Transient Gestational Exposure to Hexavalent Chromium (CrVI) Adversely Affects Testicular Differentiation: A Study in Rat Model
Authors
-
Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Taramani-Velachery Link Road, Chennai – 600113, Tamil Nadu ,IN
Ajit Kumar Navin -
Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Taramani-Velachery Link Road, Chennai – 600113, Tamil Nadu ,INNavaneethabalakrishnan Shobana
-
Department of Anatomy, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Taramani-Velachery Link Road, Chennai – 600113, Tamil Nadu ,INSankar Venkatachalam
-
Life Sciences, National College (Autonomous), Tiruchirappalli – 620001, Tamil Nadu ,INMohammad Abdulkader Akbarsha
-
Department of Veterinary Integrative Biosciences, Texas A & M University, Texas ,USSakhila K. Banu
-
Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Taramani-Velachery Link Road, Chennai – 600113 ,INMariajoseph Michael Aruldhas
DOI:
https://doi.org/10.18311/jer/2017/23852Keywords:
Gonocytes, Leydig Cell, Sertoli Cell, Steroidogenesis, TestisAbstract
Chromium (Cr), an essential trace element, turns into an endocrine disruptor and male reproductive toxicant when its concentration in drinking water exceeds the safe limit. Improper disposal of effluents from more than 50 industries that use Cr contaminate the environment, in addition to occupational exposure of the workers. Testis has come to stay as a target for the reproductive toxicity of hexavalent Cr (CrVI), whereas its impact on fetal testicular differentiation remains elusive. We tested the hypothesis "In utero exposure to CrVI may alter the level of specific proteins controlling differentiation of testicular cell types”. Pregnant Wistar rats were exposed to drinking water containing 50, 100 and 200 ppm potassium dichromate (CrVI) during gestational days 14 to 21, covering the period of fetal differentiation of testicular cells. Testes were collected on postnatal day 1 and subjected to light microscopic histological studies and immunohistochemical detection of cell-specific proteins. Testis of neonatal rats with gestational exposure to high doses of CrVI showed shrunken and dispersed tubules with fewer gonocytes, extensive vacuolization of seminiferous cord accompanied by damaged epithelium, and shrunken Leydig cells present in large interstitial spaces and loose compaction of cells when compared coeval control group. Immunosignals of androgen and estrogen receptor β increased, whereas those of estrogen receptor α, follicle stimulating hormone receptor, anti-Mullerian hormone, P450 aromatase, inhibin, c-fos and c-jun decreased. Immunosignals of steroidogenic acute regulatory protein and CYP11A1 increased, whereas 3β - hydroxy steroid dehydrogenase and CYP17A1 proteins decreased, indicating compromised steroidogenic function. Our findings support the proposed hypothesis and we conclude that gestational exposure to CrVI disrupts specific hormones and hormone receptors that control fetal differentiation of testicular cells. The detrimental effect of gestational exposure to CrVI on functional differentiation of testicular cells may have a bearing on testicular function at adulthood.
