan S, Nteeba J, Keating AF (2014) Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage. Toxicol Appl Pharmacol 281:203–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gannon AM, Stampfli MR, Foster WG (2012) Cigarette smoke exposure results in significant follicle loss via an alternative ovarian cell death pathway in mice. Toxicol Sci 125:274–284

    Article  CAS  PubMed  Google Scholar 

  • Gannon AM, Stampfli MR, Foster WG (2013) Cigarette smoke exposure elicits increased autophagy and dysregulation of mitochondrial dynamics in murine granulosa cells. Biol Reprod 88:1–11

    Google Scholar 

  • Gittens JE, Mhawi AA, Lidington D, Ouellette Y, Kidder GM (2003) Functional analysis of gap junctions in ovarian granulosa cells: distinct role for connexin 43 in early stages of folliculogenesis. Am J Physiol Cell Physiol 284:C880–C887

    Article  CAS  PubMed  Google Scholar 

  • Gittens JE, Barr KJ, Vanderhyden BC, Kidder GM (2005) Interplay between paracrine signaling and gap junctional communication in ovarian follicles. J Cell Sci 118:113–122

    Article  CAS  PubMed  Google Scholar 

  • Gore AC, Walker DM, Zama AM, Armenti AE, Uzumcu M (2011) Early life exposure to endocrine-disrupting chemicals causes lifelong molecular reprogramming of the hypothalamus and premature reproductive aging. Mol Endocrinol 25:2157–2168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grasselli F, Baratta L, Baioni L, Bussolati S, Ramoni R, Grolli S, Basini G (2010) Bisphenol A disrupts granulosa cell function. Domest Anim Endocrinol 39:34–39

    Article  CAS  PubMed  Google Scholar 

  • Guerra MT, Scarano WR, de Toledo FC, Franci JA, Kempinas Wde G (2010) Reproductive development and function of female rats exposed to di-eta-butyl-phthalate (DBP) in utero and during lactation. Reprod Toxicol 29:99–105

    Article  CAS  PubMed  Google Scholar 

  • Haney AF, Hughes SF, Hughes CL Jr (1984) Screening of potential reproductive toxicants by use of porcine granulosa cell cultures. Toxicology 30:227–241

    Article  CAS  PubMed  Google Scholar 

  • Hombach-Klonisch S, Pocar P, Kietz S, Klonisch T (2005) Molecular actions of polyhalogenated arylhydrocarbons (PAHs) in female reproduction. Curr Med Chem 12:599–616

    CAS  PubMed  Google Scholar 

  • Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Ilagan A, Voigt RC, Thomas S, Thomas BF, Hassold TJ (2003) Bisphenol a exposure causes meiotic aneuploidy in the female mouse. Curr Biol 13:546–553

    Article  CAS  PubMed  Google Scholar 

  • Hunt PA, Lawson C, Gieske M, Murdoch B, Smith H, Marre A, Hassold T, Vandevoort CA (2012) Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey. Proc Natl Acad Sci U S A 109:17525–17530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y (2002) Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. Hum Reprod 17:2839–2841

    Article  CAS  PubMed  Google Scholar 

  • Jackson LW, Howards PP, Wactawski-Wende J, Schisterman EF (2011) The association between cadmium, lead and mercury blood levels and reproductive hormones among healthy, premenopausal women. Hum Reprod 26:2887–2895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jarrell JF, Villeneuve D, Franklin C, Bartlett S, Wrixon W, Kohut J, Zouves CG (1993) Contamination of human ovarian follicular fluid and serum by chlorinated organic compounds in three Canadian cities. CMAJ 148:1321–1327

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jirsova S, Masata J, Jech L, Zvarova J (2010) Effect of polychlorinated biphenyls (PCBs) and 1,1,1-trichloro-2,2,-bis (4-chlorophenyl)-ethane (DDT) in follicular fluid on the results of in vitro fertilization-embryo transfer (IVF-ET) programs. Fertil Steril 93:1831–1836

    Article  CAS  PubMed  Google Scholar 

  • Johnson PI, Altshul L, Cramer DW, Missmer SA, Hauser R, Meeker JD (2012) Serum and follicular fluid concentrations of polybrominated diphenyl ethers and in-vitro fertilization outcome. Environ Int 45:9–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jukic AM, Calafat AM, McConnaughey DR, Longnecker MP, Hoppin JA, Weinberg CR, Wilcox AJ, Baird DD (2015) Urinary concentrations of phthalate metabolites and bisphenol a and associations with follicular-phase length, luteal-phase length, fecundability, and early pregnancy loss. Environ Health Perspect. doi:10.1289/ehp.1408164

