title: Mouse leydig cells with different androgen production potential are resistant to estrogenic stimuli but responsive to bisphenol a which attenuates testosterone metabolism.
abstract: It is well known that estrogens and estrogen-like endocrine disruptors can suppress steroidogenic gene expression, attenuate androgen production and decrease differentiation of adult Leydig cell lineage. However, there is no information about the possible link between the potency of Leydig cells to produce androgens and their sensitivity to estrogenic stimuli. Thus, the present study explored the relationship between androgen production potential of Leydig cells and their responsiveness to estrogenic compounds. To investigate this relationship we selected mouse genotypes contrasting in sex hormone levels and differing in testosterone/estradiol (T/E2) ratio. We found that two mouse genotypes, CBA/Lac and C57BL/6j have the highest and the lowest serum T/E2 ratio associated with increased serum LH level in C57BL/6j compared to CBA/Lac. Analysis of steroidogenic gene expression demonstrated significant upregulation of Cyp19 gene expression but coordinated suppression of LHR, StAR, 3βHSDI and Cyp17a1 in Leydig cells from C57BL/6j that was associated with attenuated androgen production in basal and hCG-stimulated conditions compared to CBA/Lac mice. These genotype-dependent differences in steroidogenesis were not linked to changes in the expression of estrogen receptors ERα and Gpr30, while ERβ expression was attenuated in Leydig cells from C57BL/6j compared to CBA/Lac. No effects of estrogenic agonists on steroidogenesis in Leydig cells from both genotypes were found. In contrast, xenoestrogen bisphenol A significantly potentiated hCG-activated androgen production by Leydig cells from C57BL/6j and CBA/Lac mice by suppressing conversion of testosterone into corresponding metabolite 5α-androstane-3α,17β-diol. All together our data indicate that developing mouse Leydig cells with different androgen production potential are resistant to estrogenic stimuli, while xenoestrogen BPA facilitates hCG-induced steroidogenesis in mouse Leydig cells via attenuation of testosterone metabolism. This cellular event can cause premature maturation of Leydig cells that may create abnormal intratesticular paracrine milieu and disturb proper development of germ cells.
authors: Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors: Iuliia
authors: I
authors: Savchuk
authors: Olle
authors: O
authors: Söder
authors: Konstantin
authors: K
authors: Svechnikov
mesh_terms: D000728:Androgens / Q000096:biosynthesis*; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006801:Humans; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D010636:Phenols / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013739:Testosterone / Q000378:metabolism*; D000098826:Bisphenol A Compounds
chemical_list: D000728:Androgens; D001559:Benzhydryl Compounds; D006063:Chorionic Gonadotropin; D004967:Estrogens; D008024:Ligands; D010636:Phenols; D011960:Receptors, Estrogen; D013739:Testosterone; C006780:bisphenol A; D000098826:Bisphenol A Compounds
references: Mol Cell Endocrinol. 2001 Sep;182(2):193-201
references: 11514054
references: Endocrinology. 1980 Jan;106(1):35-9
references: 7349966
references: Endocrinology. 1991 Sep;129(3):1429-35
references: 1874181
references: Proc Natl Acad Sci U S A. 1979 Sep;76(9):4460-3
references: 291977
references: Endocrinology. 2003 Jan;144(1):84-93
references: 12488333
references: Endocrinology. 1979 Aug;105(2):431-6
references: 456321
references: Mol Cell Endocrinol. 2004 Jul 30;222(1-2):113-20
references: 15249131
references: Endocrinology. 1981 Sep;109(3):763-7
references: 6973463
references: Chem Res Toxicol. 2001 Feb;14(2):149-57
references: 11258963
references: Endocrinology. 2002 Jun;143(6):2208-15
references: 12021184
references: Comp Med. 2004 Apr;54(2):179-84
references: 15134364
references: Cardiovasc Res. 2005 Jan 1;65(1):148-57
references: 15621042
references: Best Pract Res Clin Endocrinol Metab. 2002 Mar;16(1):31-41
references: 11987896
references: Endocrinology. 1998 Sep;139(9):3787-95
references: 9724031
references: Endocrinology. 2004 Feb;145(2):592-603
references: 14605012
references: Bull Exp Biol Med. 2010 Nov;149(6):739-42
references: 21165434
references: Endocrinology. 2005 May;146(5):2454-61
references: 15661855
references: Mol Cell Endocrinol. 2012 Oct 15;362(1-2):91-103
references: 22683664
references: Endocrinology. 2007 Nov;148(11):5507-19
references: 17673513
references: J Androl. 1991 Sep-Oct;12(5):295-304
references: 1662673
references: Mol Cell Endocrinol. 1982 Nov-Dec;28(3):705-16
references: 6217997
references: PLoS One. 2013;8(2):e55905
references: 23405234
references: Reproduction. 2007 Aug;134(2):271-9
references: 17660237
references: Annu Rev Physiol. 2001;63:193-213
references: 11181954
references: J Hered. 1974 Jul-Aug;65(4):204-8
references: 4471635
references: J Appl Toxicol. 2011 Aug;31(6):589-94
references: 21061451
references: Endocrinology. 2001 Jun;142(6):2435-42
references: 11356692
references: Endocrinology. 2007 Sep;148(9):4475-88
references: 17569756
references: Endocrinology. 2009 Jun;150(6):2865-72
references: 19196801
references: Endocrinology. 1980 May;106(5):1424-9
references: 6244930
references: PLoS One. 2013 Apr 19;8(4):e61726
references: 23620786
references: PLoS One. 2012;7(12):e51579
references: 23284716