The long-term goal of the proposed research is to determine the principal causes of neuroendocrine disruption and targets of the major environmental contaminants of public health concern. In this continuation proposal the proximal cause of Aroclor 1254 (PCB)-induced impairment of tryptophan hydroxylase (TPH) activity and the reproductive neuroendocrine consequences will be investigated in a fish model, Atlantic croaker. The following overall hypothesis will be tested in croaker: PCB-induced impairment of the serotonin-gonadotropin releasing hormone-luteinizing hormone (5-HT-GnRH-LH) neuroendocrine pathway controlling reproduction involves a non-coplanar congener-induced decrease in TPH activity, which is the result of oxidative effects/damage. Initially, the effects of a range of PCB concentrations on TPH activity and hypothalamic levels of the TPH protein and its mRNA will be investigated followed by experiments to investigate associations between oxidative damage and neuroendocrine disruption. Subsequently, the effects of vitamin E (an antioxidant) treatment on serotonergic functions, and its efficacy in reversing the effects of the PCB on lipid peroxidation, malondialdehyde-protein adduct formation, TPH activity, and neuroendocrine function, will be investigated. Finally, the effects of a coplanar dioxin-like PCB congener (PCB 77) on TPH activity will be compared to those observed with two non-coplanar di-ortho-substituted PCB congeners (PCB 47 and PCB 153) to identify likely causative agents of the neurotoxic effects in the PCB mixture. The consequences of PCB congener-induced impairment of hypothalamic serotonergic function on the functional integrity of the 5-HT-GnRH-LH neuroendocrine system will also be investigated. The specific objectives are to: i) determine whether the PCB-induced decrease in the hypothalamic TPH activity is accompanied by alterations in TPH protein and mRNA levels; ii) determine whether the PCB-induced decreases in TPH activity and 5-HT-GnRH-LH function are associated with oxidative damage, and the efficacy of an antioxidant in reversing these effects; iii) determine whether the non-coplanar di-ortho-substituted PCB congener component of PCB mixtures could account for their toxic effects on TPH activity and 5-HT-GnRH-LH function. There is now compelling evidence that the environmental or occupational exposure to PCBs or consumption of PCB-contaminated fish in the Great Lakes is associated with reproductive and neuroendocrine dysfunction in humans and developmental deficits in their children. However, the mechanisms of PCB neurotoxicity remain poorly understood. The proposed study will investigate a novel mechanism of PCB neurotoxicity and neuroendocrine toxicity which may also have significance for other neural functions such as those associated with mental health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES007672-04A2
Application #
6612098
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
1997-08-01
Project End
2006-03-31
Budget Start
2003-05-02
Budget End
2004-03-31
Support Year
4
Fiscal Year
2003
Total Cost
$270,513
Indirect Cost
Name
University of Texas Austin
Department
Zoology
Type
Other Domestic Higher Education
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Rahman, Saydur; Khan, Izhar A; Thomas, Peter (2011) Tryptophan hydroxylase: a target for neuroendocrine disruption. J Toxicol Environ Health B Crit Rev 14:473-94
LeRoy, Kimberly D; Thomas, Peter; Khan, Izhar A (2006) Thyroid hormone status of Atlantic croaker exposed to Aroclor 1254 and selected PCB congeners. Comp Biochem Physiol C Toxicol Pharmacol 144:263-71
Khan, Izhar A; Thomas, Peter (2006) PCB congener-specific disruption of reproductive neuroendocrine function in Atlantic croaker. Mar Environ Res 62 Suppl:S25-8
Mohamed, J Shaik; Thomas, Peter; Khan, Izhar A (2005) Isolation, cloning, and expression of three prepro-GnRH mRNAs in Atlantic croaker brain and pituitary. J Comp Neurol 488:384-95
Hawkins, M B; Godwin, J; Crews, D et al. (2005) The distributions of the duplicate oestrogen receptors ER-beta a and ER-beta b in the forebrain of the Atlantic croaker (Micropogonias undulatus): evidence for subfunctionalization after gene duplication. Proc Biol Sci 272:633-41
Khan, Izhar A; Thomas, Peter (2004) Vitamin E co-treatment reduces Aroclor 1254-induced impairment of reproductive neuroendocrine function in Atlantic croaker. Mar Environ Res 58:333-6
Khan, Izhar A; Thomas, Peter (2004) Aroclor 1254 inhibits tryptophan hydroxylase activity in rat brain. Arch Toxicol 78:316-20
Mathews, Sonya; Khan, Izhar A; Thomas, Peter (2002) Effects of the maturation-inducing steroid on LH secretion and the GnRH system at different stages of the gonadal cycle in Atlantic croaker. Gen Comp Endocrinol 126:287-97
Khan, I A; Thomas, P (2001) Disruption of neuroendocrine control of luteinizing hormone secretion by aroclor 1254 involves inhibition of hypothalamic tryptophan hydroxylase activity. Biol Reprod 64:955-64
Khan, I A; Mathews, S; Okuzawa, K et al. (2001) Alterations in the GnRH-LH system in relation to gonadal stage and Aroclor 1254 exposure in Atlantic croaker. Comp Biochem Physiol B Biochem Mol Biol 129:251-9

Showing the most recent 10 out of 14 publications