Phthalates are commonly used plasticizers and additives that are found in plastic containers, children's toys and medical equipment. Phthalates are classified as endocrine-disrupting chemicals and exposure to phthalates has been associated with several human health risks including reproductive defects. Most studies focus on a single phthalate; however, humans are exposed to a mixture of phthalates daily. We hypothesized that prenatal exposure to an environmentally relevant phthalate mixture would lead to changes in uterine morphology and function in mice in a multi-generational manner. To test this hypothesis, pregnant CD-1 dams were orally dosed with vehicle or a phthalate mixture (20 μg/kg/day, 200 μg/kg/day, 200 mg/kg/day, and 500 mg/kg/day) from gestational day 10.5 to parturition. The mixture contained 35% diethyl phthalate, 21% di-(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. The F1 pups were maintained and mated to produce two more generations (F2 and F3). At the age of 13 months, all females were euthanized and tissue samples were collected in diestrus. Our results showed that exposure to a phthalate mixture caused a decrease in progesterone levels in the treated groups in the F2 generation. The 200 mg/kg/day treatment group showed a decreased and increased luminal epithelial cell proliferation in the F1 and F2 generations respectively. In addition, these mice in the F2 generation had reduced Hand2 expression in the sub-epithelial stroma compared to the controls. A higher incidence of multilayered luminal epithelium and large dilated endometrial glands were observed in the phthalate mixture exposed groups in all generations. The mixture also caused a higher incidence of smooth muscle actin expression and collagen deposition in the endometrium compared to controls. Collectively, our results demonstrate that prenatal exposure to an environmentally relevant phthalate mixture can have adverse effects on female reproductive functions.

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产前暴露于邻苯二甲酸盐混合物会导致小鼠子宫形态和功能的多代和跨代影响。

邻苯二甲酸酯是在塑料容器，儿童玩具和医疗设备中常用的增塑剂和添加剂。邻苯二甲酸盐被列为破坏内分泌的化学物质，接触邻苯二甲酸盐与包括生殖缺陷在内的几种人类健康风险有关。大多数研究只关注一种邻苯二甲酸盐。但是，人类每天要接触邻苯二甲酸盐的混合物。我们假设，产前暴露于环境相关的邻苯二甲酸酯混合物会导致小鼠的子宫形态和功能发生多代变化。为了检验这一假设，对口服的CD-1大坝口服媒介物或邻苯二甲酸盐混合物（20μg/ kg /天，200μg/ kg /天，200 mg / kg /天和500 mg / kg /天）。孕期10.5至分娩。该混合物包含35％的邻苯二甲酸二乙酯，21％的邻苯二甲酸二（2-乙基己基）酯，15％的邻苯二甲酸二丁酯，15％的邻苯二甲酸二异壬酯，8％的邻苯二甲酸二异丁酯和5％的邻苯二甲酸苄基丁酯。维持F1幼崽并交配以产生另外两个世代（F2和F3）。在13个月大时，所有雌性动物均被安乐死并在二头肌中收集组织样本。我们的结果表明，暴露于邻苯二甲酸盐混合物会导致F2代中治疗组的孕酮水平降低。200 mg / kg /天的治疗组分别在F1和F2代中显示出减少和增加的腔上皮细胞增殖。此外，与对照组相比，这些F2代小鼠在上皮下基质中的Hand2表达降低。在所有世代的邻苯二甲酸酯混合物暴露组中，观察到多层腔上皮和大的扩张子宫内膜腺的发生率更高。与对照相比，该混合物还引起子宫内膜平滑肌肌动蛋白表达和胶原沉积的更高发生率。总体而言，我们的结果表明，产前暴露于环境相关的邻苯二甲酸酯混合物可能会对女性生殖功能产生不利影响。