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 System1

Abstract

Lead is a male reproductive toxicant. Lead exposure results in a general suppression of the hypothalamic-pituitary-testicular (HPT) axis in male rats. The mechanism(s) for this disruption by lead is unknown. Toxic lead levels seem to disrupt central nervous system (CNS) control of the HPT system, resulting in a decrease in serum testosterone levels and sperm concentrations. A study designed to elucidate the mechanisms accounting for the disruption of the normal function of the male axis by toxic lead levels at the molecular level demonstrated a 2-3-fold enhancement of mRNA levels of GnRH and the tropic hormone LH. A 3-fold increase of intracellular stores of LH was also found. Because mRNA levels of LH and GnRH and pituitary levels of stored LH are proportional to blood levels of lead, we hypothesize that lead interferes with the normal release of tropic hormones and disrupts hormonal feedback mechanisms. The observed pleiotropic effects of lead upon the male axis and other systems may be explained by simple and unique competition by lead with normal metal ion binding sites that govern genetic control of specific genes.

Long-term, low-dose lead exposure alters the gonadotropin-releasing hormone system in the male rat.

“…We reported previously that exposure to lead acetate in relatively high dose ranges for 3 weeks increased mRNA levels of GnRH and LH as well as stored levels of LH (19). Consistent with the conclusion that the reproductive axis adapts to the toxic effects of lead was the finding that the increase in GnRH, mRNA, and β-LH concentration plateaued once the animal's blood lead levels reached 50 µg/dL.…”

“…We added 1 mL 5 N HCl to all water bottles (including controls) to preclude precipitation of insoluble PbAc salts. We selected the doses of lead on the basis of previously published studies (19,22). Animals were weighed, and the volume of water consumption was measured at the beginning of study weeks 1, 4, 8, and 16.…”

“…Lead exposure is associated with neurologic (3-6), growth (3,7), and reproductive defects (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Lead exposure in men has been associated with abnormalities of spermatogenesis (9,(11)(12)(13)).…”

“…We and others have demonstrated, using the rat model, that lead exposure produces a dose-response suppression of serum testosterone and spermatogenesis accompanied by no significant changes in circulating gonadotropin levels (16,17). However, mRNA levels of GnRH in the hypothalamus and LH in the pituitary are increased with lead exposure (17)(18)(19)(20). This reported endocrine disruption was noted at blood lead levels > 30 µg/dL after exposure times of 2-8 weeks.…”

Inhibitory Mechanisms of Lead on Steroidogenesis in Ma-10 Mouse Leydig Tumor Cells

“…Exposure of Pb can result in altered spermatogenesis and substantial decrease in fertility at high blood lead levels [3, 4, 10, 14-16, 20, 29]. Pb affects testosterone production on the hypothalamicpituitary-testis axis, inhibits Leydig cell testosterone production and serum testosterone levels, induces early onset of capacitation and results in premature acrosome reaction, and delays spermatogenesis [5,9,21,22,27,28]. It has also been demonstrated with suppression of plasma testosterone accompanied by a decrease of plasma LH, resulting in delayed sexual maturation, in pups of mothers ingesting lead in drinking water [17].…”