Systems toxicology of male reproductive development: Profiling 774 chemicals for molecular targets and adverse outcomes

Environmental Health Perspectives

Volumn 124, Issue 7, 2016, Pages 1050-1061

  Leung, Maxwell C K ^a,b   Phuong, Jimmy ^b   Baker, Nancy C ^c   Sipes, Nisha S ^a,b   Klinefelter, Gary R ^d   Martin, Matthew T ^b   McLaurin, Keith W ^a,b   Woodrow Setzer, R ^b   Darney, Sally Perreault ^d,e   Judson, Richard S ^b   Knudsen, Thomas B ^b  

^a OAK RIDGE INSTITUTE FOR SCIENCE AND EDUCATION   (United States)

^b U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

^c LOCKHEED MARTIN   (United States)

^d U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

^e NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; COMPUTER MODEL; COMPUTER PROGRAM; CYTOTOXICITY; GENE REGULATORY NETWORK; GONADAL DYSGENESIS; HIGH THROUGHPUT SCREENING; HISTOLOGY; HUMAN; MALE GENITAL SYSTEM; MALE GENITAL TRACT TUMOR; MOLECULAR GENETICS; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; RABBIT; RAT; SEMEN ABNORMALITY; TESTIS ATROPHY; TOXICOLOGY; TOXREFDB; CRYPTORCHISM; DRUG EFFECTS; ENVIRONMENTAL EXPOSURE; FACTUAL DATABASE; GROWTH, DEVELOPMENT AND AGING; HYPOSPADIAS; MALE; NEOPLASM; POLLUTANT; REPRODUCTION; SEMEN ANALYSIS; STATISTICS AND NUMERICAL DATA; SYSTEM ANALYSIS; TESTIS; TESTIS TUMOR; TOXICITY;

POLLUTANT;

CRYPTORCHIDISM; DATABASES, FACTUAL; ENVIRONMENTAL EXPOSURE; ENVIRONMENTAL POLLUTANTS; HUMANS; HYPOSPADIAS; MALE; NEOPLASMS, GERM CELL AND EMBRYONAL; REPRODUCTION; SEMEN ANALYSIS; SYSTEMS ANALYSIS; TESTICULAR NEOPLASMS; TESTIS; TOXICOLOGY;

EID: 84977160684     PISSN: 00916765     EISSN: 15529924     Source Type: Journal    
DOI: 10.1289/ehp.1510385     Document Type: Article

References (98)

