Nitric Oxide Signaling as a Common Target of Organohalogens and Other Neuroendocrine Disruptors

Abstract

Organohalogen compounds such as polychlorinated biphenyls (PCB) and polybrominated diphenyl ethers (PBDE) are global environmental pollutants and highly persistent, bioaccumulative chemicals that produce adverse effects in humans and wildlife. Because of the widespread use of these organohalogens in household items and consumer products, indoor contamination is a significant source of human exposure, especially for children. One significant concern with regard to health effects associated with exposure to organohalogens is endocrine disruption. Toxicological studies on organohalogen pollutants primarily focused on sex steroid and thyroid hormone actions, and findings have largely shaped the way one envisions their disruptive effects occurring. Organohalogens exert additional effects on other systems including other complex endocrine systems that may be disregulated at various levels of organization. Over the last 20 years evidence has mounted in favor of a critical role of nitric oxide (NO) in numerous functions ranging from neuroendocrine functions to learning and memory. With its participation in multiple systems and action at several levels of integration, NO signaling has a pervasive influence on nervous and endocrine functions. Like blockers of NO synthesis, PCBs and PBDEs produce multifaceted effects on physiological systems. Based on this unique set of converging information it is proposed that organohalogen actions occur, in part, by hijacking processes associated with this ubiquitous bioactive molecule. The current review examines the emerging evidence for NO involvement in selected organohalogen actions and includes recent progress from our laboratory that adds to our current understanding of the actions of organohalogens within hypothalamic neuroendocrine circuits. The thyroid, vasopressin, and reproductive systems as well as processes associated with long-term potentiation were selected as sample targets of organohalogens that rely on regulation by NO. Information is provided about other toxicants with demonstrated interference of NO signaling. Our focus on the convergence between NO system and organohalogen toxicity offers a novel approach to understanding endocrine and neuroendocrine disruption that is particularly problematic for developing organisms. This new working model is proposed as a way to encourage future study in elucidating common mechanisms of action that are selected with a better operational understanding of the systems affected.

Acknowledgments

I am grateful to Dr. P. R. S. Kodavanti for his gift of Aroclor 1254 and DE-71 and to Dr. M. Leon-Olea for information on organohalogen and NOS immunoreactivity. I gratefully acknowledge Dr. E. R. Gillard for inspiring the work on organohalogens and nitric oxide and for critically reviewing an earlier version of this article. I am grateful to Dr. C. Coburn and undergraduates under his tutelage (B. Hou, D. Prodon, C. Cheetham, and L. Lin) who performed the NADPH-d histochemistry. I also thank R. Ornelas and R. Nichol for their help in proofreading and for ideas on organohalogen interference with NO system, and B. Martinez for clerical assistance. This work was partially supported by UC Mexus and UC Toxic Substances Research and Training Porgram. In addition, I am grateful for the generous gift provided by an anonymous donor, without which this work would not have been possible.