Downloads
Metrics
Downloads
Published
How to Cite
Issue
Section
References
Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001; 16: 972-8. https://doi.org/10.1093/humrep/16.5.972 PMid:11331648
Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 1993; 341: 1392-5 https://doi. org/10.1016/0140-6736(93)90953-E
Acerini CL, Hughes IA. Endocrine disrupting chemicals: a new and emerging public health problem? Arch Dis Child. 2006; 91: 633-41. https://doi.org/10.1136/adc.2005.088500 PMid:16861481 PMCid:PMC2083052
Nordkap L, Joensen UN, Jensen MB, Jorgensen N. Regional differences and temporal trends in male reproductive health disorders: Semen quality may be a sensitive marker of environmental exposures. Mol Cell Endocrinol. 2012; 355: 221-30. https://doi.org/10.1016/j.mce.2011.05.048 PMid:22138051
Anderson RA. Nutritional role of chromium. Sci Total Environ. 1981; 17: 13-29. https://doi.org/10.1016/0048- 9697(81)90104-2
Anderson RA, Polansky MM. Dietary and metabolite effects on trivalent chromium retention and distribution in rats. Biol Trace Elem Res. 1995; 50: 97-108. https://doi. org/10.1007/BF02789412 PMid:8605085
Cefalu WT, Wang ZQ, Zhang XH, Baldor LC, Russell JC. Oral chromium picolinate improves carbohydrate and lipid metabolism and enhances skeletal muscle Glut-4 translocation in obese, hyperinsulinemic (JCR-LA corpulent) rats. J Nutr. 2002; 132: 1107-14. https://doi.org/10.1093/ jn/132.6.1107 PMid:12042418
Piva A, Meola E, Gatta P, Biagi G, Castellani G, Mordenti A, Luchansky J, Silva S, Mordenti A. The effect of dietary supplementation with trivalent chromium on production performance of laying hens and the chromium content in the yolk. Anim Feed Sci Technol. 2003; 106: 149-63. https:// doi.org/10.1016/S0377-8401(03)00006-3
Blacksmith Institute (New York), World's worst toxic pollution problem: The top ten of toxic twenty, Report, 2011, pp. 34-37.
Kumar MK, Aruldhas MM, Banu SL, Balaji S, Vengatesh G, Ganesh MK, Shobana N, Navin AK, Felicia MM, Sankar V, Stanley JA, Ilangovan R, Banu SK, Akbarsha MA. Male reproductive toxicity of CrVI: In-utero exposure to CrVI at the critical window of testis differentiation represses the expression of Sertoli cell tight junction proteins and hormone receptors in adult F1 progeny rats. Reprod Toxicol. 2017; 69: 84-98. https://doi.org/10.1016/j.reprotox. 2017.02.007 PMid:28192182
Shobana N, Aruldhas MM, Tochhawng L, Loganathan A, Balaji S, Kumar MK, Banu LAS, Navin AK, Mayilvanan C, Ilangovan R, Balasubramanian K. Transient gestational exposure to drinking water containing excess hexavalent chromium modifies insulin signaling in liver and skeletal muscle of rat progeny. Chem Biol Interact. 2017; 277: 119-28. https://doi.org/10.1016/j.cbi.2017.09.003 PMid:28911802
Pure Earth and Green Cross (Switzerland). The World's Worst Pollution Problems series -”The New Top Six Toxic Threats: A Priority List for Remediation.” 2015; 10th Report.
Stohs JS, Bagchi D, Hassoun E, Bagchi M. Oxidative mechanism in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol. 2001; 20:77-88. https:// doi.org/10.1615/JEnvironPatholToxicolOncol.v20.i2.10 PMid:11394715
Costa M, Klein CB. Toxicity and carcinogenicity of chromium compounds in humans. Crit Rev Toxicol. 2006; 36:155-63. https://doi.org/10.1080/10408440500534032 PMid:16736941
Akpor OB, Ohiobor GO, Olaolu TD. Heavy metal pollutants in wastewater effluents: sources, effects and remediation. Adv Biosci Bioeng. 2014; 2: 37-43. https://doi. org/10.11648/j.abb.20140204.11
Blacksmith Institute. Polluted Places- India. Final report, 2007. January 2005- December 2007. Project implemented by Blacksmith Institute. Supported under Poverty and Environment Program (PEP), Asian Development Bank.
Sutton, R. Chromium-6 in U.S. Tap Water, In: Houlihan J, Sharp R, Bruzelius N, (Eds.), Environmental Working Group, Washington DC, 2010; pp. 1-23.
Salnikow K, Zhitkovich A. Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. Chem. Res. Toxicol. 2008; 21:28- 44. https://doi.org/10.1021/tx700198a PMid:17970581 PMCid:PMC2602826
Hawthorne M. Toxic chromium found in Chicago drinking water. 2011. Chicago Tribune, Chicago.
