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ToxSci Advance Access originally published online on February 9, 2005
Toxicological Sciences 2005 85(1):530-540; doi:10.1093/toxsci/kfi105
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Toxicological Sciences vol. 85 no. 1 © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

PCB126 Induces Differential Changes in Androgen, Cortisol, and Aldosterone Biosynthesis in Human Adrenocortical H295R Cells

Lih-Ann Li*,1 and Pei-Wen Wang{dagger}

* Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Kaohsiung 807, Taiwan, Republic of China; and {dagger} Division of Metabolism and Endocrinology, Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan, Republic of China

Received November 12, 2004; accepted January 27, 2005

Dioxins and polychlorinated biphenyls (PCBs) have been shown to accumulate in the adrenal glands when incorporated into the body. However, the impacts of exposure on adrenal steroidogenesis have not been thoroughly investigated. In this study, we demonstrated that dioxin-like PCB126 altered androgen, cortisol, and aldosterone biosynthesis differentially in human adrenocortical H295R cells. PCB126 diminished basal and cAMP-induced androstenedione production as well as CYP17 mRNA expression in a dose-dependent and time-dependent manner. The CYP17 repression was accompanied with decreases in the encoded 17{alpha}-hydroxylase and 17,20-lyase activities, particularly the latter. In contrast, high concentrations of PCB126 stimulated basal cortisol and aldosterone biosynthesis, including induction of CYP21B, CYP11B1, and CYP11B2 mRNA expression and elevation of the conversion of cortisol from 17-OH-progesterone and aldosterone from progesterone. cAMP abolished the positive effect of PCB126 on cortisol synthesis, while it synergistically enhanced PCB126 stimulation on CYP11B2 expression and aldosterone production. It seemed likely that the downregulation of CYP21B caused by the combination of PCB126 and cAMP counteracted the CYP11B1 induction stimulated by the co-treatment. In addition, high concentrations of PCB126 might sensitize the regulation of adrenocorticotropin (ACTH) on the adrenocortical cells by increasing ACTH receptor levels. Because adrenal steroids have profound influences on glucose tolerance, insulin sensitivity, lipid metabolism, obesity, vascular function, and cardiac remodeling, this article also discusses the potential association of the detected adrenocortical alterations with increased diabetic and cardiovascular risk found among highly exposed people.

Key Words: coplanar PCB; adrenal steroidogenesis; cAMP induction; steroidogenic genes; diabetes; cardiovascular diseases.


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