Acute Exposure to Di(2-Ethylhexyl) Phthalate in Adulthood Causes Adverse Reproductive Outcomes Later in Life and Accelerates Reproductive Aging in Female Mice
Acute Exposure to Di(2-Ethylhexyl) Phthalate in Adulthood Causes Adverse Reproductive Outcomes Later in Life and Accelerates Reproductive Aging in Female Mice
复制标题
DOI：
10.1093/toxsci/kfv317
复制
发表时间：
2016-03-01
影响因子：
3.8
通讯作者：
Flaws, Jodi A.
中科院分区：
文献类型：
--
作者：
Hannon, Patrick R.;Niermann, Sarah;Flaws, Jodi A.
人类普遍暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP），这是一种消费品中的环境毒物。研究表明，DEHP以卵巢为目标，破坏生殖和非生殖健康所需的基本过程。具体而言，暴露于DEHP 10天会加速原始卵泡的募集，并破坏成年小鼠的发情周期。然而，尚不清楚急性DEHP暴露后对卵泡发生和周期性的这些影响是否会对生殖结局产生永久性影响。此外，原始卵泡的过早消耗可导致早期生殖衰老，目前尚不清楚急性DEHP暴露是否会加速生殖衰老。本研究测试了急性DEHP暴露导致不孕、破坏发情周期、改变激素水平、通过诱导晚年闭锁消耗卵泡数量、导致加速生殖衰老的假设。成年CD-1小鼠每日经口给予溶剂或DEHP（20 μ g/kg/天-500 mg/kg/天），持续10天，并在给药后6个月和9个月评估生殖结局。与给药后6个月和9个月的对照组相比，急性DEHP暴露显著改变了发情周期，分别增加了小鼠处于发情期和发情后期/间情期的天数百分比。在给药后9个月，与对照组相比，DEHP还显著降低了胆红素B水平。此外，与给药后9个月的对照组相比，DEHP显著增加了原始卵泡中的BAX/BCL 2比率，导致原始卵泡和总卵泡数量显著减少。总的来说，急性DEHP暴露后出现的不良反应在生命后期持续存在，并与加速生殖衰老一致。
Humans are ubiquitously exposed to di(2-ethylhexyl) phthalate (DEHP), which is an environmental toxicant incorporated in consumer products. Studies have shown that DEHP targets the ovary to disrupt essential processes required for reproductive and nonreproductive health. Specifically, 10-day exposure to DEHP accelerates primordial follicle recruitment and disrupts estrous cyclicity in adult mice. However, it is unknown if these effects on folliculogenesis and cyclicity following acute DEHP exposure can have permanent effects on reproductive outcomes. Further, the premature depletion of primordial follicles can cause early reproductive senescence, and it is unknown if acute DEHP exposure accelerates reproductive aging. This study tested the hypothesis that acute DEHP exposure causes infertility, disrupts estrous cyclicity, alters hormone levels, and depletes follicle numbers by inducing atresia later in life, leading to accelerated reproductive aging. Adult CD-1 mice were orally dosed with vehicle or DEHP (20 mu g/kg/day-500 mg/kg/day) daily for 10 days, and reproductive outcomes were assessed at 6 and 9 months postdosing. Acute DEHP exposure significantly altered estrous cyclicity compared to controls at 6 and 9 months postdosing by increasing the percentage of days the mice were in estrus and metestrus/diestrus, respectively. DEHP also significantly decreased inhibin B levels compared to controls at 9 months postdosing. Further, DEHP significantly increased the BAX/BCL2 ratio in primordial follicles leading to a significant decrease in primordial and total follicle numbers compared to controls at 9 months postdosing. Collectively, the adverse effects present following acute DEHP exposure persist later in life and are consistent with accelerated reproductive aging.