EXPOsOMICs: Meet-in-the-Middle and Network Perturbation

  • Christiana A. Demetriou
  • Davide Degli Esposti
  • Kristi Pullen Fedinick
  • Paolo VineisEmail author


Systems biology has been driven by technology (the development of omics) and by statistical modelling and bioinformatics. We aim to bring biological thinking back. We suggest that three traditions of thought need to be considered: (a) causality in epidemiology, for example the “sufficient-component-cause framework”, and causality in other sciences, for example the Salmon and Dowe approach; (b) new acquisitions about disease pathogenesis, for example the “branched evolution model” in cancer, and the role of biomarkers in this process; (c) the burgeoning of omic research, with a large number of “signals” that need to be interpreted. To address the new challenges of epidemiology, the concept of the “exposome” has been proposed. We show examples from recent projects in the field, namely, new omic approaches applied to epidemiological studies; and in particular, the identification of hallmarks of cancer as intermediate steps between exposure to carcinogens and the cancer phenotype, according to the “meet-in-the-middle” concept. We use examples derived from the study of mutational spectra in tumours and benzo(a)pyrene and bisphenol A as model carcinogens. We suggest conceptualising the detection and tracing of signals in terms of information transmission.


Epidemiology Adductomics Evidential pluralism Information transition 

Supplementary material

432672_1_En_14_MOESM1_ESM.docx (3.3 mb)
Online Supplementary Table S1 Studies investigating BPA’s direct effects on at least one of the eight hallmarks of cancer


  1. Allard P, Colaiácovo MP (2010) Bisphenol A impairs the double-strand break repair machinery in the germline and causes chromosome abnormalities. Proc Natl Acad Sci U S A 107(47):20405–20410. Scholar
  2. Andreescu S, Sadik OA, McGee DW (2005) Effect of natural and synthetic estrogens on A549 lung cancer cells: correlation of chemical structures with cytotoxic effects. Chem Res Toxicol 18(3):466–474. Scholar
  3. Andrysík Z, Vondrácek J, Machala M, Krcmár P, Svihálková-Sindlerová L, Kranz A, Weiss C, Faust D, Kozubík A, Dietrich C (2007) The aryl hydrocarbon receptor-dependent deregulation of cell cycle control induced by polycyclic aromatic hydrocarbons in rat liver epithelial cells. Mutat Res 615:87–97. Scholar
  4. Aschengrau A, Coogan PF, Quinn M, Cashins LJ (1998) Occupational exposure to estrogenic chemicals and the occurrence of breast cancer: an exploratory analysis. Am J Ind Med 34(1):6–14CrossRefGoogle Scholar
  5. Ayyanan A, Laribi O, Schuepbach-Mallepell S, Schrick C, Gutierrez M, Tanos T, Lefebvre G, Rougemont J, Yalcin-Ozuysal Ö, Brisken C (2011) Perinatal exposure to bisphenol A increases adult mammary gland progesterone response and cell number. Mol Endocrinol 25(11):1915–1923. Scholar
  6. Ba Q, Li J, Huang C, Qiu H, Li J, Chu R, Zhang W, Xie D, Wu Y, Wang H (2014) Effects of benzo[a]pyrene exposure on human hepatocellular carcinoma cell angiogenesis, metastasis, and NF-κB signaling. Environ Health Perspect 123:246–254. Scholar
  7. Baird WM, Hooven LA, Mahadevan B (2005) Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action. Environ Mol Mutagen 45:106–114. Scholar
  8. Beerenwinkel N, Antal T, Dingli D, Traulsen A, Kinzler KW, Velculescu VE, Vogelstein B, Nowak MA (2007) Genetic progression and the waiting time to cancer. PLoS Comput Biol 3(11):e225. Scholar
  9. Bergeron RM, Thompson TB, Leonard LS, Pluta L, Gaido KW (1999) Estrogenicity of bisphenol A in a human endometrial carcinoma cell line. Mol Cell Endocrinol 150(1–2):179–187. Scholar
  10. Betancourt AM, Eltoum IA, Desmond RA, Russo J, Lamartiniere CA (2010a) In utero exposure to bisphenol A shifts the window of susceptibility for mammary carcinogenesis in the rat. Environ Health Perspect 118(11):1614–1619. Scholar
  11. Betancourt AM, Mobley JA, Russo J, Lamartiniere CA (2010b) Proteomic analysis in mammary glands of rat offspring exposed in utero to bisphenol A. J Proteome 73(6):1241–1253. Scholar
  12. Betancourt AM, Wang J, Jenkins S, Mobley J, Russo J, Lamartiniere CA (2012) Altered carcinogenesis and proteome in mammary glands of rats after prepubertal exposures to the hormonally active chemicals bisphenol A and genistein. J Nutr 142(7):1382S–1388S. Scholar
  13. Betancourt A, Mobley JA, Wang J, Jenkins S, Chen D, Kojima K, Russo J, Lamartiniere CA (2014) Alterations in the rat serum proteome induced by prepubertal exposure to bisphenol A and genistein. J Proteome Res 13(3):1502–1514. Scholar
  14. Bhan A, Hussain I, Ansari KI, Bobzean SA, Perrotti LI, Mandal SS (2014) Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo. J Steroid Biochem Mol Biol 141:160–170. Scholar
  15. “Bisphenol A (BPA)” (2016). Accessed 19 Sept
  16. Boehme K, Simon S, Mueller SO (2009) Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol 236(1):85–96. Scholar
  17. Bontempo P, Mita L, Doto A, Miceli M, Nebbioso A, Lepore I, Franci GL et al (2009) Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells. J Transl Med 7:48. Scholar
  18. Bouskine A, Nebout M, Brücker-Davis F, Benahmed M, Fenichel P (2009) Low doses of bisphenol A promote human seminoma cell proliferation by activating PKA and PKG via a membrane G-protein-coupled estrogen receptor. Environ Health Perspect 117(7):1053–1058. Scholar
  19. Buteau-Lozano H, Velasco G, Cristofari M, Balaguer P, Perrot-Applanat M (2008) Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism. J Endocrinol 196(2):399–412. Scholar
  20. Buterin T, Koch C, Naegeli H (2006) Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis 27(8):1567–1578. Scholar
  21. Carnero A, Blanco-Aparicio C, Kondoh H, Lleonart ME, Martinez-Leal JF, Mondello C, Scovassi AI et al (2015) Disruptive chemicals, senescence and immortality. Carcinogenesis 36(Suppl 1):S19–S37. Scholar
  22. Castillo Sanchez R, Gomez R, Perez Salazar E (2016) Bisphenol A induces migration through a GPER-, FAK-, Src-, and ERK2-dependent pathway in MDA-MB-231 breast cancer cells. Chem Res Toxicol 29(3):285–295. Scholar