    Google Scholar 

  • Jung NK, Park JY, Park JH, Kim SY, Park JK, Chang WK, Lee HC, Kim SW, Chun SY (2010) Attenuation of cell cycle progression by 2,3,7,8-tetrachlorodibenzo-p-dioxin eliciting ovulatory blockade in gonadotropin-primed immature rats. Endocr J 57:863–871

    Article  CAS  PubMed  Google Scholar 

  • Jurisicova A, Taniuchi A, Li H, Shang Y, Antenos M, Detmar J, Xu J, Matikainen T, Benito HA, Nunez G, Casper RF (2007) Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of Harakiri. J Clin Invest 117:3971–3978

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kandaraki E, Chatzigeorgiou A, Livadas S, Palioura E, Economou F, Koutsilieris M, Palimeri S, Panidis D, Diamanti-Kandarakis E (2011) Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab 96:E480–E484

    Article  CAS  PubMed  Google Scholar 

  • Kang KS, Che JH, Ryu DY, Kim TW, Li GX, Lee YS (2002) Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben). J Vet Med Sci 64:227–235

    Article  CAS  PubMed  Google Scholar 

  • Kay VR, Chambers C, Foster WG (2013) Reproductive and developmental effects of phthalate diesters in females. Crit Rev Toxicol 43:200–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kidder GM, Mhawi AA (2002) Gap junctions and ovarian folliculogenesis. Reproduction 123:613–620

    Article  CAS  PubMed  Google Scholar 

  • Kimura N, Kimura T, Suzuki M, Totsukawa K (2006) Effect of gestational exposure to nonylphenol on the development and fertility of mouse offspring. J Reprod Dev 52:789–795

    Article  CAS  PubMed  Google Scholar 

  • Knox SS, Jackson T, Javins B, Frisbee SJ, Shankar A, Ducatman AM (2011) Implications of early menopause in women exposed to perfluorocarbons. J Clin Endocrinol Metab 96:1747–1753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koh JM, Kim CH, Hong SK, Lee KU, Kim YT, Kim OJ, Kim GS (1998) Primary ovarian failure caused by a solvent containing 2-bromopropane. Eur J Endocrinol 138:554–556

    Article  CAS  PubMed  Google Scholar 

  • Koifman S, Koifman RJ, Meyer A (2002) Human reproductive system disturbances and pesticide exposure in Brazil. Cad Saude Publica 18:435–445

    Article  PubMed  Google Scholar 

  • Krotz SP, Carson SA, Tomey C, Buster JE (2012) Phthalates and bisphenol do not accumulate in human follicular fluid. J Assist Reprod Genet 29:773–777

    Article  PubMed  PubMed Central  Google Scholar 

  • Kwintkiewicz J, Nishi Y, Yanase T, Giudice LC (2010) Peroxisome proliferator-activated receptor-gamma mediates bisphenol A inhibition of FSH-stimulated IGF-1, aromatase, and estradiol in human granulosa cells. Environ Health Perspect 118:400–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • La Rocca C, Alessi E, Bergamasco B, Caserta D, Ciardo F, Fanello E, Focardi S, Guerranti C, Stecca L, Moscarini M, Perra G, Tait S, Zaghi C, Mantovani A (2012) Exposure and effective dose biomarkers for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in infertile subjects: preliminary results of the PREVIENI project. Int J Hyg Environ Health 215:206–211

    Article  PubMed  CAS  Google Scholar 

  • Laskey JW, Berman E (1993) Steroidogenic assessment using ovary culture in cycling rats: effects of Bis(2-Diethylhexyl) phthalate on ovarian steroid production. Reprod Toxicol 7:25–33

    Article  CAS  PubMed  Google Scholar 

  • Laughlin N, Bowman R, Franks P, Dierschke D (1987) Altered menstrual cycles in rhesus monkeys induced by lead. Fundam Appl Toxicol 9:722–729

    Article  CAS  PubMed  Google Scholar 

  • Lenie S, Smitz J (2009) Steroidogenesis-disrupting compounds can be effectively studied for major fertility-related endpoints using in vitro cultured mouse follicles. Toxicol Lett 185:143–152

