Department of Animal Sciences, University of Illinois, Urbana, IL, United States.
Department of Comparative Biosciences, University of Illinois, Urbana, IL, United States.
Reprod Toxicol. 2020 Apr;93:178-190. doi: 10.1016/j.reprotox.2020.02.012. Epub 2020 Feb 29.
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.
邻苯二甲酸酯是常用的增塑剂和添加剂，存在于塑料容器、儿童玩具和医疗器械中。邻苯二甲酸酯被归类为内分泌干扰化学物质，接触邻苯二甲酸酯与多种人类健康风险有关，包括生殖缺陷。大多数研究都集中在单一的邻苯二甲酸酯上；然而，人类每天都会接触到多种邻苯二甲酸酯的混合物。我们假设，在多代小鼠中，产前暴露于环境相关的邻苯二甲酸酯混合物会导致子宫形态和功能发生变化。为了验证这一假设，从妊娠第 10.5 天到分娩，用邻苯二甲酸酯混合物（20μg/kg/天、200μg/kg/天、200mg/kg/天和 500mg/kg/天）经口处理妊娠 CD-1 母鼠。混合物含有 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基酯。F1 幼崽被维持并交配以产生两代（F2 和 F3）。在 13 个月大时，所有雌性动物都被安乐死，并在动情期收集组织样本。我们的结果表明，暴露于邻苯二甲酸酯混合物会导致 F2 代处理组孕激素水平降低。200mg/kg/天的处理组在 F1 和 F2 代中分别表现出腔上皮细胞增殖减少和增加。此外，与对照组相比，这些 F2 代小鼠的上皮下基质中的 Hand2 表达减少。在所有世代中，暴露于邻苯二甲酸酯混合物的小鼠的腔上皮出现多层化和大的扩张子宫内膜腺的发生率增加。与对照组相比，混合物还导致子宫内膜中平滑肌肌动蛋白表达和胶原沉积的发生率增加。总之，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会对女性生殖功能产生不利影响。