1. Abbott BD. 2009. Review of the expression of peroxisome proliferator-activated receptors alpha (PPARα), beta (PPARβ), and gamma (PPARγ) in rodent and human development. Reprod Toxicol 27:246-257.
2. Abe N, Nakahara T, Morita A, Wada Y, Mori A, Sakamoto K, et al. 2013. KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces intrauterine growth restriction in mice. Birth Defects Res B Dev Reprod Toxicol 98:297-303.
3. Akre O, Richiardi L. 2009. Does a testicular dysgenesis syndrome exist? Hum Reprod 24:2053-2060.
4. Albert O, Jégou B. 2014. A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood. Hum Reprod Update 20:231-249.
5. Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, et al. 2010. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assess-ment. Environ Toxicol Chem 29:730-741.
6. Aschim EL, Nordenskjöld A, Giwercman A, Lundin KB, Ruhayel Y, Haugen TB, et al. 2004. Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. J Clin Endocrinol Metab 89:5105-5109.
7. Bastian M, Heymann S, Jacomy M. 2009. Gephi: an open source software for exploring and manipulating networks. In: Proceedings of the Third International Conference on Weblogs and Social Media, ICWSM, 17-20 May 2009, San Jose, California, USA.
8. Bay K, Asklund C, Skakkebaek NE, Andersson AM. 2006. Testicular dysgenesis syndrome: possible role of endocrine disrupters. Best Pract Res Clin Endocrinol Metab 20:77-90.
9. Biggs ML, Baer A, Critchlow CW. 2002. Maternal, delivery, and perinatal characteristics associated with cryptorchidism: a population-based case-control study among births in Washington State. Epidemiology 13:197-204.
10. Bishop-Bailey D. 2011. PPARs and angiogenesis. Biochem Soc Trans 39:1601-1605.
11. Brennan J, Karl J, Capel B. 2002. Divergent vascular mechanisms downstream of Sry establish the arterial system in the XY gonad. Dev Biol 244:418-428.
12. Carmichael SL, Ma C, Choudhry S, Lammer EJ, Witte JS, Shaw GM. 2013. Hypospadias and genes related to genital tubercle and early urethral development. J Urol 190:1884-1892.
13. CDC (Centers for Disease Control and Prevention). 2014. National Public Health Action Plan for the Detection, Prevention, and Management of Infertility. Atlanta, GA:CDC. Available: http://www.cdc.gov/reproductivehealth/Infertility/PDF/DRH_NAP_Final_508.pdf [accessed 24 June 2015].
14. Chai X, Zeng S, Xie W. 2013. Nuclear receptors PXR and CAR: implications for drug metabolism regula-tion, pharmaco genomics and beyond. Expert Opin Drug Metab Toxicol 9:253-266.
15. Clegg ED, Cook JC, Chapin RE, Foster PM, Daston GP. 1997. Leydig cell hyperplasia and adenoma formation: mechanisms and relevance to humans. Reprod Toxicol 11:107-121.
16. Cohn MJ. 2011. Development of the external genitalia: conserved and divergent mechanisms of appendage patterning. Dev Dyn 240:1108-1115.
17. Collins FS, Gray GM, Bucher JR. 2008. Toxicology. Transforming environmental health protection. Science 319:906-907.
18. Dalgaard MD, Weinhold N, Edsgärd D, Silver JD, Pers TH, Nielsen JE, et al. 2012. A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation. J Med Genet 49:58-65.
19. Easley DA, Kleinberg JM. 2010. Networks, Crowds, and Markets: Reasoning About a Highly Connected World. Cambridge, UK:Cambridge University Press.
20. Foote RH, Carney EW. 2000. The rabbit as a model for reproductive and developmental toxicity studies. Reprod Toxicol 14:477-493.
21. Fuxman Bass JI, Diallo A, Nelson J, Soto JM, Myers CL, Walhout AJ. 2013. Using networks to measure similarity between genes: association index selection. Nat Methods 10:1169-1176.
22. Gao J, Xie W. 2012. Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci 33:552-558.
23. Ge RS, Chen GR, Dong Q, Akingbemi B, Sottas CM, Santos M, et al. 2007. Biphasic effects of postnatal exposure to diethylhexylphthalate on the timing of puberty in male rats. J Androl 28:513-520.
24. Geller F, Feenstra B, Carstensen L, Pers TH, van Rooij IA, Körberg IB, et al. 2014. Genome-wide association analyses identify variants in developmental genes associated with hypospadias. Nat Genet 46:957-963.
25. Gräns J, Wassmur B, Celander MC. 2010. One-way inhibiting cross-talk between arylhydro carbon receptor (AhR) and estrogen receptor (ER) signaling in primary cultures of rainbow trout hepatocytes. Aquat Toxicol 100:263-270.
