Many drugs, environmental toxicants and hormones are known to produce adverse, toxic effects associated with impairment of testicular function and alteration of tissue concentrations of the hemoprotein cytochrome P-450, which mediates numerous steroidogenic reactions. Examples are chlorinated hydrocarbons such as the recently banned nematocide 1,2-dibromo-3-chloropropane (DBCP) which causes sterility, suggesting a selective action on cells of the testicular germinal epithelium; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) an environmental contaminant of chlorophenoxyacetic acids which is associated with impaired spermatogenesis, hirsutism, loss of libido and alopecia, suggesting alterations of the function of both Leydig cells and cells of the germinal epithelium in the testis; and estrogen derivatives, drugs known to depress plasma testosterone levels, suggesting a selective action on testicular Leydig cells. Previous published reports from this project have presented evidence that each of these substances is an inhibitor of the biosynthesis of rat testicular heme. These three inhibitors of rat testicular heme synthesis are appropriate, useful model compounds for investigation of the mechanisms whereby toxicants, drugs and hormones are aable to selectively regulate or impair the function of different cell types within the testis. Recent results indicate that adrenal function in the rat is impaired by TCDD, and that corticosterone can prevent the inhibition of testicular heme biosynthesis caused by this toxicant.
The specific aims of this project are to separate testicular cell types and to study the differential regulation of heme synthesis by DBCP, TCDD and estradiol, to study the inhibition of testicular heme synthesis by TCDD and its reversal by corticosterone, and to study the regulation of steroidogenesis in the adrenal gland by TCDD. A long-term objective of this project is to elucidate which enzymatic step of heme synthesis is impaired by the toxicant, and to ultimately employ known cofactors or activators of the heme biosynthetic pathway to restore synthesis to proper levels and to correct or prevent adverse effects associated with poisoning episodes. Such research studies will facilitate our understanding of the mechanism whereby environmental toxicants, drugs and hormones are toxic to endocrine organs, and will contribute to our knowledge of the process of hemo-protein (cytochrome-P-450)-mediated steroidogenesis and the role of heme in spermatogenesis.
| Bestervelt, L L; Piper, D W; Pitt, J A et al. (1994) Lipid peroxidation in the adrenal glands of male rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Lett 70:139-45 |
| Ruangwises, S; Bestervelt, L L; Piper, D W et al. (1991) Human chorionic gonadotropin treatment prevents depressed 17 alpha-hydroxylase/C17-20 lyase activities and serum testosterone concentrations in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats. Biol Reprod 45:143-50 |
| Mebus, C A; Reddy, V R; Piper, W N (1987) Depression of rat testicular 17-hydroxylase and 17,20-lyase after administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Biochem Pharmacol 36:727-31 |
| Mebus, C A; Piper, W N (1986) Decreased rat adrenal 21-hydroxylase activity associated with decreased adrenal microsomal cytochrome P-450 after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Pharmacol 35:4359-62 |