    Article  CAS  PubMed  Google Scholar 

  • Lenie S, Cortvrindt R, Adriaenssens T, Smitz J (2004) A reproducible two-step culture system for isolated primary mouse ovarian follicles as single functional units. Biol Reprod 71:1730–1738

    Article  CAS  PubMed  Google Scholar 

  • Li TY, Colley D, Barr KJ, Yee SP, Kidder GM (2007) Rescue of oogenesis in Cx37-null mutant mice by oocyte-specific replacement with Cx43. J Cell Sci 120:4117–4125

    Article  CAS  PubMed  Google Scholar 

  • Mahalingaiah S, Missmer SA, Maity A, Williams PL, Meeker JD, Berry K, Ehrlich S, Perry MJ, Cramer DW, Hauser R (2012) Association of hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) with in vitro fertilization (IVF) outcomes. Environ Health Perspect 120:316–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Markey CM, Coombs MA, Sonnenschein C, Soto AM (2003) Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs. Evol Dev 5:67–75

    Article  CAS  PubMed  Google Scholar 

  • Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA (2012) National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med 9:e1001356

    Article  PubMed  PubMed Central  Google Scholar 

  • Masutomi N, Shibutani M, Takagi H, Uneyama C, Takahashi N, Hirose M (2003) Impact of dietary exposure to methoxychlor, genistein, or diisononyl phthalate during the perinatal period on the development of the rat endocrine/reproductive systems in later life. Toxicology 192:149–170

    Article  CAS  PubMed  Google Scholar 

  • Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, Laine J, Sakai T, Korsmeyer SJ, Casper RF, Sherr DH, Tilly JL (2001) Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet 28:355–360

    Article  CAS  PubMed  Google Scholar 

  • Meeker JD, Missmer SA, Altshul L, Vitonis AF, Ryan L, Cramer DW, Hauser R (2009) Serum and follicular fluid organochlorine concentrations among women undergoing assisted reproduction technologies. Environ Health 8:32

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mlynarcikova A, Kolena J, Fickova M, Scsukova S (2005) Alterations in steroid hormone production by porcine ovarian granulosa cells caused by bisphenol A and bisphenol A dimethacrylate. Mol Cell Endocrinol 244:57–62

    Article  CAS  PubMed  Google Scholar 

  • Mlynarcikova A, Fickova M, Scsukova S (2007) The effects of selected phenol and phthalate derivatives on steroid hormone production by cultured porcine granulosa cells. Altern Lab Anim 35:71–77

    CAS  PubMed  Google Scholar 

  • Mlynarcikova A, Nagyova E, Fickova M, Scsukova S (2009) Effects of selected endocrine disruptors on meiotic maturation, cumulus expansion, synthesis of hyaluronan and progesterone by porcine oocyte-cumulus complexes. Toxicol In Vitro 23:371–377

    Article  CAS  PubMed  Google Scholar 

  • Nagao T, Saito Y, Usumi K, Nakagomi M, Yoshimura S, Ono H (2000) Disruption of the reproductive system and reproductive performance by administration of nonylphenol to newborn rats. Hum Exp Toxicol 19:284–296

    Article  CAS  PubMed  Google Scholar 

  • Neal MS, Zhu J, Holloway AC, Foster WG (2007) Follicle growth is inhibited by benzo-[a]-pyrene, at concentrations representative of human exposure, in an isolated rat follicle culture assay. Hum Reprod 22:961–967

    Article  CAS  PubMed  Google Scholar 

  • Neal MS, Zhu J, Foster WG (2008) Quantification of benzo[a]pyrene and other PAHs in the serum and follicular fluid of smokers versus non-smokers. Reprod Toxicol 25:100–106

    Article  CAS  PubMed  Google Scholar 

  • Neal MS, Mulligan Tuttle AM, Casper RF, Lagunov A, Foster WG (2010) Aryl hydrocarbon receptor antagonists attenuate the deleterious effects of benzo[a]pyrene on isolated rat follicle development. Reprod Biomed Online 21:100–108

    Article  CAS  PubMed  Google Scholar 

  • Nilsson E, Larsen G, Manikkam M, Guerrero-Bosagna C, Savenkova MI, Skinner MK (2012) Environmentally induced epigenetic transgenerational inheritance of ovarian disease. PLoS One 7:e36129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel S, Bajpayee M, Pandey AK, Parmar D, Dhawan A (2007) In vitro induction of cytotoxicity and DNA strand breaks in CHO cells exposed to cypermethrin, pendimethalin and dichlorvos. Toxicol In Vitro 21:1409–1418

