We have previously reported that the administration of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) to rats resulted in a significantly decreased serum thyroxine (T4), serum and pancreatic insulin levels, and hypoglycemia. Severe hormonal imbalance caused by low doses of TCDD could, in fact, be explained by effects on prolactin synthesis and secretion since prolactin is known to affect the development and function of endocrine organs such as the adrenal cortex, thyroid, pancreas and perhaps the adrenal medulla. In rats inoculated with a prolactin-secreting MtTW15 adenoma, increased serum prolactin resulted in a significantly decreased serum T4 concentration similar to the extent of reduction in response to TCDD administration. Prolactin has known effects on immune function, as does TCDD. We propose, therefore, to study the ability of TCDD to alter the circulating levels of major developmental and differentiative hormones. The serum prolactin levels will be monitored in rats at times after TCDD which coincide with the already demonstrated decreased body temperature and decreased serum T4. Circulating glucocorticoid levels will be measured as these hormones are known to feedback on prolactin secretion and thus regulate serum prolactin concentration. Catecholamines are major circulating trophic hormones which also may affect both prolactin and glucocorticoid levels as well as action. The effects of these hormones and their interactions to modify ornithine decarboxylase activity and RNA polymerase I activity in the liver of TCDD-treated rats will be assessed since a previous time-dependent effect of TCDD to alter the response of these enzyme activities to hormone stimulation or to partial hepatectomy has been observed in this laboratory. If detectable alterations in the regulation of one or more of these """"""""stress-axis"""""""" hormones can be defined, we then will attempt to pinpoint the lesion to the appropriate endocrine organ(s) or to the hypothalamic nucleus involved in the regulation of the synthesis and secretion of the particular hormone. Industrial exposure, environmental exposure, and extensive animal experimentation have linked TCDD to severe toxic effects in both humans and animals. Environmental pollution with polychlorobiphenyls including TCDD mandates the necessity to attempt to pinpoint the underlying mechanism(s) of the toxicity of these substances.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003587-02
Application #
3251010
Study Section
(SSS)
Project Start
1985-01-01
Project End
1987-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Zorn, N E; Russell, D H; Buckley, A R et al. (1995) Alterations in splenocyte protein kinase C (PKC) activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vivo. Toxicol Lett 78:93-100
Zorn, N E; Sauro, M D (1995) Retinoic acid induces translocation of protein kinase C (PKC) and activation of nuclear PKC (nPKC) in rat splenocytes. Int J Immunopharmacol 17:303-11
Sauro, M D; Bing, B; Zorn, N E (1992) Prolactin induces growth-related gene expression in rat aortic smooth muscle in vivo. Eur J Pharmacol 225:351-4
Buckley, A R; Crowe, P D; Bauman, P A et al. (1991) Prolactin-provoked alterations of cytosolic, membrane, and nuclear protein kinase C following partial hepatectomy. Dig Dis Sci 36:1313-9
Sauro, M D; Zorn, N E (1991) Prolactin induces proliferation of vascular smooth muscle cells through a protein kinase C-dependent mechanism. J Cell Physiol 148:133-8
Shah, G N; Laird 2nd, H E; Russell, D H (1991) Identification and characterization of a prolactin-like polypeptide synthesized by mitogen-stimulated murine lymphocytes. Int Immunol 3:297-304
Russell, D H; Zorn, N E; Buckley, A R et al. (1990) Prolactin and known modulators of rat splenocytes activate nuclear protein kinase C. Eur J Pharmacol 188:139-52
Zorn, N E; Russell, D H (1990) Vasoactive intestinal peptide (VIP) activation of nuclear protein kinase C in purified nuclei of rat splenocytes. Biochem Pharmacol 40:2689-94
Zorn, N E; Weill, C L; Russell, D H (1990) The HIV protein, GP120, activates nuclear protein kinase C in nuclei from lymphocytes and brain. Biochem Biophys Res Commun 166:1133-9
Weill, C L; Squinto, S P; Zorn, N E et al. (1990) Neuropeptide-protein kinase C mediated gene regulation. Ann N Y Acad Sci 594:130-45

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