Adrenal Corticosteroid Perturbation by the Endocrine Disruptor BDE-47 in a Human Adrenocortical Cell Line and Male Rats.

Polybrominated diphenyl ethers (PBDEs) have been previously shown to alter various endocrine biosynthetic pathways. Growing epidemiological evidence suggests that PBDEs alter cardiovascular function. The goal of this study was to examine the effects of BDE-47 on adrenal corticosteroid pathways that play vital roles in cardiovascular homeostasis and pathophysiology. The effect of BDE-47 on aldosterone and cortisol secretion was characterized in a human adrenocortical cell line. HAC15 cells were exposed to various concentrations of BDE-47 (1 nM to 100 µM). Cell viability, corticosteroid secretion, gene expression of enzymes involved in corticosteroid synthesis, and metabolic activity was examined. Additionally, Sprague Dawley male rats were orally exposed to BDE-47 (10 or 100 µg/kg), 5 days per week for 16 weeks. Organ weights and plasma corticosteroid levels were measured. In HAC15 cells, basal and stimulated aldosterone and cortisol secretion was significantly increased by BDE-47. Gene expression of several enzymes involved in corticosteroid synthesis and mitochondrial metabolism also increased. In Sprague Dawley rats, adrenal but not heart, kidney, or liver weights, were significantly increased in BDE-47 treatment groups. Plasma corticosterone levels were significantly increased in the 100 µg BDE-47/kg treatment group. No change in plasma aldosterone levels were observed with BDE-47 exposure. These data indicate that BDE-47 disrupts the regulation of corticosteroid secretion and provides further evidence that PBDEs are potential endocrine disruptors. Future studies will determine the underlying molecular mechanism of altered corticosteroid production and examine whether these alterations result in underlying cardiovascular disease in our rodent model of 16-week BDE-47 exposure.

Differential effects of long-term slow-pressor and subpressor angiotensin II on contractile and relaxant reactivity of resistance versus conductance arteries.

Vascular reactivity was evaluated in three separate arteries isolated from rats after angiotensin II (Ang II) was infused chronically in two separate experiments, one using a 14-day high, slow-pressor dose known to produce hypertension and the other using a 7-day low, subpressor but hypertensive-sensitizing dose. There were three new findings. First, there was no evidence of altered vascular reactivity in resistance arteries that might otherwise explain the hypertension due to the high Ang II or the hypertensive-sensitizing effect of the low Ang II dose. Second, the high Ang II dose exerted a novel differential effect on arterial contractile responsiveness to the sympathetic neurotransmitter, norepinephrine, depending on the level of sympathetic innervation. It clearly enhanced that responsiveness in the sparsely innervated aorta but not in small mesenteric resistance arteries or the proximal (conductance) portion of the caudal artery, both of which are densely innervated. This suggests that the increased expression of alpha adrenergic receptors after long-term exposure to Ang II as previously reported for aortic smooth muscle, is prevented in densely innervated arteries, likely due to long-term Ang II-mediated increase in sympathetic neural traffic to those vessels. Third, the same high dose of Ang II impaired aortic relaxation in response to the nitric oxide (NO) donor nitroprusside without impairing aortic endothelium-dependent relaxation. NO is the main relaxing substance released by aortic endothelium. Accordingly, it is possible that this dose of Ang II is also associated with enhanced release of and/or enhanced smooth muscle responsiveness to other endothelial relaxing substances in a compensatory capacity.