    Article  CAS  PubMed  Google Scholar 

  • Petro EM, Leroy JL, Covaci A, Fransen E, De ND, Dirtu AC, De PI, Bols PE (2012) Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence. Hum Reprod 27:1025–1033

    Article  CAS  PubMed  Google Scholar 

  • Petro EM, D’Hollander W, Covaci A, Bervoets L, Fransen E, De Neubourg D, De Pauw I, Leroy JL, Jorssen EP, Bols PE (2014) Perfluoroalkyl acid contamination of follicular fluid and its consequence for in vitro oocyte developmental competence. Sci Total Environ 496:282–288

    Article  CAS  PubMed  Google Scholar 

  • Pocar P, Brevini TA, Fischer B, Gandolfi F (2003) The impact of endocrine disruptors on oocyte competence. Reproduction 125:313–325

    Article  CAS  PubMed  Google Scholar 

  • Pollack AZ, Schisterman EF, Goldman LR, Mumford SL, Albert PS, Jones RL, Wactawski-Wende J (2011) Cadmium, lead, and mercury in relation to reproductive hormones and anovulation in premenopausal women. Environ Health Perspect 119:1156–1161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ptak A, Ludewig G, Robertson L, Lehmler HJ, Gregoraszczuk EL (2006) In vitro exposure of porcine prepubertal follicles to 4-chlorobiphenyl (PCB3) and its hydroxylated metabolites: effects on sex hormone levels and aromatase activity. Toxicol Lett 164:113–122

    Article  CAS  PubMed  Google Scholar 

  • Quignot N, Arnaud M, Robidel F, Lecomte A, Tournier M, Cren-Olive C, Barouki R, Lemazurier E (2012a) Characterization of endocrine-disrupting chemicals based on hormonal balance disruption in male and female adult rats. Reprod Toxicol 33:339–352

    Article  CAS  PubMed  Google Scholar 

  • Quignot N, Tournier M, Pouech C, Cren-Olive C, Barouki R, Lemazurier E (2012b) Quantification of steroids and endocrine disrupting chemicals in rat ovaries by LC-MS/MS for reproductive toxicology assessment. Anal Bioanal Chem 403:1629–1640

    Article  CAS  PubMed  Google Scholar 

  • Reinsberg J, Wegener-Toper P, van der Ven K, van der Ven H, Klingmueller D (2009) Effect of mono-(2-ethylhexyl) phthalate on steroid production of human granulosa cells. Toxicol Appl Pharmacol 239:116–123

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez HA, Santambrosio N, Santamaria CG, Munoz-de-Toro M, Luque EH (2010) Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary. Reprod Toxicol 30:550–557

    Article  CAS  PubMed  Google Scholar 

  • Rosenmai AK, Dybdahl M, Pedersen M, Alice van Vugt-Lussenburg BM, Wedebye EB, Taxvig C, Vinggaard AM (2014) Are structural analogues to bisphenol a safe alternatives? Toxicol Sci 139:35–47

    Article  CAS  PubMed  Google Scholar 

  • Rutstein SO, Shah IH (2004) Infecundity, infertility, and childlessness in developing countries. ORC Macro, Calverton

    Google Scholar 

  • Sadeu JC, Foster WG (2011a) Cigarette smoke condensate exposure delays follicular development and function in a stage-dependent manner. Fertil Steril 95:2410–2417

    Article  CAS  PubMed  Google Scholar 

  • Sadeu JC, Foster WG (2011b) Effect of in vitro exposure to Benzo[a]pyrene, a component of cigarette smoke, on folliculogenesis, steroidogenesis, and oocyte maturation. Reprod Toxicol 31:402–408

    Article  CAS  PubMed  Google Scholar 

  • Sadeu JC, Hughes CL, Agarwal S, Foster WG (2010) Alcohol, drugs, caffeine, tobacco, and environmental contaminant exposure: reproductive health consequences and clinical implications. Crit Rev Toxicol 40:633–652

    Article  CAS  PubMed  Google Scholar 

  • Sahambi SK, Visser JA, Themmen AP, Mayer LP, Devine PJ (2008) Correlation of serum anti-Mullerian hormone with accelerated follicle loss following 4-vinylcyclohexene diepoxide-induced follicle loss in mice. Reprod Toxicol 26:116–122

