Assessing Structure Activity.Relationships of Polyhalogenated Aromatic Hydrocarbons with Endometriosis as an Endpoint

Previous studies have shown that exposure to the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (2,3,7,8-TCDD) enhances the development of endometriotic lesions. In this study, we assessed the structure activity relationships (SARs) and mechanism(s) of endometriotic proliferation by 2,3,7,8-TCDD and related polyhalogenated aromatic hydrocarbons with ligands with varying degrees of affinity for the Ah receptor. B6C3F1 female mice were treated with 0, 1, 3, or 10 ug 2,3,7,8-tetrachlorodibenzo-ρ-dioxin/kg of body weight (bw); 3 or 30 mg 2, 4, 5, 2', 4', 5'-hexachlorobiphenyl (PCB 153)/kg bw; 100, 300, or 1000 ug 3, 4, 5, 3', 4'-pentachlorobiphenyl (PCB126)/kg of bw; 10, 30, or 100 ug 2, 3, 4, 7, 8-pentachlorodibenzofuran (4-PeCDF)/kg of bw; or 2 or 20 mg 1, 3, 6, 8-tetrachlorodibenzo-ρ-dioxin (l,3,6,8-TCDD)/kg of bw at 10 ml/kg. The animals were dosed by oral gavage a total of five times with three weeks between each dosing and terminated three weeks after the last dose. At the conclusion of sixteen weeks, endometriotic lesion diameters and weights were measured. In addition, ovaries, uterine horn, and thymus were removed from each animal. Lesions, uterine horns, and ovaries were fixed for histopathology. Livers were also excised for enzymatic analysis. Analysis of lesion diameters with the Dunnett's test revealed statistically significant results for animals treated with 1 or 3 ug 2,3,7,8-TCDD/kg bw or 100 ug 4-PeCDF/kg bw. However, animals treated with 10 ug 2,3,7,8-TCDD per kg bw did not have significantly larger lesion diameters than control animals possibly due to ovarian atrophy. Animals treated with PCB 126 showed a trend of lesions with larger mean diameters than control animals, but due to variability the increases were not statistically significant. No effect on lesion diameter was apparent in animals dosed with PCB 153 or 1,3,6,8-TCDD. Statistically significant increases in lesion diameters of animals dosed with 2,3,7,8-TCDD supports previous work stating exposure to 2,3,7,8-TCDD induces proliferation of endometriotic lesions. Because neither of the "non-dioxin-like" chemicals induced increased proliferation and both "dioxin-like" chemicals caused increased lesion diameters, the data are consistent with the hypothesis that the mechanism of increased proliferation of endometriotic lesions is Ah receptor-mediated.Master of Science in Public Healt