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In previous studies, we found that 3-methyl-4-nitrophenol (4-nitro-m-cresol; PNMC) isolated from diesel exhaust particles, and also a degradation product of the insecticide fenitrothion, exhibited testicular toxicity in the male of both immature rat and adult Japanese quail. It is well established that a functional relationship exists between the gonads and adrenals. The present study investigates the effect of PNMC on the adrenocortical functions of immature male rats. We subcutaneously injected 28-d-old rats with PNMC (1, 10 or 100 mg/kg) daily for 5 d. The adrenal glands weights significantly decreased in rats treated with 10 or 100 mg/kg PNMC. Plasma concentrations of adrenocorticotropic hormone (ACTH) were significantly increased in animals treated with 100 mg/kg PNMC. In contrast, plasma concentrations of corticosterone were significantly decreased in all PNMC-treated groups, and plasma concentrations of progesterone were significantly decreased in rats treated with 10 or 100 mg/kg PNMC. To investigate the direct effects of PNMC on the secretion of ACTH from the anterior pituitary gland, and on the secretion of corticosterone from the adrenal, we exposed cultured primary anterior pituitary and adrenal cells to PNMC (10(-8), 10(-7), 10(-6), or 10(-5 m)) for 24 h. PNMC did not change basal levels of ACTH released from cultured anterior pituitary cells. However, PNMC significantly inhibited ACTH-stimulated production of corticosterone and progesterone from cultured adrenal cells. These results clearly show that PNMC has a direct effect on the adrenal gland to reduce corticosterone secretion, and the associated increase in plasma ACTH is probably due decreased negative feedback regulation by corticosterone.

Effects of 3-Methyl-4-nitrophenol on the Suppression of Adrenocortical Function in Immature Male Rats