The actions of representatives of two classes or reproductive toxicants, a heavy metal (lead), and a polychlorinated biphenyl mixture (Aroclor 1254), on the serotonin (5-HT)-gonadotropin releasing hormone (GnRH)-gonadotropin (GtH) neuroendocrine pathway controlling GtH secretion will be investigated in an extensive teleost model of reproductive endocrine function and endocrine toxicology, the Atlantic croaker (Micropogonias undulatus). Currently, the sites and mechanisms of xenobiotic interference with the reproductive neuroendocrine pathway are poorly understood. Therefore, the following overall hypothesis will be tested: that lead and Aroclor 1254 alter GtH secretion by disrupting different components of the 5-HT-GnRH-GtH stimulatory neuroendocrine pathway controlling reproduction. Preliminary results in croaker and other vertebrate species suggest that Aroclor 1254 acts primarily on the 5- HT component, whereas lead may act on the GnRH and GtH (pituitary) components of the neuroendocrine system. Therefore all three components of the system will be investigated using multiple indices of neuroendocrine function after exposure to the model compounds. Parallel studies will be conducted with several neuropharmacological agents which either mimic the xenobiotic-induced disturbances or reverse them. Parallel disturbances of GtH secretion will be interpreted as evidence that the model compound has the same primary site of action as the neuropharmacological agent. Specific objectives are to: 1. Compare the actions of Aroclor 1254 and the neuropharmacological agents on separate components of the 5-HT-GnRH-GtH pathway and GtH secretion; correlate PCB accumulation with the degree of neuroendocrine disruption. 2. Compare the actions of lead and the neuropharmacological agents on separate components of the 5-HT-GnRH-GtH pathway and GtH secretion; correlate lead accumulation with the degree of neuroendocrine disruption. The proposed research on the effects of the model compounds on components of a major neuroendocrine system controlling reproduction, the 5-HT-GnRH-GtH pathway, should provide valuable new information on the mechanisms and targets of reproductive neuroendocrine disruption by xenobiotics in vertebrates. The further evaluation of this non- mammalian model of reproductive neuroendocrine toxicology will facilitate comparisons of the mechanisms of endocrine disruption by chemicals among a broader range of vertebrates and thus provide a more accurate prediction of their long term reproductive hazards to humans. In addition this teleost model should be valuable as a sentinel of pollution damage to aquatic ecosystems and the potential reproductive hazards of environmental contamination to human populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES007672-02S1
Application #
2897455
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1997-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Zoology
Type
Other Domestic Higher Education
DUNS #
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

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