    Article  CAS  PubMed  Google Scholar 

  • Schlebusch H, Wagner U, van der Ven H, Al-Hasani S, Diedrich K, Krebs D (1989) Polychlorinated biphenyls: the occurrence of the main congeners in follicular and sperm fluids. J Clin Chem Clin Biochem 27:663–667

    CAS  PubMed  Google Scholar 

  • Shi Z, Valdez KE, Ting AY, Franczak A, Gum SL, Petroff BK (2007) Ovarian endocrine disruption underlies premature reproductive senescence following environmentally relevant chronic exposure to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biol Reprod 76:198–202

    Article  CAS  PubMed  Google Scholar 

  • Signorile PG, Spugnini EP, Citro G, Viceconte R, Vincenzi B, Baldi F, Baldi A (2012) Endocrine disruptors in utero cause ovarian damages linked to endometriosis. Front Biosci (Elite Ed) 4:1724–1730

    Article  Google Scholar 

  • Silva MJ, Slakman AR, Reidy JA, Preau JL Jr, Herbert AR, Samandar E, Needham LL, Calafat AM (2004) Analysis of human urine for fifteen phthalate metabolites using automated solid-phase extraction. J Chromatogr B Analyt Technol Biomed Life Sci 805:161–167

    Article  CAS  PubMed  Google Scholar 

  • Smith KW, Souter I, Dimitriadis I, Ehrlich S, Williams PL, Calafat AM, Hauser R (2013) Urinary paraben concentrations and ovarian aging among women from a fertility center. Environ Health Perspect 121:1299–1305

    Article  PubMed  PubMed Central  Google Scholar 

  • Sobinoff AP, Pye V, Nixon B, Roman SD, McLaughlin EA (2010) Adding insult to injury: effects of xenobiotic-induced preantral ovotoxicity on ovarian development and oocyte fusibility. Toxicol Sci 118:653–666

    Article  CAS  PubMed  Google Scholar 

  • Songsasen N, Woodruff TK, Wildt DE (2011) In vitro growth and steroidogenesis of dog follicles are influenced by the physical and hormonal microenvironment. Reproduction 142:113–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stephen EH, Chandra A (2006) Declining estimates of infertility in the United States: 1982–2002. Fertil Steril 86:516–523

    Article  PubMed  Google Scholar 

  • Sun F, Betzendahl I, Shen Y, Cortvrindt R, Smitz J, Eichenlaub-Ritter U (2004) Preantral follicle culture as a novel in vitro assay in reproductive toxicology testing in mammalian oocytes. Mutagenesis 19:13–25

    Article  CAS  PubMed  Google Scholar 

  • Takai Y, Canning J, Perez GI, Pru JK, Schlezinger JJ, Sherr DH, Kolesnick RN, Yuan J, Flavell RA, Korsmeyer SJ, Tilly JL (2003) Bax, caspase-2, and caspase-3 are required for ovarian follicle loss caused by 4-vinylcyclohexene diepoxide exposure of female mice in vivo. Endocrinology 144:69–74

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi T, Tsutsumi O, Ikezuki Y, Takai Y, Taketani Y (2004) Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocr J 51:165–169

    Article  CAS  PubMed  Google Scholar 

  • 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 106:206–213

    Article  CAS  PubMed  Google Scholar 

  • Tian Y, Ke S, Thomas T, Meeker RJ, Gallo MA (1998) Regulation of estrogen receptor mRNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin as measured by competitive RT-PCR. J Biochem Mol Toxicol 12:71–77

    Article  CAS  PubMed  Google Scholar 

  • Trapp M, Baukloh V, Bohnet H-G, Heeschen W (1984) Pollutants in human follicular fluid. Fertil Steril 42(1):146–148

    CAS  PubMed  Google Scholar 

  • Treinen KA, Dodson WC, Heindel JJ (1990) Inhibition of FSH-stimulated cAMP accumulation and progesterone production by mono(2-ethylhexyl) phthalate in rat granulosa cell cultures. Toxicol Appl Pharmacol 106:334–340

    Article  CAS  PubMed  Google Scholar 

  • Tsutsumi O (2005) Assessment of human contamination of estrogenic endocrine-disrupting chemicals and their risk for human reproduction. J Steroid Biochem Mol Biol 93:325–330

    Article  CAS  PubMed  Google Scholar 

  • Uzumcu M, Kuhn PE, Marano JE, Armenti AE, Passantino L (2006) Early postnatal methoxychlor exposure inhibits folliculogenesis and stimulates anti-Mullerian hormone production in the rat ovary. J Endocrinol 191:549–558