Honeycutt ME. Hexavalent chromium in Texas drinking water. Toxicol Sci. 2011; 119:423-24; author reply 425. https://doi.org/10.1093/toxsci/kfq347 PMid:21081757
USEPA. Drinking water contaminants- standard and regulations, Washington DC, 2017 https://www.epa.gov/ dwstandardsregulations.
CPCB (Central Pollution Control Board), Report on groundwater quality in Kanpur: status, sources and control measures: GWQS/8/1996-97. Central Pollution Control Board, India, 1997; 1:4-5.
Sharma P, Bihari V, Agarwal SK, Verma V, Kesavachandran CN, Pangtey BS, Mathur N, Singh KP, Srivastava M, Goel SK. Groundwater contaminated with hexavalent chromium [Cr (VI)]: a health survey and clinical examination of community inhabitants (Kanpur, India). PLoS One, 2012; 7: e47877 https://doi.org/10.1371/journal.pone.0047877 PMid:23112863 PMCid:PMC3480439
INSA (Indian National Science Academy, New Delhi). Hazardous metals and minerals pollution in India, 2011, August, A position paper.
Remy LL, Byers V, Clay T. Reproductive outcomes after non-occupational exposure to hexavalent chromium, Willits California, 1983-2014. Environ Health. 2017; 16:18. https://doi.org/10.1186/s12940-017-0222-8 PMid:28264679 PMCid:PMC5340004
Shmitova LA. Content of hexavalent chromium in the biological substrates of pregnant women and women in the immediate post-natal period engaged in the manufacture of chromium compounds. Gigiena Truda i Professional'nye Zabolevaniya, 1980; 2:33-35.
Li H, Chen X, Li S, Yao W, Li L, Shi , Wang L, Castranova V, Vallyathan V, Ernst E, Chen C. Effect of Cr(VI) exposure on sperm quality: human and animal studies. Ann Occup Hyg. 2001; 45:505-11. https://doi.org/10.1016/S0003- 4878(01)00004-7
Mortensen J. Risk for reduced sperm quality among metal workers, with special reference to welders. Scand J Work Env Health. 1988; 14: 27-30. https://doi.org/10.5271/ sjweh.1954
Bonde JP. Semen quality and sex hormones among mild steel and stainless steel welders: a cross sectional study. Br J Ind Med 1990; 47: 508-514. https://doi.org/10.1136/ oem.47.8.508 PMid:2118383 PMCid:PMC1035221
Bonde JP. Subfertility in relation to welding. A case referent study among male welders. Dan Med Bull. 1990; 37:105-08.
Bonde JP. The risk of male subfecundity attributable to welding of metals: studies of semen quality, infertility, adverse pregnancy outcome and childhood malignancy. Int J Androl. 1993;16:1-29. https://doi.org/10.1111/j.1365-2605.1993. tb01367.x PMid:8070939
Figa-Talamanca I, Petrelli G. Reduction in male births among workers exposed to metal fumes. Int J Epedimiol. 2000; 29:381- 83. https://doi.org/10.1093/ije/29.2.381 PMid:10817140
Danielsson BR, Dencker L, Lindgren A, Tjalve H. Accumulation of toxic metals in male reproduction organs. Arch Toxicol. 1984; 7:177-80. https://doi.org/10.1007/978- 3-642-69132-4_26
Sipowicz MA, Anderson LM, Utermahlen WE Jr, Issaq HJ and Kasprzak KS. Uptake and tissue distribution of chromium (III) in mice after a single intraperitoneal or subcutaneous administration. Toxicol Lett. 1997; 93:9-14. https://doi.org/10.1016/S0378-4274(97)00064-7
Sutherland JE, Zhitkovich A, Kluz T, Costa M. Rats retain chromium in tissues following chronic ingestion of drinking water containing hexavalent chromium. Biol Trace Elem Res. 2000; 74:41-53. https://doi.org/10.1385/BTER:74:1:41
Behari J, Chandra SV, Tandon SK. Comparative toxicity of trivalent and hexavalent chromium to rabbits: III. Biochemical and histological changes in testicular tissue. Acta Biol Med Ger. 1978; 37:463-68.