26. Gray LE Jr, Wilson VS, Stoker T, Lambright C, Furr J, Noriega N, et al. 2006. Adverse effects of environ-mental antiandrogens and androgens on reproduc-tive development in mammals. Int J Androl 29:96-104.
27. Handschin C, Meyer UA. 2005. Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Arch Biochem Biophys 433:387-396.
28. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. 2003. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619-633.
29. Hollman DA, Milona A, van Erpecum KJ, van Mil SW. 2012. Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochim Biophys Acta 1821:1443-1452.
30. Hu Y, Wang R, Xiang Z, Qian W, Han X, Li D. 2014. Antagonistic effects of a mixture of low-dose nonylphenol and di-n-butyl phthalate (monobutyl phthalate) on the Sertoli cells and serum repro-ductive hormones in prepubertal male rats in vitro and in vivo. PLoS One 9:e93425, doi:10.1371/journal.pone.0093425.
31. Huang DW, Sherman BT, Lempicki RA. 2009a. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37:1-13.
32. Huang DW, Sherman BT, Lempicki RA. 2009b. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44-57.
33. Jain VG, Singal AK. 2013. Shorter anogenital distance correlates with undescended testis: a detailed genital anthropometric analysis in human newborns. Hum Reprod 28:2343-2349.
34. Johnson KJ, Heger NE, Boekelheide K. 2012. Of mice and men (and rats): phthalate-induced fetal testis endocrine disruption is species-dependent. Toxicol Sci 129:235-248.
35. Johnson KJ, Robbins AK, Wang Y, McCahan SM, Chacko JK, Barthold JS. 2010. Insulin-like 3 exposure of the fetal rat gubernaculum modulates expression of genes involved in neural pathways. Biol Reprod 83:774-782.
36. Kaleva M, Toppari J. 2005. Cryptorchidism: an indicator of testicular dysgenesis? Cell Tissue Res 322:167-172.
37. Kapp RW Jr. 2010. Male reproductive toxicity. In: Reproductive Toxicology (Kapp RW Jr, Tyl RW, eds). 3rd ed. New York:Informa Healthcare, 249-269.
38. Kavlock R, Chandler K, Houck K, Hunter S, Judson R, Kleinstreuer N, et al. 2012. Update on EPA’s ToxCast program: providing high throughput decision support tools for chemical risk management. Chem Res Toxicol 25:1287-1302.
39. Kelley R, Ideker T. 2005. Systematic interpretation of genetic interactions using protein networks. Nat Biotechnol 23:561-566.
40. Kilcoyne KR, Smith LB, Atanassova N, Macpherson S, McKinnell C, van den Driesche S, et al. 2014. Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells. Proc Natl Acad Sci USA 111:E1924-E1932.
41. Kleinstreuer NC, Judson RS, Reif DM, Sipes NS, Singh AV, Chandler KJ, et al. 2011. Environmental impact on vascular development predicted by high-throughput screening. Environ Health Perspect 119:1596-1603, doi:10.1289/ehp.1103412.
42. Klinefelter GR, Laskey JW, Winnik WM, Suarez JD, Roberts NL, Strader LF, et al. 2012. Novel molecular targets associated with testicular dysgenesis induced by gestational exposure to diethylhexyl phthalate in the rat: a role for estradiol. Reproduction 144:747-761.
43. Knudsen TB, Kleinstreuer NC. 2011. Disruption of embry-onic vascular development in predictive toxicology. Birth Defects Res C Embryo Today 93:312-323.
44. Knudsen TB, Martin MT, Kavlock RJ, Judson RS, Dix DJ, Singh AV. 2009. Profiling the activity of envi-ronmental chemicals in prenatal developmental toxicity studies using the U.S. EPA’s ToxRefDB. Reprod Toxicol 28:209-219.
45. Kojima Y, Kohri K, Hayashi Y. 2010. Genetic pathway of external genitalia formation and molecular etiology of hypospadias. J Pediatr Urol 6:346-354.
46. Kongsbak K, Vinggaard AM, Hadrup N, Audouze K. 2014. A computational approach to mechanistic and predictive toxicology of pesticides. ALTEX 31:11-22.
47. Latapy M, Magnien C, Del Vecchio N. 2008. Basic notions for the analysis of large two-mode networks. Soc Networks 30:31-48.
48. Laws SC, Carey SA, Ferrell JM, Bodman GJ, Cooper RL. 2000. Estrogenic activity of octylphenol, nonyl-phenol, bisphenol A and methoxychlor in rats. Toxicol Sci 54:154-167.
49. Liu J, Kapron CM. 2010. Differential induction of MAP kinase signalling pathways by cadmium in primary cultures of mouse embryo limb bud cells. Reprod Toxicol 29:286-291.
50. Liu L, Suzuki K, Nakagata N, Mihara K, Matsumaru D, Ogino Y, et al. 2012. Retinoic acid signaling regulates sonic hedgehog and bone morphogenetic protein signaling during genital tubercle development. Birth Defects Res B Dev Reprod Toxicol 95:79-88.
