Early exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin alters ovarian function in rats.

摘要

2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8 pentachlorodibenzofuran (PCDF) are widespread environmental contaminants that tend to accumulate in the environment. TCDD is a potent disruptor of developmental and reproductive systems in numerous species, and has been declared a human carcinogen. TCDD toxic actions are mediated through a ligand activated transcription factor know as the aryl hydrocarbon receptor (AHR). Since TCDD has been shown to cross the placenta and to accumulate in milk, the developing fetus/neonate is a potential target of TCDD toxic actions. The overall objective of this research was to determine if in utero and lactational exposure to TCDD or PCDF induced long-term disruptions in female reproduction. Specifically, the objectives of this research were to (1) determine whether in utero and lactational exposure (IUL) to TCDD or PCDF disrupted estrous cyclicity and ovulation, (2) determine whether TCDD disrupts ovarian function by acting at the level of the ovary, and (3) to investigate the mechanism by which TCDD disrupts ovarian function. In an effort to evaluate the reproductive consequences of IUL exposure of TCDD or PCDF, on day 15 of pregnancy, rats were treated with a single oral dose of TCDD (1.0 or 2.5 μg/kg) or PCDF (1.0 or 10.0 μg/kg) or vehicle and offspring were evaluated. To investigate the mechanism of TCDD induced alterations in female reproductive processes and the hypothesis that TCDD acts directly at the level of the ovary an immature gonadotropin-primed rat model was utilized. To investigate if RJL exposure to TCDD reduces steroid biosynthesis on a per follicle basis, intact antral follicles were isolated from the ovary and subjected to short-term incubation and steroid levels in the resulting media were evaluated. The significant findings of this research were: (1) IUL exposure to both TCDD and PCDF reduced growth, disrupted estrous cycles and reduced ovulation rates in exposed offspring, (2) TCDD reduced ovarian responsiveness to gonadotropin stimulation, (3) RJL exposure to TCDD did not reduce follicle steroid biosynthesis or the aromatase enzyme, (4) the AHR was present within ovarian follicles at all stages of development suggesting that the ovary is a direct target of TCDD.