Saxena DK, Murthy RC, Lal B, Srivastava RS, Chandra SV. Effect of hexavalent chromium on testicular maturation in the rat. ReprodToxicol. 1990; 4:223-28. https://doi. org/10.1016/0890-6238(90)90062-Z
Ernst E. Testicular toxicity following short-term exposure to tri- and hexavalent chromium: an experimental study in the rat. Toxicol Lett. 1990; 51:269-75. https://doi. org/10.1016/0378-4274(90)90069-X
Ernst E, Bonde JP. Sex hormones and epididymal sperm parameters in rats following sub-chronic treatment with hexavalent chromium. Hum Exp Toxicol. 1992; 11:255-58. https://doi.org/10.1177/096032719201100403 PMid:1354972
Murthy RC, Saxena DK, Gupta SK, Chandra SV. Ultrastructural observations in testicular tissue of chromium- treated rats. Reprod Toxicol. 1991a; 5:443-47. https://doi.org/10.1016/0890-6238(91)90008-4
Muthy RC, Saxena DK, Gupta SK, Chandra SV. Lead induced ultrastructural changes in the testis of rats. Exp Pathol. 1991b; 42:95-100. https://doi.org/10.1016/S0232- 1513(11)80054-X
Marouani N, Tebourbi O, Mahjoub S, Yacoubi MT, Sakly M, Benkhalifa M, Rhouma KB. Effects of hexavalent chromium on reproductive functions of male adult rats. Reprod Biol. 2012; 12:119-33. https://doi.org/10.1016/S1642- 431X(12)60081-3
Aruldhas MM, Govindarajulu P, Hasan GC. Effect of chronic chromium exposure on sperm maturation and male fertility. In: Final Technical Report of major research project sponsored by Council of Scientific and Industrial Research, Government of India, New Delhi. 2000; (no. 60(0022)/EMR II/97).
Subramanian S, Rajendiran G, Sekhar P, Gowri C, Govindarajulu P, Aruldhas MM. Reproductive toxicity of chromium in adult bonnet monkeys (Macaca radiata Geoffrey). Reversible oxidative stress in the semen. Toxicol Appl Pharmacol. 2006; 215:237-49. https://doi. org/10.1016/j.taap.2006.03.004 PMid:16678873
Aruldhas MM, Subramanian S, Sekhar P, Hasan GC, Govindarajulu P, Akbarsha MA. Microcanalization in the epididymis to overcome ductal obstruction caused by chronic exposure to chromium - a study in the mature bonnet monkey (Macaca radiata Geoffroy). Reproduction. 2004; 128:127-37. https://doi.org/10.1530/rep.1.00067 PMid:15232070
Aruldhas MM, Subramanian S, Sekar P, Vengatesh G, Chandrahasan G, Govindarajulu P, Akbarsha MA. Chronic chromium exposure-induced changes in testicular histoarchitecture are associated with oxidative stress: study in a non-human primate (Macaca radiata Geoffroy). Hum Reprod. 2005; 20:2801-13 https://doi.org/10.1093/humrep/ dei148 PMid:15980013
Aruldhas MM, Subramanian S, Sekhar P, Vengatesh G, Govindarajulu P and Akbarsha MA. In vivo spermatotoxic effect of chromium as reflected in the epididymal epithelial principal cells, basal cells, and intraepithelial macrophages of a nonhuman primate (Macaca radiata Geoffroy). Fertil Steril. 2006; 86:1097-105. https://doi.org/10.1016/j.fertnstert. 2006.03.025 PMid:16949592
Sekar P, Vengatesh G, Kumar MK, Balaji S, Akbarsha MA, Aruldhas MM. Impact of gestational and lactational exposure to hexavalent chromium on steroidogenic compartment of post-natal rat testis, J Endocrinol Reprod. 2011; 15:15-26.
