Environmental exposure to toxic levels of lead occurs in a number of industries with potential adverse effects on reproduction. We have demonstrated using an animal model, that Pb exposure suppresses serum testosterone (T) and spermatogenesis. However, no compensatory increase in circulating gonadotropins occurs and LH levels in Pb exposed castrated male rats do not increase to levels commensurate to those seen in non-Pb treated castrate rats. Recent data demonstrate an increase in hypothalamic levels of GnRH mRNA; and an increase in pituitary levels of luteinizing hormone (LH) mRNA and pituitary stores of LH in pb-dosed animals. These collective data indicate that Pb disrupts the reproductive axis by interfering with feedback mechanisms at the hypothalamic and pituitary levels. We hypothesize that this disruption occurs either via Pb's inhibition of secretion of GnRH from the hypothalamus and LH from the pituitary; and/or secondary to disruption of production of these hormones at the molecular level via Pb's competition with zinc finger regions within the estradiol (E2) receptor. We also reported that Pb exposed animals adapt to Pb's toxic effects on the productive axis. Changes in levels and stored hormone levels of GnRH and LH may be a mechanism by which the organism can adapt to Pb's toxic effects. Interactions by Pb with Zn in the E2 receptor may also decrease the methylation of target loci. Because DNA methylation is a molecular mechanism for parental imprinting, Pb exposure in utero may induce an inherited change in DNA methylation patterns in Pb exposed pups. We hypothesize that this is the mechanism by which Pb exposure during the critical time of sexual differentiation induces reproductive axis abnormalities in adulthood. We will specifically: 1) Determine the mechanisms by which Pb interferes with the secretion of GnRH from the hypothalamus and LH from the pituitary. 2) Determine if Pb disrupts transcription by competing with Zn finger regions within the E2 receptor. 3) Determine the mechanism(s) by which animals chronically exposed to Pb adapt to Pb's toxic effects. 4) Determine if the female reproductive system is disrupted in a fashion similar and analogues to males. 5) Determine if Pb exposure alters methylation patterns in the genes regulating reproductive hormone synthesis and determine if these changes are inherited. From the results of these experiments we will develop a general model which accounts for the disruption by Pb of biologic function at specific metal dependent sites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003749-13
Application #
2770713
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1985-06-15
Project End
2001-08-31
Budget Start
1998-09-01
Budget End
2001-08-31
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Health Research Association, Inc.
Department
Type
DUNS #
066679721
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
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
Sokol, R Z (1989) Reversibility of the toxic effect of lead on the male reproductive axis. Reprod Toxicol 3:175-80
Paliwal, V K; Ebadi, M (1989) Biochemical properties of metallothionein isoforms from bovine hippocampus. Exp Brain Res 75:477-82

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