    Article  CAS  PubMed  Google Scholar 

  • Valdez KE, Shi Z, Ting AY, Petroff BK (2009) Effect of chronic exposure to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin in female rats on ovarian gene expression. Reprod Toxicol 28:32–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Wemmel K, Gobbers E, Eichenlaub-Ritter U, Smitz J, Cortvrindt R (2005) Ovarian follicle bioassay reveals adverse effects of diazepam exposure upon follicle development and oocyte quality. Reprod Toxicol 20:183–193

    Article  PubMed  CAS  Google Scholar 

  • Vo TT, Yoo YM, Choi KC, Jeung EB (2010) Potential estrogenic effect(s) of parabens at the prepubertal stage of a postnatal female rat model. Reprod Toxicol 29:306–316

    Article  CAS  PubMed  Google Scholar 

  • Weiss JM, Bauer O, Bluthgen A, Ludwig AK, Vollersen E, Kaisi M, Al-Hasani S, Diedrich K, Ludwig M (2006) Distribution of persistent organochlorine contaminants in infertile patients from Tanzania and Germany. J Assist Reprod Genet 23:393–399

    Article  PubMed  PubMed Central  Google Scholar 

  • Willoughby KN, Sarkar AJ, Boyadjieva NI, Sarkar DK (2005) Neonatally administered tert-octylphenol affects onset of puberty and reproductive development in female rats. Endocrine 26:161–168

    Article  CAS  PubMed  Google Scholar 

  • Windham GC, Mitchell P, Anderson M, Lasley BL (2005) Cigarette smoking and effects on hormone function in premenopausal women. Environ Health Perspect 113:1285–1290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong SL, Lye EJ (2008) Lead, mercury and cadmium levels in Canadians. Health Rep 19:31–36

    PubMed  Google Scholar 

  • Xi W, Lee CK, Yeung WS, Giesy JP, Wong MH, Zhang X, Hecker M, Wong CK (2011) Effect of perinatal and postnatal bisphenol A exposure to the regulatory circuits at the hypothalamus-pituitary-gonadal axis of CD-1 mice. Reprod Toxicol 31:409–417

    Article  CAS  PubMed  Google Scholar 

  • Yang JM, Chen QY, Jiang XZ (2002) Effects of metallic mercury on the perimenstrual symptoms and menstrual outcomes of exposed workers. Am J Ind Med 42:403–409

    Article  CAS  PubMed  Google Scholar 

  • Yin S, Song C, Wu H, Chen X, Zhang Y (2015) Adverse effects of high concentrations of fluoride on characteristics of the ovary and mature oocyte of mouse. PLoS One 10:e0129594

    Article  PubMed  PubMed Central  Google Scholar 

  • Younglai EV, Foster WG, Hughes EG, Trim K, Jarrell JF (2002) Levels of environmental contaminants in human follicular fluid, serum, and seminal plasma of couples undergoing in vitro fertilization. Arch Environ Contam Toxicol 43:121–126

    Article  CAS  PubMed  Google Scholar 

  • Zachow R, Uzumcu M (2006) The methoxychlor metabolite, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane, inhibits steroidogenesis in rat ovarian granulosa cells in vitro. Reprod Toxicol 22:659–665

    Article  CAS  PubMed  Google Scholar 

  • Zama AM, Uzumcu M (2009) Fetal and neonatal exposure to the endocrine disruptor methoxychlor causes epigenetic alterations in adult ovarian genes. Endocrinology 150:4681–4691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zama AM, Uzumcu M (2010) Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective. Front Neuroendocrinol 31:420–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W, Jia H (2007) Effect and mechanism of cadmium on the progesterone synthesis of ovaries. Toxicology 239:204–212

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Pang F, Huang Y, Yan P, Lin W (2008) Cadmium exerts toxic effects on ovarian steroid hormone release in rats. Toxicol Lett 182:18–23

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Warren G. Foster .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Dominguez, M.A., Sadeu, J.C., Guerra, M.T., Furlong, H.C., Baines, S., Foster, W.G. (2016). Ovarian Toxicity of Environmental Contaminants: 50 Shades of Grey. In: Hughes, C., Waters, M. (eds) Translational Toxicology. Molecular and Integrative Toxicology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-27449-2_7

Download citation

Publish with us

Policies and ethics