Das J, Kang MH, Kim E, Kwon DN, Choi YJ, Kim JH. Hexavalent chromium induces apoptosis in male somatic and spermatogonial stem cells via redox imbalance. Sci Rep. 2015; 5:13921. https://doi.org/10.1038/srep13921 PMid:26355036 PMCid:PMC4564811
Magre S, Jost A. Sertoli cells and testicular differentiation in the rat fetus. J Electron Microsc Tech. 1991; 19:172-88. https://doi.org/10.1002/jemt.1060190205 PMid:1748901
Subramanian S. Reproductive toxicity of chromium in adult male rats: An endocrine and biochemical study. Ph.D. Thesis, University of Madras, Chennai, India, 2001.
Sun H, Brocato J, Costa M. Oral chromium exposure and toxicity. Curr Environ Health Rep. 2015; 2: 295-303 https://doi.org/10.1007/s40572-015-0054-z PMid:26231506 PMCid:PMC4522702
Johnson T. India's threatened water supplies, Council of Foreign Relations, 2007, Times of India.
Sar M, Welsch F. Differential expression of estrogen receptor- beta and estrogen receptor-alpha in the rat ovary. Endocrinology, 1999; 140:963-71. https://doi.org/10.1210/ endo.140.2.6533 PMid:9927330
Hsieh MH, Breyer BN, Eisenberg ML, Baskin LS. Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption. Curr Urol Rep. 2008; 9:137-42. https://doi.org/10.1007/s11934-008-0025-0 PMid:18419998
McIntyre BS, Barlow NJ, Foster PM. Androgen-mediated development in male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues. Toxicol Sci. 2001; 62:236-49 https://doi.org/10.1093/toxsci/62.2.236 PMid:11452136
Cowley JJ, Pewtress RK. Ano-genital distance as a factor in determining puberty acceleration in mice. J Reprod Fertil. 1986; 78: 685-91, PubMed PMID: 3643279. https://doi. org/10.1530/jrf.0.0780685
Atkinson TG, Blecher SR. Aberrant anogenital distance in XXSxr ("sex reversed”) pseudo male mice. J Zool Lond. 1994; 233:581-589. https://doi.org/10.1111/j.1469-7998.1994. tb05366.x
Fisher JS. Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction 2004; 127:305-15. https:// doi.org/10.1530/rep.1.00025 PMid:15016950
Rey R, Lukas-Croisier C, Lasala C, Bedecarras P. AMH/ MIS: what we know already about the gene, the protein and its regulation. Mol Cell Endocrinol. 2003; 211:21-31. https://doi.org/10.1016/j.mce.2003.09.007 PMid:14656472
Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest. 2008; 118(4):1479- 90. https://doi.org/10.1172/JCI34241 PMid:18340380 PMCid:PMC2267017
Jost A, Magre S, Agelopoulou R. Early stages of testicular differentiation in the rat. Hum Gene, 1981; 58:59-63. https://doi.org/10.1007/BF00284150 PMid:7286994
Magre S, Jost A. Sertoli cells and testicular differentiation in the rat fetus. J Electron Microsc Tech. 1991; 19:172-88. https://doi.org/10.1002/jemt.1060190205 PMid:1748901
Koopman P, Munsterberg A, Capel B, Vivian N, Lovell- Badge R. Expression of a candidate sex- determining gene during mouse testis differentiation. Nature. 1990; 348:450- 52. https://doi.org/10.1038/348450a0 PMid:2247150
Munsterberg A, Lovell-Badge R. Expression of the mouse anti-Müllerian hormone gene suggests a role in both male and female sex differentiation. Development. 1991; 113:613-24.
Vengatesh G, Kathiresh Kumar M, Sheerin Banu L, Aruldhas MM. Mechanism underlying infertility of male rats subjected to gestational exposure to CrVI. XXVIII National Symposium of the Society for Reproductive Biology and Comparative Endocrinology, New Delhi (India), 2010.
Kumar M, Balaji S, Navin AK, Ganesh MK, Aswini S, Chandra S, Shankar S, Akbarsha MA, Aruldhas MM. Gestational exposure to hexavalent Cr interferes with expression of specific genes involved in sex differentiation. XXXI National Symposium of the Society for Reproductive Biology and Comparative Endocrinology, Karnatak University, Dharwad, Karnataka (India), 2013.