  23. Castillo-Sanchez R, Villegas-Comonfort S, Galindo-Hernandez O, Gomez R, Salazar EP (2013) Benzo-[a]-pyrene induces FAK activation and cell migration in MDA-MB-231 breast cancer cells. Cell Biol Toxicol 29:303–319. Scholar
  24. Chappell G, Pogribny IP, Guyton KZ, Rusyn I (2016) Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: a systematic literature review. Mutat Res Rev Mutat Res 768:27–45. Scholar
  25. Charles GD, Bartels MJ, Zacharewski TR, Gollapudi BB, Freshour NL, Carney EW (2000) Activity of benzo[a]pyrene and its hydroxylated metabolites in an estrogen receptor-alpha reporter gene assay. Toxicol Sci 55:320–326CrossRefGoogle Scholar
  26. Chen Z-J, Yang X-L, Liu H, Wei W, Zhang K-S, Huang H-B, Giesy JP, Liu H-L, Du J, Wang H-S (2015) Bisphenol A modulates colorectal cancer protein profile and promotes the metastasis via induction of epithelial to mesenchymal transitions. Arch Toxicol 89(8):1371–1381. Scholar
  27. Chun TY, Gorski J (2000) High concentrations of bisphenol A induce cell growth and prolactin secretion in an estrogen-responsive pituitary tumor cell line. Toxicol Appl Pharmacol 162(3):161–165. Scholar
  28. Colerangle JB, Roy D (1997) Profound effects of the weak environmental estrogen-like chemical bisphenol A on the growth of the mammary gland of noble rats. J Steroid Biochem Mol Biol 60(1–2):153–160CrossRefGoogle Scholar
  29. Dairkee SH, Seok J, Champion S, Sayeed A, Mindrinos M, Xiao W, Davis RW, Goodson WH (2008) Bisphenol A induces a profile of tumor aggressiveness in high-risk cells from breast cancer patients. Cancer Res 68(7):2076–2080. Scholar
  30. Dairkee SH, Gloria Luciani-Torres M, Moore DH, Goodson WH (2013) Bisphenol-A-induced inactivation of the p53 axis underlying deregulation of proliferation kinetics, and cell death in non-malignant human breast epithelial cells. Carcinogenesis 34(3):703–712. Scholar
  31. De Flora S, Micale RT, La Maestra S, Izzotti A, D’Agostini F, Camoirano A, Davoli SA et al (2011) Upregulation of clusterin in prostate and DNA damage in spermatozoa from bisphenol A-treated rats and formation of DNA adducts in cultured human prostatic cells. Toxicol Sci 122(1):45–51. Scholar
  32. De Jong WH, Kroese ED, Vos JG, Van Loveren H (1999) Detection of immunotoxicity of benzo[a]pyrene in a subacute toxicity study after oral exposure in rats. Toxicol Sci 50:214–220CrossRefGoogle Scholar
  33. Dean JH, Luster MI, Boorman GA, Lauer LD, Leubke RW, Lawson L (1983) Selective immunosuppression resulting from exposure to the carcinogenic congener of benzopyrene in B6C3F1 mice. Clin Exp Immunol 52:199–206Google Scholar
  34. Deb P, Bhan A, Hussain I, Ansari KI, Bobzean SA, Pandita TK, Perrotti LI, Mandal SS (2016) Endocrine disrupting chemical, bisphenol-A, induces breast cancer associated gene HOXB9 expression in vitro and in vivo. Gene 590(2):234–243. Scholar
  35. Dhimolea E, Wadia PR, Murray TJ, Settles ML, Treitman JD, Sonnenschein C, Shioda T, Soto AM (2014) Prenatal exposure to BPA alters the epigenome of the rat mammary gland and increases the propensity to neoplastic development. PLoS One 9(7):e99800. Scholar
  36. Diel P, Olff S, Schmidt S, Michna H (2002) Effects of the environmental estrogens bisphenol A, O,p′-DDT, P-tert-octylphenol and coumestrol on apoptosis induction, cell proliferation and the expression of estrogen sensitive molecular parameters in the human breast cancer cell line MCF-7. J Steroid Biochem Mol Biol 80(1):61–70. Scholar
  37. Doherty LF, Bromer JG, Zhou Y, Aldad TS, Taylor HS (2010) In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer 1(3):146–155. Scholar
  38. Dong S, Terasaka S, Kiyama R (2011) Bisphenol A induces a rapid activation of Erk1/2 through GPR30 in human breast cancer cells. Environ Pollut 159(1):212–218. Scholar
  39. Dong Y, Araki M, Hirane M, Tanabe E, Fukushima N, Tsujiuchi T (2014) Effects of bisphenol A and 4-nonylphenol on cellular responses through the different induction of LPA receptors in liver epithelial WB-F344 cells. J Recept Signal Transduct Res 34(3):201–204. Scholar
  40. Du HJ, Tang N, Liu BC, You BR, Shen FH, Ye M, Gao A, Huang C (2006) Benzo[a]pyrene-induced cell cycle progression is through ERKs/cyclin D1 pathway and requires the activation of JNKs and p38 mapk in human diploid lung fibroblasts. Mol Cell Biochem 287:79–89. Scholar
  41. Duan B, Xuebin H, Zhao H, Qin J, Luo J (2013) The relationship between urinary bisphenol A levels and meningioma in chinese adults. Int J Clin Oncol 18(3):492–497. Scholar
  42. Engström W, Darbre P, Eriksson S, Gulliver L, Hultman T, Karamouzis MV, Klaunig JE, Mehta R, Moorwood K, Sanderson T, Sone H, Vadgama P, Wagemaker G, Ward A, Singh N, Al-Mulla F, Al-Temaimi R, Amedei A, Colacci AM, Vaccari M, Mondello C, Scovassi AI, Raju J, Hamid RA, Memeo L, Forte S, Roy R, Woodrick J, Salem HK, Ryan EP, Brown DG, Bisson WH (2015) The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling. Carcinogenesis 36(Suppl 1):S38–S60. Scholar
  43. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767CrossRefGoogle Scholar
  44. Fernandez SV, Huang Y, Snider KE, Zhou Y, Pogash TJ, Russo J (2012) Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol 41(1):369–377. Scholar
  45. Fic A, Jurković Mlakar S, Juvan P, Mlakar V, Marc J, Sollner Dolenc M, Broberg K, Peterlin Mašič L (2015) Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro 29(5):1060–1069. Scholar
  46. Fiorito G, Vlaanderen J, Polidoro S, Gulliver J, Galassi C, Ranzi A, Krogh V, Grioni S, Agnoli C, Sacerdote C, Panico S, Tsai MY, Probst-Hensch N, Hoek G, Herceg Z, Vermeulen R, Ghantous A, Vineis P, Naccarati A, EXPOsOMICS Consortium (2017) Oxidative stress and inflammation mediate the effect of air pollution on cardio- and cerebrovascular disease: a prospective study in nonsmokers. Environ Mol Mutagen 59(3):234–246. Scholar
  47. Fischer C, Mamillapalli R, Goetz LG, Jorgenson E, Ilagan Y, Taylor HS (2016) Bisphenol A (BPA) exposure in utero leads to immunoregulatory cytokine dysregulation in the mouse mammary gland: a potential mechanism programming breast cancer risk. Horm Cancer 7(4):241–251. Scholar
