Environmental exposure to toxic levels of lead occurs in a number of industries with potential adverse effects on the reproductive capacity of exposed men. We have demonstrated, using an animal model, that lead exposure results in a dose-response suppression of spermatogenesis, serum testosterone and intratesticular testosterone. Investigations into the mechanisms of the toxic action of lead on the hypothalamic-pituitary-testicular axis suggest that lead exposure results in a disruption of the hypothalamic control of pituitary hormone secretion. As a consequence, hypothalamic GnRH release is decreased pituitary LH content is increased, and LH and FSH release is impaired. These alterations result in decreased circulating testosterone levels and impaired spermatogenesis. The proposed studies are designed to study in greater detail the mechanisms by which lead exerts its toxic actions at each level of the axis. We will specifically: 1) characterize the mechanisms by which lead exerts its toxic effects on the regulation, synthesis and secretion of catecholamines in the CNS, of GnRH in the hypothalamus and of LH in the pituitary gland, 2) study in greater detail the toxic effects of lead on sperm function, and 3) determine the long-term effects of perinatal lead exposure on neurobehavioral sexual differentiation in the male. These studies will clarify the mechanism(s) by which lead exposure alters the reproductive system in man. Such information will further enhance our understanding of lead toxicity and provide potential therapeutic approaches to the pathologic consequences of lead exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003749-07
Application #
3251388
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1985-06-15
Project End
1993-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
City
Torrance
State
CA
Country
United States
Zip Code
90502
Sokol, R Z; Berman, N; Okuda, H et al. (1998) Effects of lead exposure on GnRH and LH secretion in male rats: response to castration and alpha-methyl-p-tyrosine (AMPT) challenge. Reprod Toxicol 12:347-55
Klein, D; Kern, R M; Sokol, R Z (1995) A method for quantification and correction of proteins after transfer to immobilization membranes. Biochem Mol Biol Int 36:59-66
Klein, D; Tabor, D E; Sokol, R Z et al. (1994) Inclusion of synthetic DNA templates of similar length and base composition to PCR-amplified products in restriction enzyme digestions: an efficient aid in characterization of point mutations. Somat Cell Mol Genet 20:61-5
Klein, D; Wan, Y J; Kamyab, S et al. (1994) Effects of toxic levels of lead on gene regulation in the male axis: increase in messenger ribonucleic acids and intracellular stores of gonadotrophs within the central nervous system. Biol Reprod 50:802-11
McGivern, R F; Raum, W J; Handa, R J et al. (1992) Comparison of two weeks versus one week of prenatal ethanol exposure in the rat on gonadal organ weights, sperm count, and onset of puberty. Neurotoxicol Teratol 14:351-8
Sokol, R Z; Berman, N (1991) The effect of age of exposure on lead-induced testicular toxicity. Toxicology 69:269-78
McGivern, R F; Sokol, R Z; Berman, N G (1991) Prenatal lead exposure in the rat during the third week of gestation: long-term behavioral, physiological, and anatomical effects associated with reproduction. Toxicol Appl Pharmacol 110:206-15
Sokol, R Z (1990) The effect of duration of exposure on the expression of lead toxicity on the male reproductive axis. J Androl 11:521-6
Paliwal, V K; Ebadi, M (1989) Biochemical properties of metallothionein isoforms from bovine hippocampus. Exp Brain Res 75:477-82
Sokol, R Z (1989) Reversibility of the toxic effect of lead on the male reproductive axis. Reprod Toxicol 3:175-80

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