Behringer RR, Finegold MJ, Cate RL. Müllerian inhibiting substance function during mammalian sexual development. Cell. 1994; 79: 415-25. https://doi.org/10.1016/0092-8674(94)90251-8
Rouiller-Fabre V, Carmona S, Merhi RA, Cate R, Habert R, Vigier B. Effect of anti-Müllerian hormone on Sertoli and Leydig cell function in fetal and immature rats. Endocrinology. 1998; 139:1213-20. https://doi.org/10.1210/ en.139.3.1213 PMid:9492056
Rey RA, Musse M, Venara M, Chemes HE. Ontogeny of the androgen receptor expression in the fetal and postnatal testis: its relevance on Sertoli cell maturation and the onset of adult spermatogenesis. Microsc Res Tech. 2009; 72:787-95.
Al-Attar L, Noel K, Dutertre M, Belville C, Forest MG, Burgoyne PS, Josso N, Rey R. Hormonal and cellular regulation of Sertoli cell anti-Mullerian hormone production in the postnatal mouse. J Clin Invest. 1997; 100: 1335-43.
Sharpe RM, McKinnell C, Kivlin C, Fisher JS. Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction. 2003; 125:769-84. https://doi.org/10.1530/ reprod/125.6.769 PMid:12773099
Majdic G, McNeilly AS, Sharpe RM, Evans LR, Groome NP, Saunders PT. Testicular expression of inhibin and activin subunits and follistatin in the rat and human fetus and neonate and during postnatal development in the rat. Endocrinology. 1997; 138:2136-47. https://doi.org/10.1210/ en.138.5.2136 PMid:9112414
Vale W, Rivier C, Hsueh A. Chemical and biological characterization of the inhibin family of protein hormones. Recent Prog Horm Res. 1988; 44:1-34.
Grinspon RP, Rey R. Anti-Mullerian hormone and Sertoli cell function in paediatric male hypogonadism. Horm Re. Paedter. 2010; 73:81-92. https://doi.org/10.1159/000277140 PMid:20190544
Warren DW, Huhtaniemi IT, Tapanainen J, Dufau ML, Catt KJ. Ontogeny of gonadotropin receptors in the fetal and neonatal rat testis. Endocrinology. 1984; 114:470-476. https://doi.org/10.1210/endo-114-2-470 PMid:6317355
Rannikki AS, Zhang FP, Huhtaniemi IT. Ontogeny of follicle- stimulating hormone receptor gene expression in the rat testis and ovary. Mol Cell Endocrinol. 1995; 107:199- 208. https://doi.org/10.1016/0303-7207(94)03444-X
Lecerf L, Rouiller-Fabre V, Levacher C, Gautier C, Saez JM, et al. Stimulatory effect of follicle-stimulating hormone on basal and luteinizing hormone-stimulated testosterone secretions by the fetal rat testis in vitro. Endocrinology. 1993; 133:2313- 18. https://doi.org/10.1210/en.133.5.2313 PMid:8404683
Vergouwen RP, Huiskamp R, Bas RJ, Roepers-Gajadien HL, Davids JA, de Rooij GD. Postnatal development of testicular cell populations in mice. J Reprod Fertil. 1993; 99:479-85.