  48. Gao M, Long J, Li Y, Shah W, Fu L, Liu J, Wang Y (2010) Mitochondrial decay is involved in BaP-induced cervical damage. Free Radic Biol Med 49:1735–1745. Scholar
  49. Gassman NR, Coskun E, Stefanick DF, Horton JK, Jaruga P, Dizdaroglu M, Wilson SH (2015) Bisphenol A promotes cell survival following oxidative DNA damage in mouse fibroblasts. PLoS One 10(2):e0118819. Scholar
  50. Ge L-C, Chen Z-J, Liu H-Y, Zhang K-S, Liu H, Huang H-B, Zhang G et al (2014a) Involvement of activating ERK1/2 through G protein coupled receptor 30 and estrogen receptor α/β in low doses of bisphenol A promoting growth of sertoli TM4 cells. Toxicol Lett 226(1):81–89. Scholar
  51. Ge L-C, Chen Z-J, Liu H, Zhang K-S, Su Q, Ma X-Y, Huang H-B et al (2014b) Signaling related with biphasic effects of bisphenol A (BPA) on sertoli cell proliferation: a comparative proteomic analysis. Biochim Biophys Acta 1840(9):2663–2673. Scholar
  52. Gerlinger M, McGranahan N, Dewhurst SM, Burrell RA, Tomlinson I, Swanton C (2014) Cancer: evolution within a lifetime. Annu Rev Genet 48:215–236. Scholar
  53. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892. Scholar
  54. Gerstung M, Eriksson N, Lin J, Vogelstein B, Beerenwinkel N (2011) The temporal order of genetic and pathway alterations in tumorigenesis. PLoS One 6(11):e27136. Scholar
  55. Gertz J, Reddy TE, Varley KE, Garabedian MJ, Myers RM (2012) Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res 22(11):2153–2162. Scholar
  56. Ginsberg GL, Atherholt TB, Butler GH (1989) Benzo[a]pyrene-induced immunotoxicity: comparison to DNA adduct formation in vivo, in cultured splenocytes, and in microsomal systems. J Toxicol Environ Health 28:205–220. Scholar
  57. Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A et al (2015) Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 36(Suppl 1):S254–S296CrossRefGoogle Scholar
  58. Goodson WH, Luciani MG, Aejaz Sayeed S, Jaffee IM, Moore DH, Dairkee SH (2011) Activation of the mTOR pathway by low levels of xenoestrogens in breast epithelial cells from high-risk women. Carcinogenesis 32(11):1724–1733. Scholar
  59. Gould JC, Leonard LS, Maness SC, Wagner BL, Conner K, Zacharewski T, Safe S, McDonnell DP, Gaido KW (1998) Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. Mol Cell Endocrinol 142(1–2):203–214CrossRefGoogle Scholar
  60. Grassi TF, da Silva GN, Bidinotto LT, Rossi BF, Quinalha MM, Kass L, Muñoz-de-Toro M, Barbisan LF (2016) Global gene expression and morphological alterations in the mammary gland after gestational exposure to bisphenol A, genistein and indole-3-carbinol in female Sprague-Dawley offspring. Toxicol Appl Pharmacol 303:101–109. Scholar
  61. Greathouse KL, Bredfeldt T, Everitt JI, Lin K, Berry T, Kannan K, Mittelstadt ML, Ho S-m, Walker CL (2012) Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res 10(4):546–557. Scholar
  62. Gudjonsson T, Villadsen R, Rønnov-Jessen L, Petersen OW (2004) Immortalization protocols used in cell culture models of human breast morphogenesis. Cell Mol Life Sci 61(19-20):2523–2534. Scholar
  63. Hall JM, Korach KS (2013) Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis. Mol Carcinog 52(9):715–725. Scholar
  64. Hamouchene H, Arlt VM, Giddings I, Phillips DH (2011) Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics 12:333. Scholar
  65. Han D, Tachibana H, Yamada K (2001) Inhibition of environmental estrogen-induced proliferation of human breast carcinoma MCF-7 cells by flavonoids. In Vitro Cell Dev Biol Anim 37(5):275–282Google Scholar
  66. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364CrossRefGoogle Scholar
  67. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70CrossRefGoogle Scholar
  68. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674CrossRefGoogle Scholar
  69. Hanna CW, Bloom MS, Robinson WP, Kim D, Parsons PJ, vom Saal FS, Taylor JA, Steuerwald AJ, Fujimoto VY (2012) DNA methylation changes in whole blood is associated with exposure to the environmental contaminants, mercury, lead, cadmium and bisphenol A, in women undergoing ovarian stimulation for IVF. Hum Reprod 27(5):1401–1410. Scholar
  70. Hanrahan V, Currie MJ, Gunningham SP, Morrin HR, Scott PAE, Robinson BA, Fox SB (2003) The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression. J Pathol 200(2):183–194. Scholar
  71. Harbst K, Lauss M, Cirenajwis H, Isaksson K, Rosengren F, Torngren T, Kvist A et al (2016) Multi-region whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma. Cancer Res 76(16):4765–4774. Scholar
  72. Hayes L, Weening A, Morey LM (2016) Differential effects of estradiol and bisphenol A on SET8 and SIRT1 expression in ovarian cancer cells. Dose Response 14(2):1559325816640682. Scholar
  73. Hess-Wilson JK, Boldison J, Weaver KE, Knudsen KE (2006) Xenoestrogen action in breast cancer: impact on ER-dependent transcription and mitogenesis. Breast Cancer Res Treat 96(3):279–292. Scholar
  74. Hiroi H, Tsutsumi O, Takeuchi T, Momoeda M, Ikezuki Y, Okamura A, Yokota H, Taketani Y (2004) Differences in serum bisphenol A concentrations in premenopausal normal women and women with endometrial hyperplasia. Endocr J 51(6):595–600CrossRefGoogle Scholar
  75. Ho S-M, Cheong A, Lam H-M, Wen-Yang H, Shi G-B, Zhu X, Chen J et al (2015) Exposure of human prostaspheres to bisphenol A epigenetically regulates SNORD family noncoding RNAs via histone modification. Endocrinology 156(11):3984–3995. Scholar
  76. Hu W, Feng Z, Tang M-S (2003) Preferential carcinogen-DNA adduct formation at codons 12 and 14 in the human K-ras gene and their possible mechanisms. Biochemistry 42:10012–10023. Scholar
  77. Hussain I, Bhan A, Ansari KI, Deb P, Bobzean SAM, Perrotti LI, Mandal SS (2015) Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox-containing gene associated with breast cancer. Biochim Biophys Acta 1849(6):697–708. Scholar
  78. Hwang K-A, Park S-H, Yi B-R, Choi K-C (2011) Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol A using microarray analysis. Lab Anim Res 27(2):99–107. Scholar
