Department of Biology, East Carolina University, Greenville, NC 27858, USA.
Department of Biology, East Carolina University, Greenville, NC 27858, USA.
Toxicol Appl Pharmacol. 2021 Feb 15;413:115407. doi: 10.1016/j.taap.2021.115407. Epub 2021 Jan 9.
Endocrine disrupting compounds (EDCs) are ubiquitous environmental pollutants that alter endocrine system function, induce birth defects, and a myriad of other negative health outcomes. Although the mechanism of toxicity of many EDCs have been studied in detail, little work has focused on understanding the mechanisms through which pregnant dams and fetuses protect themselves from EDCs, or if those protective mechanisms are sexually dimorphic in fetuses. In this study, we examined proteomic alterations in the livers of mouse dams and their male and female fetuses induced by vinclozolin, a model antiandrogenic EDC. Dam livers upregulated nine phase I and phase II detoxification pathways and pathway analysis revealed that more pathways are significantly enriched in dam livers than in fetal livers. Phase I and II detoxification proteins are also involved in steroid and steroid hormone biosynthesis and vinclozolin likely alters steroid levels in both the dam and the fetus. The response of the fetal liver proteome to vinclozolin exposure is sexually dimorphic. Female fetal livers upregulated proteins in xenobiotic metabolism pathways, whereas male fetal livers upregulated proteins in oxidative phosphorylation pathways. These results suggest that female fetuses increase protective mechanisms, whereas male fetuses increase ATP production and several disease pathways that are indicative of oxidative damage. Females fetuses upregulate proteins and protective pathways that were similar to the dams whereas males did not. If this sexually dimorphic pattern is typical, then males might generally be more sensitive to EDCs.
内分泌干扰化合物 (EDCs) 是普遍存在的环境污染物，它们会改变内分泌系统的功能，导致出生缺陷和许多其他负面健康后果。尽管许多 EDC 的毒性机制已经进行了详细研究，但很少有工作关注于了解怀孕母体和胎儿自身免受 EDC 影响的机制，或者这些保护机制在胎儿中是否存在性别差异。在这项研究中，我们研究了抗雄激素 EDC 乙烯菌核利诱导的母鼠及其雄性和雌性胎儿肝脏中的蛋白质组变化。母鼠肝脏中上调了九个 I 相和 II 相解毒途径，途径分析表明，母鼠肝脏中明显富集的途径比胎儿肝脏中的多。I 相和 II 相解毒蛋白也参与类固醇和类固醇激素的生物合成，乙烯菌核利可能会改变母体和胎儿中的类固醇水平。胎儿肝脏蛋白质组对乙烯菌核利暴露的反应具有性别二态性。雌性胎儿肝脏上调了外源物质代谢途径中的蛋白质，而雄性胎儿肝脏上调了氧化磷酸化途径中的蛋白质。这些结果表明，雌性胎儿增加了保护机制，而雄性胎儿增加了 ATP 产生和几个表明氧化损伤的疾病途径。雌性胎儿上调的蛋白质和保护途径与母体相似，而雄性胎儿则没有。如果这种性别二态模式是典型的，那么男性可能通常对 EDC 更敏感。