Orth JM. The role of follicle-stimulating hormone in controlling Sertoli cell proliferation in testes of fetal rats. Endocrinology. 1984; 115:1248-55. https://doi.org/10.1210/ endo-115-4-1248 PMid:6090096
Migrenne S, Moreau E, Pakarinen P, Dierich A, Merlet J, Habert R, Racine C. Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal Life. PLoS ONE. 2012; 7:e53257. https://doi.org/10.1371/journal. pone.0053257 PMid:23300903 PMCid:PMC3531970
Migrenne S, Racine C, Guillou F, Habert R. Pituitary hormones inhibit the function and differentiation of fetal Sertoli cells. Endocrinology. 2003; 144:2617-22. https://doi. org/10.1210/en.2002-0011 PMid:12746325
Hall SH, Joseph DR, French FS, Conti M. Folliclestimulating hormone induces transient expression of the protooncogene c-fos in primary Sertoli cell cultures. Mol Endocrinol. 1988; 2:55-61. https://doi.org/10.1210/mend- 2-1-55 PMid:3135483
Heckert LL, Daggett MA, Chen J. Multiple promoter elements contribute to activity of the follicle- stimulating hormone receptor (FSHR) gene in testicular Sertoli cells. Mol Endocrinol. 1998; 12:1499 -512. https://doi. org/10.1210/me.12.10.1499 PMid:9773974
El-Gehani, F, Zhang FP, Pakarinen P, Rannikko A, Huhtaniemi I. Gonadotropin-independent regulation of steroidogenesis in the fetal rat testis. Biol Reprod. 1998; 58:116-23. https:// doi.org/10.1095/biolreprod58.1.116 PMid:9472931
Zhang FP, Hamalainen T, Kaipia A, Pakarinen P, Huhtaniemi I. Ontogeny of luteinizing hormone receptor gene expression in the rat testis. Endocrinology. 1994; 134:2206-13. https://doi.org/10.1210/en.134.5.2206 PMid:8156923
Zhang, FP, Poutanen M, Wilbertz J, Huhtaniemi I. Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LHRKO) mice. Mol Endocrinol. 2001; 15:172- 183. https://doi.org/10.1210/ me.15.1.172 PMid:11145748
Saez JM. Leydig cells: endocrine, paracrine, and autocrine regulation. Endocr Rev. 1994; 15:574-626. https://doi. org/10.1210/edrv-15-5-574 PMid:7843069
Zhang FP, Pakarainen T, Zhu F, Poutanen M, Huhtaniemi I. Molecular characterization of postnatal development of testicular steroidogenesis in luteinizing hormone receptor knockout mice. Endocrinology. 2004; 145:1453-63.
Kendall SK, Samuelson LC, Saunders TL, Wood RI, Camper SA. Targeted disruption of the pituitary glycoprotein hormone alpha-subunit produces hypogonadal and hypothyroid mice. Genes Dev. 1995; 9:2007-19.
O'Shaughnessy PJ, Baker P, Sohnius U, Haavisto AM, Charlton HM, Huhtaniemi I. Fetal development of Leydig cell activity in the mouse is independent of pituitary gonadotroph function. Endocrinology. 1998; 139:1141-46.
O'Shaughnessy PJ, Baker PJ, Heikkila M, Vainio S, McMahon AP. Localization of 17-beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase isoform expression in the developing mouse testis- androstenedione is the major androgen secreted by fetal/neonatal Leydig cells. Endocrinology. 2000; 141:2631-37. https://doi.org/10.1210/ en.141.7.2631 PMid:10875268
Shima Y, Miyabayashi K, Haraguchi S, Arakiwa T, Otake H, Baba TT, Matsuzaki S, Shishido Y, Ariyama H, Tachibana T. Contribution of Leydig and Sertoli cells to testosterone production in mouse fetal testis. Mol Endocrinol. 2013; 27:63-73. https://doi.org/10.1097/HNP.0b013e318280f738 PMid:23399706
Adamsson A, Salonen V, Pranko J, Toppari J. Effects of maternal exposure to di-isononyl phthalate (DINP) and 1, 1-dichloro-2, 2-bis (p-chlorophenyl) ethylene (p,p'-DDE) on steroidogenesis in the fetal rat testis and adrenal gland. Reprod Toxicol. 2009; 28:66-74. https://doi.org/10.1016/j. reprotox.2009.03.002 PMid:19490997
Stocco DM, Clark BJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev. 1996; 17:221-44.