  79. Hwang K-A, Kang N-H, Yi B-R, Lee H-R, Park M-A, Choi K-C (2013) Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17β-estradiol or bisphenol A via the inhibition of cell cycle progression. Int J Oncol 42(2):733–740. Scholar
  80. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2010) Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures. IARC Monogr Eval Carcinog Risks Hum 92:1–853Google Scholar
  81. Ibrahim MAA, Elbakry RH, Bayomy NA (2016) Effect of bisphenol A on morphology, apoptosis and proliferation in the resting mammary gland of the adult albino rat. Int J Exp Pathol 97(1):27–36. Scholar
  82. Ichihara T, Yoshino H, Imai N, Tsutsumi T, Kawabe M, Tamano S, Inaguma S, Suzuki S, Shirai T (2003) Lack of carcinogenic risk in the prostate with transplacental and lactational exposure to bisphenol A in rats. J Toxicol Sci 28(3):165–171CrossRefGoogle Scholar
  83. International Agency for Research on Cancer, Weltgesundheitsorganisation (Ed) (2012) IARC monographs on the evaluation of carcinogenic risks to humans, volume 100 F, chemical agents and related occupations: this publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 20–27 October 2009. IARC, LyonGoogle Scholar
  84. Ishido M (2004) Transient inhibition of synergistically insulin-like growth factor-1- and bisphenol A-induced poliferation of estrogen receptor alpha (ERalpha)-positive human breast cancer MCF-7 cells by melatonin. Environ Sci 11(3):163–170Google Scholar
  85. Ito Y, Koessler T, Ibrahim AEK, Rai S, Vowler SL, Abu-Amero S, Silva A-L et al (2008) Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer. Hum Mol Genet 17(17):2633–2643. Scholar
  86. Izzotti A, Kanitz S, D’Agostini F, Camoirano A, De Flora S (2009) Formation of adducts by bisphenol A, an endocrine disruptor, in DNA in vitro and in liver and mammary tissue of mice. Mutat Res 679(1–2):28–32. Scholar
  87. Izzotti A, Longobardi M, Cartiglia C, D’Agostini F, Kanitz S, De Flora S (2010) Pharmacological modulation of genome and proteome alterations in mice treated with the endocrine disruptor bisphenol A. Curr Cancer Drug Targets 10(2):147–154CrossRefGoogle Scholar
  88. Jenkins S, Raghuraman N, Eltoum I, Carpenter M, Russo J, Lamartiniere CA (2009) Oral exposure to bisphenol A increases dimethylbenzanthracene-induced mammary cancer in rats. Environ Health Perspect 117(6):910–915. Scholar
  89. Jenkins S, Wang J, Eltoum I, Desmond R, Lamartiniere CA (2011) Chronic oral exposure to bisphenol A results in a nonmonotonic dose response in mammary carcinogenesis and metastasis in MMTV-erbB2 mice. Environ Health Perspect 119(11):1604–1609. Scholar
  90. Jorgensen EM, Alderman MH, Taylor HS (2016) Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure. FASEB J 30(9):3194–3201. Scholar
  91. Jung J-W, Park S-B, Lee S-J, Seo M-S, Trosko JE, Kang K-S (2011) Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS One 6(11):e28068. Scholar
  92. Kabil A, Silva E, Kortenkamp A (2008) Estrogens and genomic instability in human breast cancer cells--involvement of Src/Raf/Erk signaling in micronucleus formation by estrogenic chemicals. Carcinogenesis 29(10):1862–1868. Scholar
  93. Kang NH, Hwang KA, Kim TH, Hyun SH, Jeung EB, Choi KC (2012) Induced growth of BG-1 ovarian cancer cells by 17β-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression. Mol Med Rep 6(1):151–156. Scholar
  94. Kang NH, Hwang KA, Lee HR, Choi DW, Choi KC (2013) Resveratrol regulates the cell viability promoted by 17β-estradiol or bisphenol A via down-regulation of the cross-talk between estrogen receptor α and insulin growth factor-1 receptor in BG-1 ovarian cancer cells. Food Chem Toxicol 59:373–379. Scholar
  95. Kanu N, Grönroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A et al (2015) SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene 34(46):5699–5708. Scholar
  96. Katchy A, Pinto C, Jonsson P, Nguyen-Vu T, Pandelova M, Riu A, Schramm K-W et al (2014) Coexposure to phytoestrogens and bisphenol A mimics estrogenic effects in an additive manner. Toxicol Sci 138(1):21–35. Scholar
  97. Kim JY, Jeong HG (2003) Down-regulation of inducible nitric oxide synthase and tumor necrosis factor-alpha expression by bisphenol A via nuclear factor-kappaB inactivation in macrophages. Cancer Lett 196(1):69–76CrossRefGoogle Scholar
  98. Kim K, Son TG, Park HR, Kim SJ, Kim HS, Kim HS, Kim TS, Jung KK, Han SY, Lee J (2009) Potencies of bisphenol A on the neuronal differentiation and hippocampal neurogenesis. J Toxic Environ Health A 72(21–22):1343–1351. Scholar
  99. Kim KB, Seo KW, Kim YJ, Park M, Park CW, Kim PY, Kim JI, Lee SH (2003) Estrogenic effects of phenolic compounds on glucose-6-phosphate dehydrogenase in MCF-7 cells and uterine glutathione peroxidase in rats. Chemosphere 50(9):1167–1173CrossRefGoogle Scholar
  100. Kim YS, Choi KC, Hwang KA (2015a) Genistein suppressed epithelial-mesenchymal transition and migration efficacies of BG-1 ovarian cancer cells activated by estrogenic chemicals via estrogen receptor pathway and downregulation of TGF-β signaling pathway. Phytomedicine 22(11):993–999. Scholar
  101. Kim Y-S, Hwang K-A, Hyun S-H, Nam K-H, Lee C-K, Choi K-C (2015b) Bisphenol A and nonylphenol have the potential to stimulate the migration of ovarian cancer cells by inducing epithelial–mesenchymal transition via an estrogen receptor dependent pathway. Chem Res Toxicol 28(4):662–671. Scholar
  102. Klotz DM, Hewitt SC, Korach KS, Diaugustine RP (2000) Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: requirement of estrogen receptor-alpha. Endocrinology 141(9):3430–3439. Scholar
  103. Kochukov MY, Jeng Y-J, Watson CS (2009) Alkylphenol Xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes. Environ Health Perspect 117(5):723–730. Scholar
  104. Kogita A, Yoshioka Y, Sakai K, Togashi Y, Sogabe S, Nakai T, Okuno K, Nishio K (2015) Inter- and intra-tumor profiling of multi-regional colon cancer and metastasis. Biochem Biophys Res Commun 458(1):52–56. Scholar
