2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) interference of the synthesis and/or secretion of the anterior pituitary hormone adrenocorticotropin (ACTH).

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic, undesired by-product formed during incineration, paper pulp bleaching and synthesis of chlorinated phenoxyacetic acid herbicides. Both humans and animals exhibit anorexia, progressive weight loss, mobilization of adipose tissue stores, and hypoglycemia after exposure to TCDD suggesting adrenal insufficiency. Adrenal steroidogenesis is regulated by the anterior pituitary hormone adrenocorticotropin (ACTH). TCDD treated rats exhibit elevated plasma ACTH concentrations, but plasma corticosterone (predominant corticosteroid in rat) levels are depressed. The research tested the hypothesis that TCDD interferes with anterior pituitary function by compromising ACTH synthesis and/or secretion thereby impairing adrenal steroidogenesis. TCDD (10$\sp{-9}$-10$\sp{-13}$ M) caused an early (6 hour) and persistent (10 day) increase in basal levels of ACTH in primary cultures of rat anterior pituitary cells. However, pituitary responsiveness to corticotropin releasing hormone (CRH) and vasopressin was decreased. Adenosine 3$\sp\prime$,5$\sp\prime$-monophosphate (cAMP) stimulation increased secretion of ACTH after TCDD exposure suggesting that TCDD acts before cAMP formation. The increased basal ACTH concentrations appear to be mediated through the Aryl hydrocarbon receptor (Ah receptor) since: (1) the Ah receptor antagonist $\alpha$-naphthoflavone (ANF) blocks the stimulatory effect of TCDD on basal ACTH concentrations; (2) the Ah receptor agonist $\beta$-naphthoflavone (BNF) mimics the ACTH increases observed with TCDD exposure; (3) another halogenated aromatic hydrocarbon, 3,3$\sp\prime$,4,4$\sp\prime$,5-pentachlorobiphenyl (PCB), binds the Ah receptor and increases basal ACTH levels similarly to TCDD and (4) the halogenated aromatic hydrocarbon, 2,2$\sp\prime$,4,4$\sp\prime$,5,5$\sp\prime$-hexachlorobiphenyl (HCB), with no affinity for the Ah receptor, had no effect on basal ACTH concentrations. ACTH isolated from basal or CRH-stimulated media from pituitary cells exposed to TCDD did not stimulate corticosterone secretion from adrenal cell cultures as well as ACTH purchased from a commercial supplier suggesting that TCDD exposure alters the bioactivity of this peptide hormone. Understanding the regulation of ACTH secretion may lead to using its measurement and monitoring to assess exposure and risk of humans exposed to TCDD and other chlorinated hydrocarbons.