Excess Androgens in Utero Alters Fetal Testis Development
Excess Androgens in Utero Alters Fetal Testis Development
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DOI：
10.1210/en.2012-2153
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发表时间：
2013-05-01
期刊：
影响因子：
4.8
通讯作者：
Duncan, W. Colin
中科院分区：
文献类型：
--
作者：
Connolly, Fiona;Rae, Michael T.;Duncan, W. Colin
产前雄激素化会在成年女性后代中诱发多囊卵巢综合征样表型，这与胎儿卵巢中可检测到的改变有关，表明这种情况的妊娠起源。因此，我们使用绵羊动物模型研究了产前雄激素暴露增加是否也改变了睾丸发育。从妊娠第 62 天到第 70 天/第 90 天，每两周一次母体丙酸睾酮（TP；100 mg）会改变男性发育轨迹。男性胎儿血清 LH 降低 (P < .01)，睾丸 STAR、CYP11 和 CYP17 丰度降低。与此一致的是，体外基础睾丸 T 合成减少 (P < .001)。在产前暴露于 TP 的所有睾丸中，间质细胞分布均受到严重干扰 (P < .001)。为了检查雌激素的贡献，在第 62 天和第 82 天给胎儿注射 TP（20 mg）、强效雌激素激动剂己烯雌酚（DES；20 mg）或载体对照，并在第 90 天进行评估。胎儿（直接）TP 治疗（但不是 DES）的效果与母体（间接）TP 暴露平行，支持直接雄激素效应。第 102 天停止母体雄激素化使间质细胞分布恢复正常，但在第 112 天基础 T 输出增加，证明间质细胞发育可塑性。从第 30 天开始的早期母体雄激素暴露同样影响了第 90 天的间质细胞发育，但还影响了支持细胞和生殖细胞标记物的表达。我们在这项研究中表明，当雄激素的产生对于男性发育至关重要时，产前雄激素暴露的增加会改变间质细胞的发育和功能。这支持了与多囊卵巢综合征相关的妊娠背景可能对男性胎儿产生影响的概念。 （内分泌学154：1921-1933，2013）
Prenatal androgenization induces a polycystic ovary syndrome-like phenotype in adult female offspring, which is associated with alterations that can be detected in the fetal ovary, suggesting gestational origins of this condition. We therefore investigated whether increased prenatal androgen exposure also altered testicular development using ovine animal models. Biweekly maternal testosterone propionate (TP; 100 mg) from day 62 to day 70/day 90 of gestation altered male developmental trajectory. In male fetuses serum LH was decreased (P < .01), and testicular STAR, CYP11, and CYP17 abundance were reduced. Coincident with this, basal testicular T synthesis was decreased in vitro (P < .001). Leydig cell distribution was severely perturbed in all testes prenatally exposed to TP (P < .001). To examine the contribution of estrogens, fetuses were injected with TP (20 mg), the potent estrogen agonist, diethylstilbestrol (DES; 20 mg), or vehicle control at day 62 and day 82 and assessed at day 90. The effects of fetal (direct) TP treatment, but not DES, paralleled maternal (indirect) TP exposure, supporting a direct androgen effect. Cessation of maternal androgenization at day 102 returned Leydig cell distribution to normal but increased basal T output, at day 112, demonstrating Leydig cell developmental plasticity. Earlier maternal androgen exposure from day 30 similarly influenced Leydig cell development at day 90 but additionally affected the expression of Sertoli and germ cell markers. We show in this study that increased prenatal androgen exposure alters development and function of Leydig cells at a time when androgen production is paramount for male development. This supports the concept that gestational antecedents associated with polycystic ovary syndrome may have effects on the male fetus. (Endocrinology 154: 1921-1933, 2013)