  105. Kometani T, Yoshino I, Miura N, Okazaki H, Ohba T, Takenaka T, Shoji F, Yano T, Maehara Y (2009) Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway. Cancer Lett 278:27–33. Scholar
  106. Kravchenko J, Corsini E, Williams MA, Decker W, Manjili MH, Otsuki T, Singh N, Al-Mulla F, Al-Temaimi R, Amedei A, Colacci AM, Vaccari M, Mondello C, Scovassi AI, Raju J, Hamid RA, Memeo L, Forte S, Roy R, Woodrick J, Salem HK, Ryan EP, Brown DG, Bisson WH, Lowe L, Lyerly HK (2015) Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions. Carcinogenesis 36(Suppl 1):S111–S127. Scholar
  107. Lam H-M, Ho S-M, Chen J, Medvedovic M, Tam NNC (2015) Bisphenol A disrupts HNF4α-regulated gene networks linking to prostate preneoplasia and immune disruption in noble rats. Endocrinology 157(1):207–219. Scholar
  108. Lamartiniere CA, Jenkins S, Betancourt AM, Wang J, Russo J (2011) Exposure to the endocrine disruptor bisphenol A alters susceptibility for mammary cancer. Horm Mol Biol Clin Invest 5(2):45–52. Scholar
  109. Lee HR, Hwang KA, Park MA, Yi BR, Jeung EB, Choi KC (2012a) Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway. Int J Mol Med 29(5):883–890. Scholar
  110. Lee H-S, Pyo M-Y, Yang M (2012b) Set, a putative oncogene, as a biomarker for prenatal exposure to bisphenol A. Asian Pac J Cancer Prev 13(6):2711–2715CrossRefGoogle Scholar
  111. Lee H-S, Park E-J, Oh J-H, Moon G, Hwang M-S, Kim S-Y, Shin M-K et al (2014) Bisphenol A exerts estrogenic effects by modulating CDK1/2 and p38 MAP kinase activity. Biosci Biotechnol Biochem 78(8):1371–1375. Scholar
  112. Li E, Xu Z, Zhao H, Sun Z, Wang L, Guo Z, Zhao Y, Gao Z, Wang Q (2015) Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-KB and STAT3 signaling in a bionic airway chip culture and in animal models. Oncotarget 6(11):8900–8913Google Scholar
  113. Lin Y, Sun X, Qiu L, Wei J, Huang Q, Fang C, Ye T, Kang M, Shen H, Dong S (2013) Exposure to bisphenol A induces dysfunction of insulin secretion and apoptosis through the damage of mitochondria in rat insulinoma (INS-1) cells. Cell Death Dis 4:e460. Scholar
  114. Liu J, Jin X, Zhao N, Ye X, Ying C (2015) Bisphenol A promotes X-linked inhibitor of apoptosis protein-dependent angiogenesis via G protein-coupled estrogen receptor pathway. J Appl Toxicol 35(11):1309–1317. Scholar
  115. Liu Y, Mei C, Liu H, Wang H, Zeng G, Lin J, Xu M (2014) Modulation of cytokine expression in human macrophages by endocrine-disrupting chemical bisphenol-A. Biochem Biophys Res Commun 451(4):592–598. Scholar
  116. Liu Z, Muehlbauer K-R, Schmeiser HH, Hergenhahn M, Belharazem D, Hollstein MC (2005) p53 mutations in benzo(a)pyrene-exposed human p53 knock-in murine fibroblasts correlate with p53 mutations in human lung tumors. Cancer Res 65:2583–2587. Scholar
  117. Ma X-F, Zhang J, Shuai H-L, Guan B-Z, Luo X, Yan R-L (2015) IKKβ/NF-κB mediated the low doses of bisphenol A induced migration of cervical cancer cells. Arch Biochem Biophys 573:52–58. Scholar
  118. Mandrup K, Boberg J, Isling LK, Christiansen S, Hass U (2016) Low-dose effects of bisphenol A on mammary gland development in rats. Andrology 4(4):673–683. Scholar
  119. Markey CM, Luque EH, Munoz De Toro M, Sonnenschein C, Soto AM (2001) In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod 65(4):1215–1223CrossRefGoogle Scholar
  120. Maruyama S, Fujimoto N, Yin H, Ito A (1999) Growth stimulation of a rat pituitary cell line MtT/E-2 by environmental estrogens in vitro and in vivo. Endocr J 46(4):513–520CrossRefGoogle Scholar
  121. Mavrofrydi O, Papazafiri P (2012) Hypoxia-inducible factor-lα increase is an early and sensitive marker of lung cells responding to benzo[a]pyrene. J Environ Pathol Toxicol Oncol 31:335–347. Scholar
  122. Meng F, Knapp GW, Green T, Ross JA, Parsons BL (2010) K-Ras mutant fraction in A/J mouse lung increases as a function of benzo[a]pyrene dose. Environ Mol Mutagen 51:146–155. Scholar
  123. Miyakoshi T, Miyajima K, Takekoshi S, Osamura RY (2009) The influence of endocrine disrupting chemicals on the proliferation of ERalpha knockdown-human breast cancer cell line MCF-7; new attempts by RNAi technology. Acta Histochem Cytochem 42(2):23–28. Scholar
  124. Mlynarcikova A, Macho L, Fickova M (2013) Bisphenol A alone or in combination with estradiol modulates cell cycle- and apoptosis-related proteins and genes in MCF7 cells. Endocr Regul 47(4):189–199CrossRefGoogle Scholar
  125. Moral R, Wang R, Russo IH, Lamartiniere CA, Pereira J, Russo J (2008) Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature. J Endocrinol 196(1):101–112. Scholar
  126. Moriyama K, Tagami T, Akamizu T, Usui T, Saijo M, Kanamoto N, Hataya Y, Shimatsu A, Kuzuya H, Nakao K (2002) Thyroid hormone action is disrupted by bisphenol A as an antagonist. J Clin Endocrinol Metab 87(11):5185–5190. Scholar
  127. Murray TJ, Maffini MV, Ucci AA, Sonnenschein C, Soto AM (2007) Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reprod Toxicol 23(3):383–390. Scholar
  128. Nahta R, Al-Mulla F, Al-Temaimi R, Amedei A, Andrade-Vieira R, Bay SN, Brown DG et al (2015) Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression. Carcinogenesis 36(Suppl 1):S2–S18. Scholar
  129. Nakagawa Y, Suzuki T (2001) Metabolism of bisphenol A in isolated rat hepatocytes and oestrogenic activity of a hydroxylated metabolite in MCF-7 human breast cancer cells. Xenobiotica 31(3):113–123. Scholar
  130. National Academy of Sciences (US) (2017) Using 21st century science to improve risk-related evaluations. National Academies Press, Washington, DCGoogle Scholar
  131. Newbold RF, Warren W, Medcalf AS, Amos J (1980) Mutagenicity of carcinogenic methylating agents is associated with a specific DNA modification. Nature 283:596–599CrossRefGoogle Scholar
  132. Newbold RR, Jefferson WN, Padilla-Banks E (2007) Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol 24(2):253–258. Scholar
  133. Newbold RR, Jefferson WN, Padilla-Banks E (2009) Prenatal exposure to bisphenol A at environmentally relevant doses adversely affects the murine female reproductive tract later in life. Environ Health Perspect 117(6):879–885. Scholar
