Laboratorio de Fisio-Patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.
J Endocrinol. 2020 Dec;247(3):239-250. doi: 10.1530/JOE-20-0304.
Prenatal androgen exposure affects reproductive functions and has been proposed as an underlying cause of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal androgen exposure on ovarian lipid metabolism and to deepen our understanding of steroidogenesis regulation during adulthood. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. This treatment leads to two different phenotypes: irregular ovulatory and anovulatory animals. Our results showed that prenatally hyperandrogenized (PH) animals displayed altered lipid and hormonal profile together with alterations in steroidogenesis and ovarian lipid metabolism. Moreover, PH animals showed alterations in the PPARg system, impaired mRNA levels of cholesterol receptors (Ldlr and Srb1) and decreased expression of the rate-limiting enzyme of de novo cholesterol production (Hmgcr). Anovulatory PH animals presented an increase of ovarian cholesteryl esters levels and lipid peroxidation index. Together with alterations in cholesterol metabolism, we found an impairment of the steroidogenic pathway in PH animals in a phenotype-specific manner. Regarding fatty acid metabolism, our results showed, in PH animals, an altered expression of Srebp1 and Atgl, which are involved in fatty acid metabolism and triglycerides hydrolysis, respectively. In conclusion, fatty acid and cholesterol metabolism, which are key players in steroidogenesis acting as a source of energy and substrate for steroid production, were affected in animals exposed to androgens during gestation. These results suggest that prenatal androgen exposure leads to long-term effects that affect ovary lipid metabolism and ovarian steroid formation from the very first steps.
产前雄激素暴露会影响生殖功能，并被认为是多囊卵巢综合征（PCOS）的潜在病因。在这项研究中，我们旨在研究产前雄激素暴露对卵巢脂质代谢的影响，并深入了解成年期类固醇生成的调节。用睾酮使怀孕的大鼠雄激素过多，然后研究成年的雌性后代。这种处理会导致两种不同的表型：不规则排卵和无排卵动物。我们的结果表明，产前雄激素过多（PH）动物表现出脂质和激素谱的改变，以及类固醇生成和卵巢脂质代谢的改变。此外，PH 动物表现出 PPARg 系统的改变，胆固醇受体（Ldlr 和 Srb1）的 mRNA 水平降低，以及从头胆固醇产生的限速酶（Hmgcr）的表达减少。无排卵 PH 动物的卵巢胆甾醇酯水平和脂质过氧化指数增加。伴随着胆固醇代谢的改变，我们发现 PH 动物的类固醇生成途径以表型特异性的方式受损。关于脂肪酸代谢，我们的结果表明，在 PH 动物中，涉及脂肪酸代谢和甘油三酯水解的 Srebp1 和 Atgl 的表达发生改变。总之，在怀孕期间暴露于雄激素的动物中，脂肪酸和胆固醇代谢受到影响，而这两者都是类固醇生成的关键参与者，作为类固醇生成的能量和底物来源。这些结果表明，产前雄激素暴露会导致长期影响，从而影响卵巢脂质代谢和卵巢类固醇的形成。
