Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Biol Reprod. 2022 Aug 9;107(2):514-528. doi: 10.1093/biolre/ioac059.
Long-chain polyunsaturated fatty acids (LCPUFAs) are critical for fetal brain development. Infants born to preeclamptic mothers or those born growth restricted due to placental insufficiency have reduced LCPUFA and are at higher risk for developing neurodevelopmental disorders. Since plasma levels of testosterone (T) and fatty acid-binding protein 4 (FABP4) are elevated in preeclampsia, we hypothesized that elevated T induces the expression of FABP4 in the placenta leading to compromised transplacental transport of LCPUFAs. Increased maternal T in pregnant rats significantly decreased n-3 and n-6 LCPUFA levels in maternal and fetal circulation, but increased their placental accumulation. Dietary LCPUFAs supplementation in T dams increased LCPUFA levels in the maternal circulation and further augmented placental storage, while failing to increase fetal levels. The placenta in T dams exhibited increased FABP4 mRNA and protein levels. In vitro, T dose-dependently upregulated FABP4 transcription in trophoblasts. Testosterone stimulated androgen receptor (AR) recruitment to the androgen response element and trans-activated FABP4 promoter activity, both of which were abolished by AR antagonist. Testosterone in pregnant rats and cultured trophoblasts significantly reduced transplacental transport of C14-docosahexaenoic acid (DHA) and increased C14-DHA accumulation in the placenta. Importantly, FABP4 overexpression by itself in pregnant rats and trophoblasts increased transplacental transport of C14-DHA with no significant placental accumulation. Testosterone exposure, in contrast, inhibited this FABP4-mediated effect by promoting C14-DHA placental accumulation.
长链多不饱和脂肪酸（LCPUFAs）对胎儿大脑发育至关重要。患有先兆子痫的母亲所生的婴儿或因胎盘功能不全而生长受限的婴儿，其 LCPUFA 水平降低，患神经发育障碍的风险更高。由于先兆子痫患者的血浆睾酮（T）和脂肪酸结合蛋白 4（FABP4）水平升高，我们假设升高的 T 诱导胎盘 FABP4 的表达，导致 LCPUFA 的跨胎盘转运受损。怀孕大鼠的母体 T 增加显著降低了母体和胎儿循环中的 n-3 和 n-6 LCPUFA 水平，但增加了它们在胎盘的积累。在 T 处理的母鼠中补充饮食 LCPUFAs 增加了母体循环中的 LCPUFA 水平，并进一步增加了胎盘储存，但未能增加胎儿水平。T 处理的母鼠胎盘的 FABP4 mRNA 和蛋白水平增加。在体外，T 以剂量依赖的方式上调滋养细胞中的 FABP4 转录。睾酮刺激雄激素受体（AR）募集到雄激素反应元件并转激活 FABP4 启动子活性，这两种作用都被 AR 拮抗剂所阻断。在怀孕大鼠和培养的滋养细胞中，睾酮显著降低了 C14-二十二碳六烯酸（DHA）的跨胎盘转运，并增加了胎盘内 C14-DHA 的积累。重要的是，FABP4 过表达本身在怀孕大鼠和滋养细胞中增加了 C14-DHA 的跨胎盘转运，但没有显著的胎盘积累。相比之下，睾酮暴露通过促进 C14-DHA 胎盘积累来抑制这种 FABP4 介导的作用。