51. Lottrup G, Jørgensen A, Nielsen JE, Jørgensen N, Duno M, Vinggaard AM, et al. 2013. Identification of a novel androgen receptor mutation in a family with multiple components compatible with the testicular dysgenesis syndrome. J Clin Endocrinol Metab 98:2223-2229.
52. Madak-Erdogan Z, Charn TH, Jiang Y, Liu ET, Katzenellenbogen JA, Katzenellenbogen BS. 2013. Integrative genomics of gene and metabolic regula-tion by estrogen receptors α and β, and their coregu-lators. Mol Syst Biol 9:676, doi:10.1038/msb.2013.28.
53. Mark M, Ghyselinck NB, Chambon P. 2006. Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogen-esis. Annu Rev Pharmacol Toxicol 46:451-480.
54. Mark M, Teletin M, Vernet N, Ghyselinck NB. 2015. Role of retinoic acid receptor (RAR) signaling in post-natal male germ cell differentiation. Biochim Biophys Acta 1849:84-93.
55. Martin MT, Judson RS, Reif DM, Kavlock RJ, Dix DJ. 2009a. Profiling chemicals based on chronic toxicity results from the U.S. EPA ToxRef Database. Environ Health Perspect 117:392-399, doi:10.1289/ehp.0800074.
56. Martin MT, Mendez E, Corum DG, Judson RS, Kavlock RJ, Rotroff DM, et al. 2009b. Profiling the reproductive toxicity of chemicals from multigen-eration studies in the toxicity reference database. Toxicol Sci 110:181-190.
57. McClelland K, Bowles J, Koopman P. 2012. Male sex determination: insights into molecular mecha-nisms. Asian J Androl 14:164-171.
58. Meeks JJ, Sheinfeld J, Eggener SE. 2012. Environmental toxicology of testicular cancer. Urol Oncol 30:212-215.
59. Mitchard T, Jarvis P, Stewart J. 2012. Assessment of male rodent fertility in general toxicology 6-month studies. Birth Defects Res B Dev Reprod Toxicol 95:410-420.
60. Mitchell RT, Sharpe RM, Anderson RA, McKinnell C, Macpherson S, Smith LB, et al. 2013. Diethyl-stilboestrol exposure does not reduce testosterone production in human fetal testis xenografts. PLoS One 8:e61726, doi:10.1371/journal.pone.0061726.
61. Morita A, Nakahara T, Abe N, Kurauchi Y, Mori A, Sakamoto K, et al. 2014. Treatment of mid-pregnant mice with KRN633, an inhibitor of vascular endothe-lial growth factor receptor tyrosine kinase, induces abnormal retinal vascular patterning in their newborn pups. Birth Defects Res B Dev Reprod Toxicol 101:293-299.
62. Mylchreest E, Cattley RC, Foster PM. 1998. Male reproductive tract malformations in rats following gestational and lactational exposure to di(n-butyl) phthalate: an antiandrogenic mechanism? Toxicol Sci 43:47-60.
63. Mylchreest E, Sar M, Wallace DG, Foster PM. 2002. Fetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate. Reprod Toxicol 16:19-28.
64. Mylchreest E, Wallace DG, Cattley RC, Foster PM. 2000. Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl) phthalate during late gesta-tion. Toxicol Sci 55:143-151.
65. NRC (National Research Council). 2007. Toxicity Testing in the 21st Century: a Vision and a Strategy. Washington, DC:National Academies Press.
66. OECD (Organization for Economic Co-operation and Development). 2011. Test No. 443: Extended One-Generation Reproductive Toxicity Study, OECD Guidelines for the Testing of Chemicals, Section 4. Paris, France:OECD Publishing. Available: http://dx.doi.org/10.1787/9789264122550-en [accessed 24 June 2015].
67. Ono M, Harley VR. 2013. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol 9:79-91.
68. Parks LG, Ostby JS, Lambright CR, Abbott BD, Klinefelter GR, Barlow NJ, et al. 2000. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci 58:339-349.
69. Qi S, Fu W, Wang C, Liu C, Quan C, Kourouma A, et al. 2014. BPA-induced apoptosis of rat Sertoli cells through Fas/FasL and JNKs/p38 MAPK pathways. Reprod Toxicol 50:108-116.
70. R Core Team. 2013. R: A Language and Environment for Statistical Computing. Vienna, Austria:R Foundation for Statistical Computing. Available: http://www.R-project.org/[accessed 16 November 2015].
71. Reynolds LP, Redmer DA. 2001. Angiogenesis in the placenta. Biol Reprod 64:1033-1040.
72. Sakurai T, Takai R, Bürgin H, Ishihara K, Sakamoto Y, Amano J, et al. 2012. The effects of interleukin-6 signal blockade on fertility, embryo-fetal develop-ment, and immunization in vivo. Birth Defects Res B Dev Reprod Toxicol 95:304-317.
73. Sakurai T, Takai R, Bürgin H, Shioda A, Sakamoto Y, Amano J, et al. 2013. The effects of interleukin-6 signal blockade on immune system, reproductive and skeletal development in juvenile mice. Birth Defects Res B Dev Reprod Toxicol 98:170-182.
