TCDD-induced expression of Ah receptor responsive genes in the pituitary and brain of cellular retinol-binding protein (CRBP-I) knockout mice

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The 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is a highly toxic, widespread environmental contaminant. Most of the toxic damage caused by TCDD is considered to be secondary to the binding of TCDD to the aryl hydrocarbon receptor, the AH receptor (AHR). TCDD is known to affect the vitamin A homeostasis. The effects of TCDD on body weight and on the expressions of AHR-associated genes may be modulated by the retinoid system. Therefore, we investigated the regulation pattern of expression of the AHR associated genes after TCDD exposure in wild-type 129/SV/C57BL/6 mice and in mice deficient in cellular retinol-binding protein type I (CRBP-I) of the same mixed genetic background. A single oral dose of TCDD (50 or 250 μg/kg) was administrated by gavage. Different brain areas, including cortex, hypothalamus, cerebellum, and olfactory bulb, as well as pituitary and liver, were dissected from CRBP-I knockout homozygous mice (−/−) and wild-type mice (+/+) killed at two time points (7 or 28 days after treatment). Compared with vehicle-treated controls, the relative levels of cytochrome P450 1A1 (CYP1A1) mRNA and protein expression in TCDD-treated animals were dramatically increased in mice of both CRBP-I genotypes (−/−, +/+). CYP1A1 mRNA levels increased up to 1400-fold in the pituitary, 110-fold in the brain, and up to 1600-fold in the liver. A general observation was that the relative induction of CYP1A1 and AHR transcription after TCDD dosing was highest in the +/+ mice. A high TCDD-induced aryl hydrocarbon receptor repressor (AHRR) mRNA expression was observed in the liver and in brain tissues. Interestingly, however, mice that lacked the CRBP-I protein (−/−) were found to have a significantly higher basal expression of AHRR gene in the pituitary compared to the wild-type (CRBP-I +/+) mice and in accordance a less pronounced induction of CYP1A1 and AHR was observed in the pituitary of the −/− mice. Immunohistochemical double staining analyses of the expression pattern of CYP1A1 and AHRR proteins in the pituitary revealed a colocalization of these two proteins. We conclude that the vitamin A homeostasis seems to have some influence to the TCDD-induced activation of AHR-regulated gene transcription in the brain and pituitary of the adult mouse.

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