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

Humans and other animals are exposed to a wide array of man-made toxicants, many of which act as endocrine disruptors that exhibit differential effects across the lifespan. In humans, while the impact of adult exposure is known for some compounds, the potential consequences of developmental exposure to endocrine disrupting chemicals (EDCs) is more difficult to ascertain. Animal studies have revealed that exposure to EDCs prior to puberty can lead to adult reproductive disease and dysfunction. Specifically, in adult female mice with an early life exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we demonstrated a transgenerational occurrence of several reproductive diseases that have been linked to endometriosis in women. Herein, we review the evidence for TCDD-associated development of adult reproductive disease as well as known epigenetic alterations associated with TCDD and/or endometriosis. We will also introduce new "Organ-on-Chip" models which, combined with our established murine model, are expected to further enhance our ability to examine alterations in gene-environment interactions that lead to heritable disease.

Dietary fish oil supplementation inhibits formation of endometriosis-associated adhesions in a chimeric mouse model.

OBJECTIVE: To examine whether dietary fish oil supplementation reduces development of spontaneous endometriosis-associated adhesions using an established model. DESIGN: Laboratory-based study. SETTING: Medical center research laboratory. PATIENT(S)/ANIMAL(S): Disease-free women of reproductive age and nude mice. INTERVENTION(S): Women were not provided any intervention. Mice were randomized to receive fish oil supplementation or control diet. MAIN OUTCOME MEASURE(S): Experimental endometriosis was established in mice via injection of human endometrial tissue within 16 hours of ovariectomy. Mice were provided standard or menhaden fish oil-supplemented diets for ≥ 2 weeks before initiation of experimental endometriosis and until killing them 1 week later. At necropsy, mice were examined for the presence and extent of adhesions and endometriotic-like lesions. Tissues were excised and morphologically characterized. RESULT(S): Adhesions/lesions were reduced in mice provided with dietary fish oil compared with control animals. Leukocytes were more numerous within the adhesions/lesions of the mice maintained on the standard diet compared with animals provided with fish oil. As indicated by staining intensity, collagen deposition was greater at adhesion sites within control mice compared with fish oil-supplemented animals. CONCLUSION(S): Wound-healing associated with surgery created an inflammatory peritoneal microenvironment that promoted the development of both experimental endometriosis and adhesions in a murine model. Targeting excessive inflammation with fish oil may be an effective adjuvant therapy to reduce the development of postsurgical adhesions related to endometriosis.

Progesterone-dependent regulation of endometrial cannabinoid receptor type 1 (CB1-R) expression is disrupted in women with endometriosis and in isolated stromal cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

OBJECTIVE: To examine the differentiation-related expression of cannabinoid receptor type 1 (CB1-R) messenger RNA (mRNA) and protein in endometrial tissue obtained from women with and without endometriosis and to determine the impact of acute 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on CB1-R gene expression in isolated endometrial stromal cells. DESIGN: Laboratory-based study. SETTING: University-affiliated medical center. PATIENT(S): Women with and without endometriosis undergoing volunteer endometrial biopsies after informed consent. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Analysis of in vivo CB1-R mRNA and protein expression in human endometrial tissues and mRNA expression in isolated stromal cells after exposure to TCDD or a progesterone receptor antagonist (onapristone). RESULT(S): Expression of CB1-R mRNA and protein was highest during the progesterone-dominated secretory phase in control samples, but expression was minimal in the endometrial tissues acquired from women with endometriosis, regardless of the cycle phase. Although progesterone was found to induce CB1-R mRNA expression in endometrial stromal cells from control donors, steroid-induced expression of this gene was inhibited by cotreatment with either TCDD or onapristone. CONCLUSION(S): Our studies reveal a role for the anti-inflammatory actions of progesterone in regulating endometrial cannabinoid signaling, which is disrupted in women with endometriosis. We demonstrate for the first time that acute TCDD exposure disrupts cannabinoid signaling in the human endometrium.