74. Scott HM, Hutchison GR, Mahood IK, Hallmark N, Welsh M, De Gendt K, et al. 2007. Role of andro-gens in fetal testis development and dysgenesis. Endocrinology 148:2027-2036.
75. Scott HM, Mason JI, Sharpe RM. 2009. Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. Endocr Rev 30:883-925.
76. Sharan R, Ulitsky I, Shamir R. 2007. Network-based prediction of protein function. Mol Syst Biol 3:88, doi:10.1038/msb4100129.
77. Sharpe RM, Skakkebaek NE. 2008. Testicular dysgen-esis syndrome: mechanistic insights and potential new downstream effects. Fertil Steril 89:e33-e38.
78. Sipes NS, Martin MT, Reif DM, Kleinstreuer NC, Judson RS, Singh AV, et al. 2011. Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data. Toxicol Sci 124:109-127.
79. Skakkebæk NE, Rajpert-De Meyts E, Main KM. 2001. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environ-mental aspects. Hum Reprod 16:972-978.
80. Spade DJ, Hall SJ, Saffarini CM, Huse SM, McDonnell EV, Boekelheide K. 2014. Differential response to abiraterone acetate and di-n-butyl phthalate in an androgen-sensitive human fetal testis xenograft bioassay. Toxicol Sci 138:148-160.
81. Spielmann H. 2009. The way forward in reproductive/developmental toxicity testing. Altern Lab Anim 37:641-656.
82. Storvik M, Huuskonen P, Pehkonen P, Pasanen M. 2014. The unique characteristics of the placental transcriptome and the hormonal metabolism enzymes in placenta. Reprod Toxicol 47:9-14.
83. Sturla SJ, Boobis AR, FitzGerald RE, Hoeng J, Kavlock RJ, Schirmer K, et al. 2014. Systems toxi-cology: from basic research to risk assessment. Chem Res Toxicol 27:314-329.
84. Swedenborg E, Kotka M, Seifert M, Kanno J, Pongratz I, Rüegg J. 2012. The aryl hydrocarbon receptor ligands 2,3,7,8-tetrachloro dibenzo-p-dioxin and 3-methylcholanthrene regulate distinct genetic networks. Mol Cell Endocrinol 362:39-47.
85. Thankamony A, Lek N, Carroll D, Williams M, Dunger DB, Acerini CL, et al. 2014. Anogenital distance and penile length in infants with hypospadias or cryptorchidism: comparison with normative data. Environ Health Perspect 122:207-211, doi:10.1289/ehp.1307178.
86. Trabert B, Zugna D, Richiardi L, McGlynn KA, Akre O. 2013. Congenital malformations and testicular germ cell tumors. Int J Cancer 133:1900-1904.
87. van den Driesche S, McKinnell C, Calarrão A, Kennedy L, Hutchison GR, Hrabalkova L, et al. 2015. Comparative effects of di(n-butyl) phthalate exposure on fetal germ cell development in the rat and in human fetal testis xenografts. Environ Health Perspect 123:223-230, doi:10.1289/ehp.1408248.
88. Vaucher L, Funaro MG, Mehta A, Mielnik A, Bolyakov A, Prossnitz ER, et al. 2014. Activation of GPER-1 estradiol receptor downregulates production of testosterone in isolated rat Leydig cells and adult human testis. PLoS One 9:e92425, doi:10.1371/journal.pone.0092425.
89. Veeramachaneni DN. 2008. Impact of environmental pollutants on the male: effects on germ cell differ-entiation. Anim Reprod Sci 105:144-157.
90. Veeramachaneni DN, Klinefelter GR. 2014. Phthalate-induced pathology in the foetal testis involves more than decreased testosterone production. Reproduction 147:435-442.
91. Virtanen HE, Rajpert-De Meyts E, Main KM, Skakkebaek NE, Toppari J. 2005. Testicular dysgenesis syndrome and the development and occurrence of male reproductive disorders. Toxicol Appl Pharmacol 207(2 suppl):501-505.
92. Wang H, LeCluyse EL. 2003. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 42:1331-1357.
93. Ward JH. 1963. Hierarchical grouping to optimize an objective function. J Am Stat Assoc 58:236-244.
94. Waye A, Trudeau VL. 2011. Neuroendocrine disruption: more than hormones are upset. J Toxicol Environ Health B Crit Rev 14:270-291.
95. Willson TM, Kliewer SA. 2002. PXR, CAR and drug metabolism. Nat Rev Drug Discov 1:259-266.
96. Wilson VS, Blystone CR, Hotchkiss AK, Rider CV, Gray LE Jr. 2008. Diverse mechanisms of anti-androgen action: impact on male rat reproductive tract development. Int J Androl 31:178-187.
97. Woodruff TJ, Zota AR, Schwartz JM. 2011. Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ Health Perspect 119:878-885, doi:10.1289/ehp.1002727.
98. Yoshida H, Hashizume M, Suzuki M, Mihara M. 2011. Induction of high-dose tolerance to the rat anti-mouse IL-6 receptor antibody in NZB/NZW F1 mice. Rheumatol Int 31:1445-1449.