Developmental methoxychlor exposure affects multiple reproductive parameters and ovarian folliculogenesis and gene expression in adult rats.
Developmental methoxychlor exposure affects multiple reproductive parameters and ovarian folliculogenesis and gene expression in adult rats.
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DOI：
10.1016/j.taap.2008.09.010
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发表时间：
2008-12-01
影响因子：
3.8
通讯作者：
Uzumcu, Mehmet
中科院分区：
文献类型：
--
作者：
Armenti, AnnMarie E.;Zama, Aparna Mahakah;Passantino, Lisa;Uzumcu, Mehmet
关键词：
甲氧滴滴涕（MXC）是一种具有雌激素、抗雌激素和抗雄激素特性的有机氯农药。为了研究短暂发育暴露于MXC是否会导致成年卵巢功能障碍，我们在妊娠后19天至出生后第7天期间将Fischer大鼠暴露于20 μg/kg/天（低剂量;环境相关剂量）或100 mg/kg/天（高剂量）MXC。多个生殖参数，血清激素水平，卵巢形态和分子标记物进行了检查，从青春期前到成年阶段。MXC高剂量组能显著促进小鼠青春期开始和首次发情，减少产仔数，增加不规则发情周期（P < 0.05）。MXC可降低青春期前女性对外源性促性腺激素的超排卵反应（P < 0.05）。暴露于高剂量MXC的大鼠从4个月大开始，不规则的动情周期逐渐增加，所有动物在6个月时均表现出异常周期。MXC高剂量降低血清孕酮，但升高黄体生成素（LH）。卵泡组成分析显示，高剂量MXC处理组的腔前卵泡和早期腔卵泡百分比增加，黄体百分比减少（P < 0.05）。免疫组化染色和染色强度定量显示，高剂量MXC可降低窦前卵泡和早期卵泡中雌激素受体β的表达，而高、低剂量MXC可上调窦前卵泡和早期卵泡中抗苗勒管激素的表达（P < 0.05）。MXC高剂量组显著降低大腔卵泡LH受体表达（P < 0.01），下调细胞色素P450侧链裂解。这些结果表明，发育中的MXC暴露导致排卵和生育能力降低以及过早衰老，可能是通过改变卵巢基因表达和卵泡发生。
Methoxychlor (MXC) is an organochlorine pesticide with estrogenic, anti-estrogenic, and anti-androgenic properties. To investigate whether transient developmental exposure to MXC could cause adult ovarian dysfunction, we exposed Fischer rats to 20 μg/kg/day (low dose; environmentally relevant dose) or 100 mg/kg/day (high dose) MXC between 19 days post-coitum and postnatal day 7. Multiple reproductive parameters, serum hormone levels, and ovarian morphology and molecular markers were examined from prepubertal through adult stages. High dose MXC accelerated pubertal onset and first estrus, reduced litter size, and increased irregular cyclicity (P < 0.05). MXC reduced superovulatory response to exogenous gonadotropins in prepubertal females (P < 0.05). Rats exposed to high dose MXC had increasing irregular estrous cyclicity beginning at 4 months of age, with all animals showing abnormal cycles by 6 months. High dose MXC reduced serum progesterone, but increased luteinizing hormone (LH). Follicular composition analysis revealed an increase in the percentage of preantral and early antral follicles and a reduction in the percentage of corpora lutea in high dose MXC-treated ovaries (P < 0.05). Immunohistochemical staining and quantification of the staining intensity showed that estrogen receptor β was reduced by high dose MXC while anti-Mullerian hormone was upregulated by both low- and high dose MXC in preantral and early antral follicles (P < 0.05). High dose MXC significantly reduced LH receptor expression in large antral follicles (P < 0.01), and down-regulated cytochrome P450 side-chain cleavage. These results demonstrated that developmental MXC exposure results in reduced ovulation and fertility and premature aging, possibly by altering ovarian gene expression and folliculogenesis.
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