Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression.
Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression.
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DOI：
10.1210/en.2012-2129
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发表时间：
2013-03
期刊：
影响因子：
4.8
通讯作者：
A. Veiga-Lopez;Lacey J. Luense;L. Christenson;V. Padmanabhan
中科院分区：
文献类型：
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作者：
A. Veiga-Lopez;Lacey J. Luense;L. Christenson;V. Padmanabhan
双酚A（BPA）是一种普遍存在的环境内分泌干扰化学品，是聚碳酸酯塑料和环氧树脂的成分。由于其雌激素特性，人们越来越关注在器官分化早期的关键时期暴露的风险。绵羊产前BPA治疗导致低出生体重、高促性腺激素和卵巢周期中断。本研究验证了妊娠期暴露于环境相关剂量的双酚A会诱导卵巢转录组（mRNA和microRNA）早期扰动的假设。从妊娠第30天至第90天，用双酚A（0.5 mg/kg，sc，每日一次，在BPA处理胎儿的脐动脉样本中产生约2.6 ng/mL的未结合BPA，接近母体循环中测得的BPA中位数水平）处理妊娠Suffolk母羊。类固醇生成酶，类固醇/促性腺激素受体，关键的卵巢调节因子和microRNA生物合成成分的表达通过RT-PCR使用来自妊娠第65天和第90天收集的胎儿卵巢的RNA进行测量。在大多数类固醇生成酶、类固醇受体和关键的卵巢调节因子中，年龄依赖性效应是明显的。产前BPA增加Cyp 19和5α-还原酶在第65天的表达，但不是第90天，卵巢。产前BPA改变了胎儿卵巢microRNA的表达，在妊娠第65天有45个下调（>1.5倍），在妊娠第90天有11个下调。这些包括靶向Sry相关的高迁移率族盒（SOX）家族基因、kit配体和胰岛素相关基因的microRNA。这项研究的结果表明，暴露于环境相关剂量的BPA改变胎儿卵巢类固醇基因和microRNA表达的性腺分化，卵泡发育和胰岛素稳态的相关性。
Bisphenol-A (BPA), a ubiquitous environmental endocrine disrupting chemical, is a component of polycarbonate plastic and epoxy resins. Because of its estrogenic properties, there is increasing concern relative to risks from exposures during critical periods of early organ differentiation. Prenatal BPA treatment in sheep results in low birth weight, hypergonadotropism, and ovarian cycle disruptions. This study tested the hypothesis that gestational exposure to bisphenol A, at an environmentally relevant dose, induces early perturbations in the ovarian transcriptome (mRNA and microRNA). Pregnant Suffolk ewes were treated with bisphenol A (0.5 mg/kg, sc, daily, produced ∼2.6 ng/mL of unconjugated BPA in umbilical arterial samples of BPA treated fetuses approaching median levels of BPA measured in maternal circulation) from days 30 to 90 of gestation. Expression of steroidogenic enzymes, steroid/gonadotropin receptors, key ovarian regulators, and microRNA biogenesis components were measured by RT-PCR using RNA derived from fetal ovaries collected on gestational days 65 and 90. An age-dependent effect was evident in most steroidogenic enzymes, steroid receptors, and key ovarian regulators. Prenatal BPA increased Cyp19 and 5α-reductase expression in day 65, but not day 90, ovaries. Fetal ovarian microRNA expression was altered by prenatal BPA with 45 down-regulated (>1.5-fold) at day 65 and 11 down-regulated at day 90 of gestation. These included microRNAs targeting Sry-related high-mobility-group box (SOX) family genes, kit ligand, and insulin-related genes. The results of this study demonstrate that exposure to BPA at an environmentally relevant dose alters fetal ovarian steroidogenic gene and microRNA expression of relevance to gonadal differentiation, folliculogenesis, and insulin homeostasis.