  134. Newby DE, Mannucci PM, Tell GS, Baccarelli AA, Brook RD, Donaldson K et al (2015) Expert position paper on air pollution and cardiovascular disease. Eur Heart J 36(2):83–93bCrossRefGoogle Scholar
  135. Ochieng J, Nangami GN, Ogunkua O, Miousse IR, Koturbash I, Odero-Marah V, McCawley LJ, Nangia-Makker P, Ahmed N, Luqmani Y, Chen Z, Papagerakis S, Wolf GT, Dong C, Zhou BP, Brown DG, Colacci AM, Hamid RA, Mondello C, Raju J, Ryan EP, Woodrick J, Scovassi AI, Singh N, Vaccari M, Roy R, Forte S, Memeo L, Salem HK, Amedei A, Al-Temaimi R, Al-Mulla F, Bisson WH, Eltom SE (2015) The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis. Carcinogenesis 36(Suppl 1):S128–S159. Scholar
  136. Oikawa S (2005) Sequence-specific DNA damage by reactive oxygen species: implications for carcinogenesis and aging. Environ Health Prev Med 10(2):65–71. Scholar
  137. Ono T, Miki C (2000) Factors influencing tissue concentration of vascular endothelial growth factor in colorectal carcinoma. Am J Gastroenterol 95(4):1062–1067. Scholar
  138. Ooe H, Taira T, Iguchi-Ariga SM, Ariga H (2005) Induction of reactive oxygen species by bisphenol A and abrogation of bisphenol A-induced cell injury by DJ-1. Toxicol Sci 88(1):114–126. Scholar
  139. Park M-A, Choi K-C (2014) Effects of 4-nonylphenol and bisphenol A on stimulation of cell growth via disruption of the transforming growth factor-β signaling pathway in ovarian cancer models. Chem Res Toxicol 27(1):119–128. Scholar
  140. Park S-H, Kim K-Y, An B-S, Choi J-H, Jeung E-B, Leung PCK, Choi K-C (2009) Cell growth of ovarian cancer cells is stimulated by xenoestrogens through an estrogen-dependent pathway, but their stimulation of cell growth appears not to be involved in the activation of the mitogen-activated protein kinases ERK-1 and p38. J Reprod Dev 55(1):23–29CrossRefGoogle Scholar
  141. Parsons DW, Jones S, Zhang X, Lin JC-H, Leary RJ, Angenendt P et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807CrossRefGoogle Scholar
  142. Phillips TD, Richardson M, Cheng Y-SL, He L, McDonald TJ, Cizmas LH, Safe SH, Donnelly KC, Wang F, Moorthy B, Zhou G-D (2015) Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures. Arch Toxicol 89:967–977. Scholar
  143. Pieters N, Koppen G, Smeets K, Napierska D, Plusquin M, De Prins S, Van De Weghe H, Nelen V, Cox B, Cuypers A, Hoet P, Schoeters G, Nawrot TS (2013) Decreased mitochondrial DNA content in association with exposure to polycyclic aromatic hydrocarbons in house dust during wintertime: from a population enquiry to cell culture. PLoS One 8:e63208. Scholar
  144. Pisapia L, Del Pozzo G, Barba P, Caputo L, Mita L, Viggiano E, Russo GL et al (2012) Effects of some endocrine disruptors on cell cycle progression and murine dendritic cell differentiation. Gen Comp Endocrinol 178(1):54–63. Scholar
  145. Ptak A, Gregoraszczuk EL (2015) Effects of bisphenol A and 17β-Estradiol on vascular endothelial growth factor a and its receptor expression in the non-cancer and cancer ovarian cell lines. Cell Biol Toxicol 31(3):187–197. Scholar
  146. Ptak A, Wróbel A, Gregoraszczuk EL (2011) Effect of bisphenol-A on the expression of selected genes involved in cell cycle and apoptosis in the OVCAR-3 cell line. Toxicol Lett 202(1):30–35. Scholar
  147. Ptak A, Rak-Mardyła A, Gregoraszczuk EL (2013) Cooperation of bisphenol A and leptin in inhibition of caspase-3 expression and activity in OVCAR-3 ovarian cancer cells. Toxicol In Vitro 27(6):1937–1943. Scholar
  148. Ptak A, Hoffmann M, Gruca I, Barć J (2014) Bisphenol A induce ovarian cancer cell migration via the MAPK and PI3K/Akt signalling pathways. Toxicol Lett 229(2):357–365. Scholar
  149. Pupo M, Pisano A, Lappano R, Santolla MF, De Francesco EM, Abonante S, Rosano C, Maggiolini M (2012) Bisphenol A induces gene expression changes and proliferative effects through GPER in breast cancer cells and cancer-associated fibroblasts. Environ Health Perspect 120(8):1177–1182. Scholar
  150. Qian W, Zhu J, Mao C, Liu J, Wang Y, Wang Q, Liu Y, Gao R, Xiao H, Wang J (2014) Involvement of CaM-CaMKII-ERK in bisphenol A-induced sertoli cell apoptosis. Toxicology 324:27–34. Scholar
  151. Qin X-Y, Fukuda T, Yang L, Zaha H, Akanuma H, Zeng Q, Yoshinaga J, Sone H (2012) Effects of bisphenol A exposure on the proliferation and senescence of normal human mammary epithelial cells. Cancer Biol Ther 13(5):296–306. Scholar
  152. Qiu S-X, Yang RZ, Gross ML (2004) Synthesis and liquid chromatography/tandem mass spectrometric characterization of the adducts of bisphenol A O-quinone with glutathione and nucleotide monophosphates. Chem Res Toxicol 17(8):1038–1046. Scholar
  153. Raica M, Cimpean AM, Ribatti D (2009) Angiogenesis in pre-malignant conditions. Eur J Cancer 45(11):1924–1934. Scholar
  154. Rappaport SM (2016) Genetic factors are not the major causes of chronic diseases. PLoS One 11(4):e0154387. Scholar
  155. Recchia AG, Vivacqua A, Gabriele S, Carpino A, Fasanella G, Rago V, Bonofiglio D, Maggiolini M (2004) Xenoestrogens and the induction of proliferative effects in breast cancer cells via direct activation of oestrogen receptor α. Food Addit Contam 21(2):134–144. Scholar
  156. Rosenberg DW, Giardina C, Tanaka T (2009) Mouse models for the study of colon carcinogenesis. Carcinogenesis 30(2):183–196. Scholar
  157. Rothman KJ, Greenland S (2005) Causation and causal inference in epidemiology. Am J Public Health 95(Suppl 1):S144–S150CrossRefGoogle Scholar
  158. Roy D, Morgan M, Yoo C, Deoraj A, Roy S, Yadav VK, Garoub M, Assaggaf H, Doke M (2015) Integrated bioinformatics, environmental epidemiologic and genomic approaches to identify environmental and molecular links between endometriosis and breast cancer. Int J Mol Sci 16(10):25285–25322. Scholar
  159. Salazar I, Pavani M, Aranda W, Maya JD, Morello A, Ferreira J (2004) Alterations of rat liver mitochondrial oxidative phosphorylation and calcium uptake by benzo[a]pyrene. Toxicol Appl Pharmacol 198:1–10. Scholar
