Chlorinated, hydrocarbon pesticides, such as DDT and Chlordecone (Kepone Registered Trademark), are recognized for both their neurotoxicity and their reproductive toxicity. Until recently, few attempts had been made to relate these two mainfestations of toxicity and these had relied upon long-term exposure designs. The hypothalamicpituitary axis (via luteinizing hormone (LH) and follicle stimulating hormone (FSH) regulates gonadal function, but gonadal secretions (e.g. estrogen and progesterone in the female and testosterone in the male) feed back on both the hypothalamus and the pituitary to modify neural activity and the release of pituitary hormones. With long-term exposure, neuroendocrine changes could result from disruption of these feedback loops as well as direct neural/pituitary actions of the pesticide. Using a short-term exposure design, we have obtained evidence for direct neuroen docrine effects of chlordecone. Female rats were examined 8-60 hours after exposure to chlordecone. Effects of chlordecone were seen on the CNS estrogen receptor, on hypothalamic serotonin systems, on neuroendocrine parameters and on sexual behavior. Some of the data are compatible with a weak estrogen-like action of chlordecone, but overall, the data suggest that chlordecone mimicked the negative feedback effects of estradiol on the hypothalamic-pituitary axis but that the pesticide inhibited the positive feedback actions of estradiol on LH release and on sexual receptivity in the adult female. Studies are proposed to examine these findings. Three mechanisms for chlordecone's antagonism of the facilitory role of estradiol are postulated: (1) Chlordecone inhibits the induction of brain progesterone receptors. (2) Chlordecone disrupts neurotransmitter changes in response to estradiol. (3) Chlordecone directly affects anterior pituitary sensitivity to luteinizing hormone releasing factor (LHRH). These studies will contribute to the understanding of chlorinated pesticides' neural and reproductive effects. They will also provide an impetus for the inclusion of neuroendocrine parameters in the study of neurotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003351-02
Application #
3250583
Study Section
Toxicology Study Section (TOX)
Project Start
1984-03-01
Project End
1987-02-28
Budget Start
1985-03-01
Budget End
1986-02-28
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Texas Woman's University
Department
Type
Schools of Arts and Sciences
DUNS #
068979848
City
Denton
State
TX
Country
United States
Zip Code
76201
Williams, J; Montanez, S; Uphouse, L (1992) Effects of chlordecone on food intake and body weight in the male rat. Neurotoxicology 13:453-62
Brown, H E; Salamanca, S; Stewart, G et al. (1991) Chlordecone (Kepone) on the night of proestrus inhibits female sexual behavior in CDF-344 rats. Toxicol Appl Pharmacol 110:97-106
Williams, J; Uphouse, L (1991) Vaginal cyclicity, sexual receptivity, and eating behavior of the female rat following treatment with chlordecone. Reprod Toxicol 5:65-71
Uphouse, L; Eckols, K; Croissant, D et al. (1990) Serotonergic changes following proestrous treatment with p,p'-DDT. Neurotoxicology 11:533-8
Williams, J; Eckols, K; Uphouse, L (1989) Estradiol and chlordecone interactions with the estradiol receptor. Toxicol Appl Pharmacol 98:413-21
Uphouse, L; Williams, J (1989) Diestrous treatment with lindane disrupts the female rat reproductive cycle. Toxicol Lett 48:21-8
Eckols, K; Williams, J; Uphouse, L (1989) Effects of chlordecone on progesterone receptors in immature and adult rats. Toxicol Appl Pharmacol 100:506-16
Uphouse, L; Williams, J (1989) Sexual behavior of intact female rats after treatment with o,p'-DDT or p,p'-DDT. Reprod Toxicol 3:33-41
Williams, J; Eckols, K; Stewart, G et al. (1988) Proestrous effects of chlordecone on the serotonin system. Neurotoxicology 9:597-610
Pinkston, G; Uphouse, L (1987) Postovulatory reduction of fertility in chlordecone treated female rats. Reprod Toxicol 1:105-9

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