Developmental Toxicant Exposure Is Associated with Transgenerational Adenomyosis in a Murine Model.
Developmental Toxicant Exposure Is Associated with Transgenerational Adenomyosis in a Murine Model.
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DOI：
10.1095/biolreprod.116.138370
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发表时间：
2016-10-01
影响因子：
3.6
通讯作者：
Osteen KG
中科院分区：
文献类型：
--
作者：
Bruner-Tran KL;Duleba AJ;Taylor HS;Osteen KG
常见的环境毒物2，3，7，8-四氯二苯并-对二恶英(TCDD或通常称为二恶英)是一种已知的内分泌干扰物，已在实验模型中与子宫内膜异位症的发生有关。使用小鼠模型，我们先前证明了在子宫内接触TCDD促进了一种“子宫内膜异位症样”子宫表型的跨代发展，这种子宫表型包括对孕酮的反应降低，以及亚生育和早产风险增加。由于子宫腺肌病在患有子宫内膜异位症的妇女中经常被观察到是一种共病，在此，我们试图确定有直接或间接TCDD暴露史的未怀孕小鼠的子宫腺肌病的发生率。通过组织学评估和免疫组织化学染色，我们分析了子宫腺肌病、微血管密度以及雌激素受体α和β(ESR1和ESR2)的表达。我们的研究表明，未暴露的对照组小鼠没有表现出子宫腺肌病，而这种疾病经常发生在有早期TCDD暴露史的小鼠身上。发育期接触TCDD的跨代影响被证明，因为只有间接接触(F3)的一组小鼠也表现出子宫腺肌病。与对照组相比，暴露于TCDD的所有组小鼠子宫内的微血管密度都显著增加，且密度与疾病的严重程度相关。与对照组相比，ESR1和ESR2蛋白在实验小鼠中的表达都发生了变化。与患有子宫内膜异位症的女性相似，我们观察到与对照组相比，所有F1小鼠的ESR1/Esr2mRNA的比率显著降低。虽然这项回溯性研究并不是专门针对子宫腺肌病的相关机制设计的，但我们的数据表明，发育中的TCDD暴露会永久性地改变成人的类固醇反应，这可能有助于子宫腺肌病的跨代发展。
The common environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or, commonly, dioxin) is a known endocrine disruptor that has been linked to the development of endometriosis in experimental models. Using a murine model, we previously demonstrated that in utero TCDD exposure promotes the transgenerational development of an “endometriosis-like” uterine phenotype consisting of reduced responsiveness to progesterone, as well as subfertility and an increased risk of preterm birth. Because adenomyosis is frequently observed as a comorbidity in women with endometriosis, herein we sought to determine the incidence of adenomyosis in nonpregnant mice with a history of direct or indirect TCDD exposure. Using histologic assessment and immunohistochemical staining, we analyzed murine uteri for adenomyosis, microvessel density, and expression of estrogen receptors alpha and beta (ESR1 and ESR2). Our studies revealed that unexposed control mice did not exhibit adenomyosis, whereas this disease was frequently observed in mice with a history of early-life TCDD exposure. A transgenerational impact of developmental TCDD exposure was demonstrated, because a subset of mice with only an indirect exposure (F3) also exhibited adenomyosis. Microvessel density within the uterus was significantly higher in all groups of TCDD-exposed mice compared with control animals, with density correlated to the severity of disease. Both ESR1 and ESR2 proteins exhibited alterations in expression in experimental mice compared with controls. Similar to women with endometriosis, we observed a significant reduction in the ratio of Esr1:Esr2 mRNA in all F1 mice compared with controls. Although this retrospective study was not designed to specifically address mechanisms associated with the development of adenomyosis, our data suggest that developmental TCDD exposure permanently alters adult steroid responses, which may contribute to the transgenerational development of adenomyosis.