  160. Sang H, Zhang L, Li J (2012) Anti-benzopyrene-7,8-diol-9,10-epoxide induces apoptosis via mitochondrial pathway in human bronchiolar epithelium cells independent of the mitochondria permeability transition pore. Food Chem Toxicol 50:2417–2423. Scholar
  161. Schafer TE, Lapp CA, Hanes CM, Lewis JB, Wataha JC, Schuster GS (1999) Estrogenicity of bisphenol A and bisphenol A dimethacrylate in vitro. J Biomed Mater Res 45(3):192–197CrossRefGoogle Scholar
  162. Sengupta S, Obiorah I, Maximov PY, Curpan R, Jordan VC (2013) Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol 169(1):167–178. Scholar
  163. Severson PL, Vrba L, Stampfer MR, Futscher BW (2014) Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen 775–776:48–54. Scholar
  164. Sheng Z-G, Huang W, Liu Y-X, Zhu B-Z (2013) Bisphenol A at a low concentration boosts mouse spermatogonial cell proliferation by inducing the G protein-coupled receptor 30 expression. Toxicol Appl Pharmacol 267(1):88–94. Scholar
  165. Shi T, Zhao C, Li Z, Zhang Q, Jin X (2016) Bisphenol a exposure promotes the migration of NCM460 cells via estrogen receptor-mediated integrin β1/MMP-9 pathway. Environ Toxicol 31(7):799–807. Scholar
  166. Sigounas G, Hairr JW, Cooke CD, Owen JR, Asch AS, Weidner DA, Wiley JE (2010) Role of benzo[alpha]pyrene in generation of clustered DNA damage in human breast tissue. Free Radic Biol Med 49:77–87. Scholar
  167. Singleton DW, Feng Y, Yang J, Puga A, Lee AV, Khan SA (2006) Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-alpha-positive human cells. Environ Res 100(1):86–92. Scholar
  168. Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314(5797):268–274CrossRefGoogle Scholar
  169. Smith LC, Ralston-Hooper KJ, Lee Ferguson P, Sabo-Attwood T (2016a) The G protein-coupled estrogen receptor agonist G-1 inhibits nuclear estrogen receptor activity and stimulates novel phosphoproteomic signatures. Toxicol Sci 151(2):434–446. Scholar
  170. Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert PF, Hecht SS, Bucher JR, Stewart BW, Baan RA, Cogliano VJ, Straif K (2016b) Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124(6):713–721CrossRefGoogle Scholar
  171. Song H, Zhang T, Yang P, Li M, Yang Y, Wang Y, Du J, Pan K, Zhang K (2015) Low doses of bisphenol A stimulate the proliferation of breast cancer cells via ERK1/2/ERRγ signals. Toxicol In Vitro 30(1 Pt B):521–528. Scholar
  172. Stolpmann K, Brinkmann J, Salzmann S, Genkinger D, Fritsche E, Hutzler C, Wajant H, Luch A, Henkler F (2012) Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L- and TRAIL-induced apoptosis. Cell Death Dis 3:e388. Scholar
  173. Susiarjo M, Sasson I, Mesaros C, Bartolomei MS (2013) Bisphenol a exposure disrupts genomic imprinting in the mouse. PLoS Genet 9(4):e1003401. Scholar
  174. Tabuchi Y, Zhao Q-L, Kondo T (2002) DNA microarray analysis of differentially expressed genes responsive to bisphenol A, an alkylphenol derivative, in an in vitro mouse sertoli cell model. Jpn J Pharmacol 89(4):413–416CrossRefGoogle Scholar
  175. Takahashi Y, Ellis LM, Mai M (2003) The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion. Oncol Rep 10(1):9–13Google Scholar
  176. Tang W-y, Morey LM, Cheung YY, Birch L, Prins GS, Ho S-m (2012) Neonatal exposure to estradiol/bisphenol A alters promoter methylation and expression of Nsbp1 and Hpcal1 genes and transcriptional programs of Dnmt3a/B and Mbd2/4 in the rat prostate gland throughout life. Endocrinology 153(1):42–55. Scholar
  177. Terasaka H, Kadoma Y, Sakagami H, Fujisawa S (2005) Cytotoxicity and apoptosis-inducing activity of bisphenol A and hydroquinone in HL-60 cells. Anticancer Res 25(3B):2241–2247Google Scholar
  178. Terasaka S, Aita Y, Inoue A, Hayashi S, Nishigaki M, Aoyagi K, Sasaki H et al (2004) Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals. Environ Health Perspect 112(7):773–781CrossRefGoogle Scholar
  179. Tian S, Pan L, Sun X (2013) An investigation of endocrine disrupting effects and toxic mechanisms modulated by benzo[a]pyrene in female scallop Chlamys farreri. Aquat Toxicol 144–145:162–171. Scholar
  180. Tilghman SL, Bratton MR, Chris Segar H, Martin EC, Rhodes LV, Li M, McLachlan JA, Wiese TE, Nephew KP, Burow ME (2012) Endocrine disruptor regulation of microRNA expression in breast carcinoma cells. PLoS One 7(3):e32754. Scholar
  181. Tsutsui T, Tamura Y, Yagi E, Hasegawa K, Takahashi M, Maizumi N, Yamaguchi F, Barrett JC (1998) Bisphenol-A induces cellular transformation, aneuploidy and DNA adduct formation in cultured Syrian hamster embryo cells. Int J Cancer 75(2):290–294CrossRefGoogle Scholar
  182. Umannová L, Machala M, Topinka J, Schmuczerová J, Krčmář P, Neca J, Šujanová K, Kozubík A, Vondracek J (2011) Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and production of proinflammatory mediators in aleolar epithelial type II cells. Toxicol Lett 206:121–129. Scholar
  183. Uzoigwe JC, Prum T, Bresnahan E, Garelnabi M (2013) The emerging role of outdoor and indoor air pollution in cardiovascular disease. N Am J Med Sci 5(8):445–453CrossRefGoogle Scholar
  184. Vineis P, van Veldhoven K, Chadeau-Hyam M, Athersuch TJ (2013) Advancing the application of omics-based biomarkers in environmental epidemiology. Environ Mol Mutagen 54(7):461–467CrossRefGoogle Scholar
  185. Vineis P, Chadeau-Hyam M, Gmuender H, Gulliver J, Herceg Z, Kleinjans J, Kogevinas M, Kyrtopoulos S, Nieuwenhuijsen M, Phillips DH, Probst-Hensch N, Scalbert A, Vermeulen R, Wild CP, EXPOsOMICS Consortium (2017) The exposome in practice: design of the EXPOsOMICS project. Int J Hyg Environ Health 220(2 Pt A):142–151CrossRefGoogle Scholar
  186. Vivacqua A, Recchia AG, Fasanella G, Gabriele S, Carpino A, Rago V, Di Gioia ML et al (2003) The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor alpha in MCF7 breast cancer cells. Endocrine 22(3):275–284. Scholar
  187. Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10(8):789–799CrossRefGoogle Scholar
  188. Wang B-Y, Wu S-Y, Tang S-C, Lai C-H, Ou C-C, Wu M-F, Hsiao Y-M, Ko J-L (2015a) Benzo[a]pyrene-induced cell cycle progression occurs via ERK-induced Chk1 pathway activation in human lung cancer cells. Mutat Res 773:1–8. Scholar
