Abstract：
The theory of \"Developmental Origins of Health and Disease (DOHaD)\" espouses that environmental exposures to toxicants during critical developmental stages can affect health outcomes in adulthood. Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that can be transferred to developing organisms via the placenta and breast milk as an environmental endocrine disruptor. We herein implemented a cross-fostering model to decipher the contributions of prenatal vs. postnatal exposure to low or high dose DEHP (30 or 500 mg/kg-bw•d) on reproductive outcomes in male offspring and the underlying mechanism of action. Unexpectedly, we observed that postnatal DEHP exposure programmed weight gain in a dose-dependent manner, in-utero exposure to high dose DEHP appeared to constitute a significant factor in the weight loss of male offspring. Moreover, in the low dose group, offspring of control that were suckled by DEHP dams (CC-DE) generated a considerable number of adverse reproductive outcomes compared with the offspring of DEHP that were suckled by control dams (DE-CC), based on histopathologic alterations in the testis, blockage of sex hormone secretion, and transcriptional inhibition of steroid-hormone-related factors in the hypothalamic-pituitary-testicular (HPT) axis. However, DE-CC group affected reproductive dysfunction in male offspring more so than CC-DE in the high dose group. Mechanistically, DEHP contributed to the inhibition of steroidogenesis by perturbing the Wnt/β-catenin-signaling pathway. These studies confirm the sensitivity window in which future reproductive outcomes in offspring are influenced following developmental exposure to DEHP at two different dosages, and reveals a critical role for the Wnt/β-catenin signaling pathway in DEHP-induced male reproductive disorders.
摘要：
“健康与疾病的发育起源（DOHaD）”理论认为，在关键的发育阶段，环境暴露于有毒物质会影响成年后的健康结果。邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种增塑剂，可以通过胎盘和母乳作为环境内分泌干扰物转移到发育中的生物体中。我们在此实施了一个交叉培养模型来破译产前与出生后暴露于低或高剂量DEHP（30或500mg/kg·bw·d）对雄性后代生殖结局的影响及其潜在机制。出乎意料的是,我们观察到出生后DEHP暴露以剂量依赖性方式编程体重增加，子宫内暴露于高剂量DEHP似乎是雄性后代体重减轻的重要因素。此外，在低剂量组中，与由对照水坝（DE-CC）哺乳的DEHP后代相比，由DEHP水坝（CC-DE）哺乳的对照后代产生了相当数量的不良生殖结果，基于睾丸的组织病理学改变，性激素分泌受阻,和下丘脑-垂体-睾丸（HPT）轴中类固醇激素相关因子的转录抑制。然而,DE-CC组比高剂量组的CC-DE对雄性后代生殖功能障碍的影响更大。机械上,DEHP通过扰乱Wnt/β-连环蛋白信号通路来抑制类固醇生成。这些研究证实了在发育暴露于两种不同剂量的DEHP后影响后代未来生殖结果的敏感性窗口，并揭示了Wnt/β-catenin信号通路在DEHP诱导的男性生殖障碍中的关键作用。
