Developmental Toxicant Exposure Is Associated with Transgenerational Adenomyosis in a Murine Model

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.