  189. Wang K-H, Kao A-P, Chang C-C, Lin T-C, Kuo T-C (2015b) Bisphenol A-induced epithelial to mesenchymal transition is mediated by cyclooxygenase-2 up-regulation in human endometrial carcinoma cells. Reprod Toxicol 58:229–233. Scholar
  190. Wang Y, Zhai W, Wang H, Xia X, Zhang C (2015c) Benzo(a)pyrene promotes A549 cell migration and invasion through up-regulating Twist. Arch Toxicol 89:451–458. Scholar
  191. Wang D, Gao H, Bandyopadhyay A, Wu A, Yeh IT, Chen Y, Zou Y et al (2014a) Pubertal bisphenol A exposure alters murine mammary stem cell function leading to early neoplasia in regenerated glands. Cancer Prev Res (Phila) 7(4):445–455. Scholar
  192. Wang J, Jenkins S, Lamartiniere CA (2014b) Cell proliferation and apoptosis in rat mammary glands following combinational exposure to bisphenol A and genistein. BMC Cancer 14:379. Scholar
  193. Wang K-H, Kao A-P, Chang C-C, Lin T-C, Kuo T-C (2013) Bisphenol A at environmentally relevant doses induces cyclooxygenase-2 expression and promotes invasion of human mesenchymal stem cells derived from uterine myoma tissue. Taiwan J Obstet Gynecol 52(2):246–252. Scholar
  194. Wei SJ, Chang RL, Merkler KA, Gwynne M, Cui XX, Murthy B, Huang MT, Xie JG, Lu YP, Lou YR, Jerina DM, Conney AH (1999) Dose-dependent mutation profile in the c-Ha-ras proto-oncogene of skin tumors in mice initiated with benzo[a]pyrene. Carcinogenesis 20:1689–1696CrossRefGoogle Scholar
  195. Wen J, Pan L (2015) Short-term exposure to benzo[a]pyrene disrupts reproductive endocrine status in the swimming crab Portunus trituberculatus. Comp Biochem Physiol C Toxicol Pharmacol 174–175:13–20. Scholar
  196. Wetherill YB, Petre CE, Monk KR, Puga A, Knudsen KE (2002) The xenoestrogen bisphenol A induces inappropriate androgen receptor activation and mitogenesis in prostatic adenocarcinoma cells. Mol Cancer Ther 1(7):515–524Google Scholar
  197. Williams KE, Lemieux GA, Hassis ME, Olshen AB, Fisher SJ, Werb Z (2016) Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals. Proc Natl Acad Sci U S A 113(10):E1343–E1351. Scholar
  198. Wolf K, Stafoggia M, Cesaroni G, Andersen ZJ, Beelen R, Galassi C et al (2015) Long-term exposure to particulate matter constituents and the incidence of coronary events in 11 european cohorts. Epidemiology 26(4):565–574CrossRefGoogle Scholar
  199. Wong MP, Cheung N, Yuen ST, Leung SY, Chung LP (1999) Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumour progression. Int J Cancer 81(6):845–850CrossRefGoogle Scholar
  200. Wong RLY, Wang Q, Treviño LS, Bosland MC, Chen J, Medvedovic M, Prins GS, Kannan K, Ho S-M, Walker CL (2015) Identification of secretaglobin Scgb2a1 as a target for developmental reprogramming by BPA in the rat prostate. Epigenetics 10(2):127–134. Scholar
  201. Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, Shen D et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113. Scholar
  202. World Health Organization (Ed) (2010) Who guidelines for indoor air quality: selected pollutants. WHO, CopenhagenGoogle Scholar
  203. Xin F, Jiang L, Liu X, Geng C, Wang W, Zhong L, Yang G, Chen M (2014) Bisphenol A induces oxidative stress-associated DNA damage in INS-1 cells. Mutat Res Genet Toxicol Environ Mutagen 769:29–33. Scholar
  204. Yachida S, Jones S, Bozic I, Antal T, Leary R, Baojin F, Kamiyama M et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117. Scholar
  205. Yasaei H, Gilham E, Pickles JC, Roberts TP, O’Donovan M, Newbold RF (2013) Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells. Oncogene 32:171–179. Scholar
  206. Yoshida M, Shimomoto T, Katashima S, Watanabe G, Taya K, Maekawa A (2004) Maternal exposure to low doses of bisphenol A has no effects on development of female reproductive tract and uterine carcinogenesis in donryu rats. J Reprod Dev 50(3):349–360CrossRefGoogle Scholar
  207. Yu Z, Zhang L, Desheng W (2004) Effects of three environmental estrogens on expression of proliferation and apoptosis-associated genes in PEO4 cells. Wei Sheng Yan Jiu 33(4):404–406Google Scholar
  208. Zhang J, Chang L, Jin H, Xia Y, Wang L, He W, Li W, Chen H (2016a) Benzopyrene promotes lung cancer A549 cell migration and invasion through up-regulating cytokine IL8 and chemokines CCL2 and CCL3 expression. Exp Biol Med (Maywood) 241:1516–1523. Scholar
  209. Zhang X-L, Liu N, Weng S-F, Wang H-S (2016b) Bisphenol A increases the migration and invasion of triple-negative breast cancer cells via oestrogen-related receptor gamma. Basic Clin Pharmacol Toxicol 119(4):389–395. Scholar
  210. Zhang K-S, Chen H-Q, Chen Y-S, Qiu K-F, Zheng X-B, Li G-C, Yang H-D, Wen C-J (2014) Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway. Biomed Pharmacother 68(8):1037–1043. Scholar
  211. Zhang W, Fang Y, Shi X, Zhang M, Wang X, Tan Y (2012) Effect of bisphenol A on the EGFR-STAT3 pathway in MCF-7 breast cancer cells. Mol Med Rep 5(1):41–47. Scholar
  212. Zhang X, Gaspard JP, Chung DC (2001) Regulation of vascular endothelial growth factor by the Wnt and K-Ras pathways in colonic neoplasia. Cancer Res 61(16):6050–6054Google Scholar
  213. Zhu H, Xiao X, Zheng J, Zheng S, Dong K, Yong Y (2009) Growth-promoting effect of bisphenol A on neuroblastoma in vitro and in vivo. J Pediatr Surg 44(4):672–680. Scholar
  214. Zhu H, Zheng J, Xiao X, Zheng S, Dong K, Liu J, Wang Y (2010) Environmental endocrine disruptors promote invasion and metastasis of SK-N-SH human neuroblastoma cells. Oncol Rep 23(1):129–139CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Christiana A. Demetriou
    • 1
  • Davide Degli Esposti
    • 2
  • Kristi Pullen Fedinick
    • 3
  • Paolo Vineis
    • 4
    • 5
    Email author
  1. 1.Neurology Clinic DThe Cyprus Institute of Neurology and GeneticsNicosiaCyprus
  2. 2.Ecotoxicology Team, UR RiverlyNational Research Institute of Science and Technology for Environment and Agriculture (Irstea)Lyon-VilleurbanneFrance
  3. 3.Natural Resources Defense CouncilWashingtonUSA
  4. 4.Imperial College LondonLondonUK
  5. 5.HuGeF FoundationTorinoItaly

Personalised recommendations