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Title: Altered regulation of adrenal steroidogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats.

Authors: DiBartolomeis, M J; Moore, R W; Peterson, R E; Christian, B J; Jefcoate, C R

Published In Biochem Pharmacol, (1987 Jan 01)

Abstract: A single treatment of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (50 micrograms/kg) produced two distinct effects on adrenal steroidogenesis in rats 13 days post-treatment. In unstressed rats, the very low corticosterone levels early in the light phase (AM) increased 4-fold relative to ad libitum-fed control (ALC) rats, but the peak level of corticosterone that is seen late in the light phase (PM) decreased up to 40% relative to ALC rats. The AM stimulation was also observed in rats pair-fed to compensate for the diminished feed intake of TCDD-treated animals, indicating that the change results from nutritional deprivation. The PM suppression, however, was not observed in pair-fed rats. In rats given a lower dose of TCDD (15 micrograms/kg), there was no AM stimulation, whereas the suppression of the PM diurnal peak of corticosterone was retained. Plasma adrenocorticotropin (ACTH) levels and adrenal size were not changed by these treatments, indicating that TCDD affects adrenal responsiveness. TCDD did not, however, have a significant effect on corticosterone secretion in rats receiving high doses of ACTH. In control animals, the availability of cholesterol to cytochrome P-450scc limits the rate of steroidogenesis. While the specific content of the cytochrome was unaffected by TCDD, cholesterol turnover by this enzyme appeared to be affected following TCDD treatment, as evidenced by small increases in the mitochondrial levels of free cholesterol, reactive cholesterol, and in the proportion of P-450scc complexed with cholesterol relative to both ad libitum- and pair-fed controls. This accumulation of mitochondrial cholesterol following TCDD treatment is consistent with an inhibition of cholesterol metabolism at cytochrome P-450scc in vivo that is removed upon isolation of the mitochondria. These TCDD-induced increases were enhanced substantially in ACTH-stimulated rats, probably because ACTH enhances cholesterol influx into the mitochondria. Normally, substrate availability is rate limiting in cholesterol side-chain cleavage, and the AM stimulation of steroidogenesis by TCDD may result from such increased cholesterol transfer. The inhibition of cholesterol side-chain cleavage resulting from TCDD treatment may, however, only become rate limiting for corticosterone synthesis when cholesterol transfer is more substantially activated, as for peak PM secretion.

PubMed ID: 3026405 Exiting the NIEHS site

MeSH Terms: Adrenal Cortex Hormones/biosynthesis*; Adrenal Glands/drug effects*; Adrenal Glands/metabolism; Adrenocorticotropic Hormone/blood; Animals; Circadian Rhythm; Corticosterone/blood; Cytochrome P-450 Enzyme System/metabolism; Dioxins/toxicity*; Male; Polychlorinated Dibenzodioxins/toxicity*; Rats; Rats, Inbred Strains

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