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.

Endocrine Disruption of Vasopressin Systems and Related Behaviors

“…A single paper also suggests that long-term exposure to chlorobenzenes (solvents) may also disrupt neurohypophysial AVP and OT release (149). Complementary work by multiple research teams has identified NO signaling as a potent target of many EDCs including PBDEs, PCBs, and other organohalogens (representative examples include (74, 150, 151)) suggesting another possible route by which EDCs could impact AVP function. Concomitant work focused on the parvocellular aspects of AVP signaling has also found evidence of NO endocrine disruption by GEN, BPA, and other EDCs (39, 74, 151).…”

Milestones on Steroids and the Nervous System: 10 Years of Basic and Translational Research

“… sexual behaviour and neural circuits related to its control are more sensitive endpoints than others currently used in toxicological studies (70, 71); neuropeptides and enzymes are major targets for the action of EDCs in the vertebrate brain (72); among different peptidergic systems kisspeptin in rodents (73–77), vasotocin in birds (48, 78, 79), as well as the enzyme aromatase in fishes (80–82), or the enzyme NO‐synthase in rodents (83, 84), appear to be the most sensitive to low levels of EDCs during early development; alterations of these circuits may induce profound effects on sexual behaviour (85), puberty (74), reproductive physiology (86) and feeding behaviour (87); neural circuits can be altered also at synaptic levels, for example, in the hippocampus (63, 88–90), and have profound effects on learning and memory (91); the putative mechanisms of action needs to be more thoroughly explored (69) but, in addition to EDCs binding to steroid or thyroid hormone receptors, they include the aryl hydrocarbon receptor, its interactions with ERβ, the activation of the P450 cytochromes, which are involved in the metabolism of most steroid hormones, the peroxisome proliferator‐activated receptor γ and retinoid receptors important in adipose tissue. …”

“…among different peptidergic systems kisspeptin in rodents (73–77), vasotocin in birds (48, 78, 79), as well as the enzyme aromatase in fishes (80–82), or the enzyme NO‐synthase in rodents (83, 84), appear to be the most sensitive to low levels of EDCs during early development;…”

Permanently compromised NADPH-diaphorase activity within the osmotically activated supraoptic nucleus after in utero but not adult exposure to Aroclor 1254

“…These modes of action include (1) altered intracellular calcium homeostasis (Inglefield et al, 2001), (2) modulation of PKC (Kodavanti and Ward, 2005), (3) altered glutamate neurotransmission (Mariussen and Fonnum, 2001), and (4) decreased levels of neurotransmitters such as dopamine (Seegal et al, 2002) and serotonin (Khan and Thomas, 2004) in rodent brain. Increasing evidence suggests that nitric oxide (NO) signaling might also be disrupted by PCBs and other endocrine disrupting chemicals (EDCs, Sharma and Kodavanti, 2002;Martini et al, 2010;Currá s-Collazo, 2011). NO which is produced by nitric oxide synthase (NOS), is a gaseous neurotransmitter that serves an important role in neuroendocrine function (Garthwaite and Boulton, 1995), in synaptic processes associated with learning and memory such as a retrograde messenger underlying long term potentiation (LTP), (Bohme et al, 1991;O'Dell et al, 1991;Schuman and Madison, 1991), and in neurodegeneration (Liberatore et al, 1999;Palumbo et al, 2007).…”