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BIOCHEMICAL AND REPRODUCTIVE EFFECTS OF GESTATIONAL/LACTATIONAL EXPOSURE TO PCB'S WITH RESPECT TO ENDOGENOUS SEX STEROIDS AND THE PROESTROGEN, METHOXYCHLOR
Description:
Polychlorinated biphenyls (PCB's) bioaccumulate in the food chain of humans and many wildlife species, can be readily transferred transplacentally and lactationally to offspring, and have caused reproductive toxicity. PCB's are potent inducers in juveniles and adults of cytochromes P450. Among the important P450-mediated reactions on endobiotics in the liver are hydroxylations of the sex steroids which inactivate these hormones. Induction of P450 could thereby decrease the circulating levels of active sex steroids. Appropriate levels of sex steroids during reproductive system development are crucial in the normal development of the mammalian reproductive system.
P450's also catalyze bioactivations and detoxications of numerous xenobiotics; of particular significance here is the demethylation of the widely used insecticide methoxychlor (MXC) to its dihydroxy metabolite. MXC is a proestrogen and its metabolite activates the estrogen receptor. When administered in vivo, MXC is estrogenic and a reproductive toxicant at high doses. Its reproductive effect at low doses is not well described. Induction of P450 could increase the amount of MXC bioactivation, and therefore its estrogenicity.
The following hypothesis is proposed: Gestational/lactational exposure to PCB's will cause induction and possibly imprinting of the hepatic P450's which will result in altered metabolism of estrogens [both endogenous and xenobiotic proestrogens (such as MXC)] and androgens, with subsequent alteration in reproductive system maturation and function. Experiments are proposed in which rats will be exposed to PCB's during gestation and lactation, and later tested for biochemical alterations in the hepatic hydroxylation of 17?-estradiol and testosterone, blood levels of estradiol and testosterone, sensitive indicators of estrogenic effects in females [i.e., uterine ornithine decarboxylase (ODC) and progesterone receptors, and cytology/histology of the reproductive system], and sensitive indicators of androgenic effects in males [i.e., sperm counts, testicular ODC and cytology/histology of the reproductive system.] This project will determine: 1) if chemicals, such as PCB's, which are acquired while the reproductive system is developing and which induce P450's, can lead to reproductive toxicity by altering the circulating levels of the sex steroids; 2) whether MXC can induce reproductive toxicity at low, environmentally relevant levels of exposure, and whether induction of P450 exacerbates any effect; 3) whether the uterine progesterone receptor, which is under the control of estrogen, might be a highly sensitive biomarker with potential for use in short term tests for the screening of xenobiotics for estrogenic activity; and 4) whether short term tests of patterns of neonatal P450 induction predict possible indirect reproductive effects of P450 inducers.