Rone MB, Midzak AS, Issop L, Rammouz G, Jagannathan S, Fan J, Ye X, Blonder J, Venestra T, Papadopoulos V. Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones. Mol Endocrinol. 2012; 26:1868-82. https://doi.org/10.1210/me.2012-1159 PMid:22973050 PMCid:PMC5416962
Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev. 2004; 25:947-70. https://doi.org/10.1210/ er.2003-0030 PMid:15583024
Morohashi KI, Omura T. Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function. FASEB J. 1996; 10:1569-77. https:// doi.org/10.1096/fasebj.10.14.9002548 PMid:9002548
Gregory CW, DePhilip RM. Detection of steroidogenic acute regulatory protein (StAR) in mitochondria of cultured rat Sertoli cells incubated with follicle-stimulating hormone. Biol Reprod. 1998; 58:470-74. https://doi. org/10.1095/biolreprod58.2.470 PMid:9475403
Ishikawa T, Hwang K, Lazzarino D, Morris PL. Sertoli cell expression of steroidogenic acute regulatory protein-related lipid transfer 1 and 5 domain-containing proteins and sterol regulatory element binding protein-1 are interleukin-1 beta regulated by activation of c-Jun N-terminal kinase and cyclooxygenase-2 and cytokine induction. Endocrinology. 2005; 146:5100-11. https://doi.org/10.1210/en.2005-0567 PMid:16123165
Chen H, Hardy MP, Zirkin BR. Age-related decreases in Leydig cell testosterone production are not restored by exposure to LH in vitro. Endocrinology. 2002; 143:1637-42. https://doi.org/10.1210/en.143.5.1637 PMid:11956144
Song L, Tang X, Kong Y, Ma H, Zou S. The expression of serum steroid sex hormones and steroidogenic enzymes following intraperitoneal administration of dehydroepiandrosterone (DHEA) in male rats Steroids. 2010; 75:213-18. https://doi.org/10.1016/j.steroids.2009.11.007 PMid:19961867
Van Pelt A, De Rooij D, Van der Burg B, Van der Saag P, Gustafsson J, Kuiper G. Ontogeny of estrogen receptor-beta expression in rat testis. Endocrinology.1999; 140: 478-483. https://doi.org/10.1210/en.140.1.478 PMid:9886860
Jefferson W, Couse J, Banks E, Korach K, Newbold R. Expression of estrogen receptor b is developmentally regulated in reproductive tissues of male and female mice. Biol Reprod. 2000; 62: 310-317. https://doi.org/10.1095/biolreprod62.2.310 PMid:10642567
O'Donnell L, Robertson KM, Jones ME, Simpson ER. Estrogen and spermatogenesis. Endocr Rev. 2001; 22:289- 318.
Greco TL, Payne AH. Ontogeny of expression of the genes for steroidogenic enzymes P450 side-chain cleavage, 3 betahydroxysteroid dehydrogenase, P450 17 alpha-hydroxylase/ C17-20 lyase, and P450 aromatase in fetal mouse gonads. Endocrinology. 1994; 135:262-68. https://doi.org/10.1210/ en.135.1.262 PMid:8013361
Delbès G, Levacher C, Habert R. Estrogen effects on fetal and neonatal testicular development. Reproduction. 2006; 132:527-38. https://doi.org/10.1530/rep.1.01231 PMid:17008464
Delbes G, Levacher C, Duquenne C, Racine C, Pakarinen P, Habert R. Endogenous estrogens inhibit mouse fetal Leydig cell development via estrogen receptor alpha. Endocrinology. 2005; 146:2454-61. https://doi.org/10.1210/ en.2004-1540 PMid:15661855
Delbes G, Levacher C, Pairault C, Racine C, Duquenne C, Krust A. Estrogen receptor beta-mediated inhibition of male germ cell line development in mice by endogenous estrogens during perinatal life. Endocrinology, 2004; 145:3395-403. https://doi.org/10.1210/en.2003-1479 PMid:15044378
Korach, KS, Couse J, Curtis S, Washburn T, Lindzey J, Kimbro K, Eddy E, Migliaccio S, Snedeker S, Lubahn D, Schomberg D, Smith E. Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. Rec Prog Horm Res.1996; 51:929-35.
