The Aryl Hydrocarbon Receptor Pathway and Sexual Differentiation of Neuroendocrine Functions

Abstract

Historically, much of the research on health effects of environmental pollutants focused on ascertaining whether compounds were carcinogenic. More recent findings show that environmental contaminants also exert insidious effects by disrupting hormone action. Of particular concern are findings that developmental exposure to dioxins, chemicals that act through the aryl hydrocarbon receptor pathway, permanently alters sexually differentiated neural functions in animal models. In this review, we focus on mechanisms through which dioxins disrupt neuroendocrine development as exemplified by effects on a brain region critical for ovulation in rodents. We also provide evidence that dysregulation of GABAergic neural development may be a general mechanism underlying a broad spectrum of effects seen after perinatal dioxin exposure.

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

“…TCDD (>99.5% pure) was obtained from Cambridge Isotope Laboratory (Andover, MA). [6, H]E 2 and [6,7-3 H]E 1 (specific activities of 51 and 58 Ci/ mmol, respectively) and [4][5][6][7][8][9][10][11][12][13][14] C]E 2 (specific activities of 55.1 mCi/mmol) were purchased from PerkinElmer Life Science Products (Boston, MA). All the organic solvents used in this study were of HPLC grade or better, and were obtained from Fisher Scientific (Atlanta, GA).…”

“…The reaction mixture consisted of liver microsomal protein (1 mg/mL), [4][5][6][7][8][9][10][11][12][13][14] C]E 2 (dissolved in 2 μL ethanol), 2 mM NADPH and 5 mM ascorbic acid in a final volume of 1.0 mL TrisHCl (100 mM)/HEPES (50 mM) buffer, pH 7.4. The reaction was initiated by addition of microsomal protein and lasted for 30 min at 37°C with constant mild shaking.…”

“…Assay of the enzymatic desulfation of E 1 -3-sulfate E 1 -3-sulfatase activity in hepatic microsomes of female C3H/HeN mice was determined by measuring the formation of radioactive E 1 from [6, H]E 1 -3-sulfate (the substrate) as described previously [42,43]. The incubation mixture consisted of rat liver microsomal protein (0.1 to 0.5 mg/mL) and 50 μM E 1 -3-sulfate (containing 0.2−1.0 μCi of [6, H]E 1 -3-sulfate) in a final volume of 0.5 to 1.0 mL Tris-HCl buffer (25 mM, pH 7.4).…”

“…2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD 6 ), an accidental byproduct formed during the manufacturing and incineration process of chlorine-based products, is generally considered to be among the most potent environmental toxicants known to date. Contamination of TCDD in the environment is widespread, and its resistance to biodegradation results in its presence in the environment [1] and in human body for long periods of time [2].…”

“…Contamination of TCDD in the environment is widespread, and its resistance to biodegradation results in its presence in the environment [1] and in human body for long periods of time [2]. TCDD is a developmental and reproductive toxicant and causes immunotoxicity, dermal and hepatic toxicity, and a plethora of endocrine-disrupting effects [3][4][5][6][7][8]. In addition, TCDD is also considered a carcinogen, increasing the incidence of a variety of cancers in humans as well as in laboratory animals [4,[9][10][11][12][13].…”