Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
Biol Reprod. 2018 May 1;98(5):664-682. doi: 10.1093/biolre/ioy008.
Reproductive abnormalities are included as health complications in offspring exposed to poor prenatal nutrition. We have previously shown in a rodent model that offspring born to nutrient restriction during pregnancy are born small, enter puberty early, and display characteristics of early ovarian aging as adults. The present study investigated whether key proteins involved in follicle recruitment and growth mediate ovarian follicle loss. Pregnant rats were randomized to a standard diet throughout pregnancy and lactation (CON), or a calorie-restricted (50% of control) diet (UN) during pregnancy. Offspring reproductive phenotype was investigated at postnatal days 4, 27, and 65. Maternal UN resulted in young adult (P65) irregular estrous cyclicity due to persistent estrus, a significant loss of antral follicles, corpora lutea, and an increase in atretic follicles. This decrease in growing follicles in UN offspring appears to be due to increased apoptosis as seen by immunopositive staining of pro-apoptotic factor CASP3 (caspase 3) in ovaries of young adult offspring. UN prepubertal offspring had reduced expression levels of Fshr in antral follicles, which may contribute to a decrease in PI3K/AKT activation evident as a decrease in pAKT immunolocalization in prepubertal antral follicles. Moreover, neonatal ovaries of UN offspring show decreased levels of immunopositive staining for AMHR2 (anti-mullerian hormone receptor 2). Collectively, these data demonstrate that maternal UN during pregnancy impacts ovarian function in offspring as early as P65 and provides a model for understanding the mechanisms driving early life UN-induced follicle loss and reproductive dysfunction.
生殖异常被认为是胎儿在不良产前营养环境下的健康并发症。我们之前在啮齿动物模型中已经证明，在怀孕期间受到营养限制的后代出生时体型较小，青春期提前，成年后表现出卵巢早衰的特征。本研究旨在探讨参与卵泡募集和生长的关键蛋白是否介导了卵巢卵泡的损失。怀孕的大鼠被随机分为在整个怀孕期间和哺乳期给予标准饮食（CON）或怀孕期间给予热量限制（50%对照）饮食（UN）。在产后第 4、27 和 65 天，研究了后代的生殖表型。UN 母亲导致年轻成年（P65）的发情周期不规则，因为持续发情，导致窦卵泡、黄体和闭锁卵泡大量丢失。UN 后代生长卵泡的减少似乎是由于凋亡增加所致，因为年轻成年后代卵巢中促凋亡因子 CASP3（半胱天冬酶 3）的免疫阳性染色增加。UN 未成熟的后代窦卵泡中的 Fshr 表达水平降低，这可能导致 PI3K/AKT 激活减少，这表现为未成熟窦卵泡中 pAKT 免疫定位减少。此外，UN 后代的新生卵巢中 AMHR2（抗苗勒氏管激素受体 2）的免疫阳性染色减少。综上所述，这些数据表明，孕期 UN 会对后代的卵巢功能产生影响，早在 P65 就会产生影响，并为理解早期 UN 诱导的卵泡损失和生殖功能障碍的机制提供了一个模型。
