REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF DIOXIN

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The long-term objectives are to determine the mechanisms by which 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) adversely affects the male reproductive system of rats exposed in adulthood or during fetal and neonatal development. Effects in animals exposed after weaning are largely due to severe reductions in plasma androgen concentrations, which in turn result from (1) inhibited testicular steroidogenesis and (2) altered regulation of LH secretion. TCDD inhibits testicular steroidogenesis by inhibiting mobilization of cholesterol to the initial enzyme in the testosterone biosynthetic pathway (cytochrome P450sec). We propose to investigate the mechanisms responsible for the inhibition of cholesterol mobilization. The altered regulation of LH secretion involves increased potencies of gonadal steroids as feedback inhibitors of LH secretion. This is due in part to pituitary dysfunction; whether hypothalamic dysfunction is also involved is unknown. We will investigate the roles both organs play in the altered regulation of LH secretion, and examine mechanisms responsible for effects of TCDD at each site. These studies should increase understanding of the mechanisms by which TCDD modulates cellular responsiveness to hormones and neurotransmitters. The developing male reproductive system is extremely sensitive to in utero and lactational TCDD exposure (ED50 0.16 mug/kg dam) and the effects may be permanent. Sex organ development is inhibited, spermatogenesis is reduced, the regulation of LH secretion is feminized, and adult sexual behavior is both demasculinized and feminized. We will determine the extent to which these effects are due to in utero versus lactational TCDD exposure, and the extent to which effect on male sex organs are due to reductions in (1) plasma androgen concentrations and/or (2) androgen responsiveness. Potential hypothalamic/pituitary, testicular, and peripheral mechanisms by which TCDD reduces plasma testosterone concentrations perinatally will be investigated. Mechanisms by which TCDD reduces the androgen responsiveness of fetal and neonatal sex organs will be determined. Effects of TCDD on brain limbic area 17beta-estradiol concentrations neonatally will be compared with effects on sexual behavior and LH secretion patterns in adulthood. If daily sperm production in adults is reduced because the number of Sertoli cells per testis is decreased, effects of TCDD on the perinatal process of Sertoli cell proliferation, and on Sertoli cell FSH responsiveness, will be determined. Results of the above studies should lead to a greater understanding of the risks which in utero and lactational exposure to TCDD and related compounds pose to the male reproductive system of the adult.