Tryptophan hydroxylase: a target for neuroendocrine disruption.

Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin (5-HT) synthesis, performs an essential role in the maintenance of serotonergic functions in the central nervous system (CNS), including regulation of the neuroendocrine system controlling reproduction. The results of recent studies in a teleost model of neuroendocrine disruption, Atlantic croaker, indicated that hypothalamic TPH is a major site of interference of hypothalamic-pituitary-gonadal function by environmental stressors. The effects of exposure to two different types of environmental stressors, low dissolved oxygen (hypoxia) and a polychlorinated biphenyl mixture (Aroclor 1254), on the stimulatory brain serotonergic system controlling reproductive neuroendocrine function in Atlantic croaker are reviewed. Exposure to both stressors produced decreases in TPH activity, which were accompanied by a fall in hypothalamic 5-HT and gonadotropin-releasing hormone (GnRH I) content in the preoptic-anterior hypothalamic area and were associated with reduction in luteinizing hormone (LH) secretion and gonadal development. Pharmacological restoration of hypothalamic 5-HT levels after exposure to both stressors also restored neuroendocrine and reproductive functions, indicating that the serotonergic system is an important site for hypoxia- and Aroclor 1254-induced inhibition of reproductive neuroendocrine functions. The mechanisms underlying downregulation of TPH activity by these stressors remain unclear but may involve alterations in hypothalamic antioxidant status. In support of this hypothesis, treatment with an antioxidant, vitamin E, was found to reverse the inhibitory effects of Aroclor 1254 on TPH activity. The results suggest that TPH is a major target for neuroendocrine disruption by diverse environmental stressors.