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

Abstract

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.

Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models

“…Adenomyosis, like endometriosis, has been associated with reduced fertility, pelvic pain, heavy menstrual bleeding and dysmenorrhea [5, 101]. The causes of adenomyosis are currently unknown, although both human and animal studies have suggested a role of inflammatory processes in the development of this disease [102–105]. In our murine model, we recently reported the transgenerational occurrence of adenomyosis in mice exhibiting the endometriosis-like uterine phenotype as a consequence of developmental TCDD exposure of F1 animals [102].…”

“…The causes of adenomyosis are currently unknown, although both human and animal studies have suggested a role of inflammatory processes in the development of this disease [102–105]. In our murine model, we recently reported the transgenerational occurrence of adenomyosis in mice exhibiting the endometriosis-like uterine phenotype as a consequence of developmental TCDD exposure of F1 animals [102]. Within this recent study, we conducted a retrospective analysis of uteri from TCDD exposed F1 female mice and two generations of their offspring to determine whether histological evidence of adenomyosis was present.…”

“…As we discussed in a previous review [102], reduced fertility and an increased risk of sPTB in female mice across multiple generations following a single, developmental exposure to TCDD strongly suggests toxicant mediated epigenetic modifications have occurred. Epigenetic marking of DNA is now recognized as an important mechanism by which gene expression can be altered without a change to the DNA sequence.…”

“…We recently assessed the presence of adenomyosis, nests of endometrial glands and stromal within the muscle, in archived samples of human and murine uteri [102]. Using smooth muscle actin (SMA) immunohistochemistry, which localizes to both myometrial cells and muscle cells surrounding some vessels, we frequently identified muscles cells within the endometrial layer of women with endometriosis and within tissues obtained from mice with a history of direct (F1-F2) or ancestral (F3) TCDD exposure.…”

“… 1 Data compiled from references 10, 101 and 102. 2 Delivery was considered term when occurring E19–E21 (plug date is considered E0.5). 3 Whole uteri collected from non-pregnant mice at estrus. …”