Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2013 Aug 15;8(8):e71722. doi: 10.1371/journal.pone.0071722. eCollection 2013.
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.
众所周知，雌激素和类雌激素内分泌干扰物可以抑制甾体生成基因的表达，减弱雄激素的产生，并减少成年莱迪希细胞谱系的分化。然而，关于莱迪希细胞产生雄激素的能力与其对雌激素刺激的敏感性之间的可能联系，尚无信息。因此，本研究探讨了莱迪希细胞雄激素产生潜力与其对雌激素化合物反应性之间的关系。为了研究这种关系，我们选择了在性激素水平上存在差异且睾丸酮/雌二醇（T/E2）比值不同的两种小鼠基因型。我们发现，两种小鼠基因型，CBA/Lac 和 C57BL/6j，具有最高和最低的血清 T/E2 比值，与 C57BL/6j 相比，血清 LH 水平升高。甾体生成基因表达分析表明，C57BL/6j 中的 Cyp19 基因表达显著上调，但 LHR、StAR、3βHSDI 和 Cyp17a1 的协同抑制导致基础和 hCG 刺激条件下雄激素产生减弱，与 CBA/Lac 小鼠相比。这些甾体生成的基因型依赖性差异与雌激素受体 ERα 和 Gpr30 的表达变化无关，而 ERβ 在 C57BL/6j 中的表达下调与 CBA/Lac 相比。在两种基因型的莱迪希细胞中，均未发现雌激素激动剂对甾体生成的影响。相反，外源性雌激素双酚 A 通过抑制睾酮转化为相应的代谢物 5α-雄烷-3α,17β-二醇，显著增强了来自 C57BL/6j 和 CBA/Lac 小鼠的 hCG 激活的雄激素产生。总的来说，我们的数据表明，具有不同雄激素产生潜力的发育中的小鼠莱迪希细胞对雌激素刺激具有抗性，而外源性雌激素 BPA 通过抑制睾酮代谢促进小鼠莱迪希细胞中的 hCG 诱导的甾体生成。这种细胞事件可能导致莱迪希细胞过早成熟，从而导致睾丸内旁分泌环境异常，并干扰生殖细胞的正常发育。
