On The Mechanism Of Toxicity Of Lead In The Male Reproductive System.

Abstract

Lead has been associated with infertility since the times of the Roman Empire. It causes asthenospermia, hypospermia, and teratospermia. However, it is only recently that the mechanism of lead toxicity in the reproductive system has been investigated. Sertoli cells, the only somatic cells in the semi-niferous tubule, provide both structural and functional support for the developing germ cells. Hence, agents that affect the structure or function of Sertoli cells could impair the process of spermatogenesis. Therefore, the effect of lead acetate on the morphology and metabolism of primary cultures of Sertoli cells prepared from rat testis was studied. Lead acetate at concentrations as low as 0.05 mM was found to increase lactate production by Sertoli cells and to decrease glucose utilization, protein synthesis and secretion. These effects were accompanied by morphological changes. However, lead acetate exposure for 12 hrs. at concentrations as high as 0.10 mM did not kill the cells, as evaluated by viability tests. The effects of lead on carbohydrate metabolism of Sertoli cells were compared with its effects on isolated testicular mitochondria. Lead acetate (as low as 0.04 mM) stimulated State 4 respiration (in the absence of ADP) and inhibited State 3 respiration (in the presence of ADP). The respiratory control ratio (State 3 divided by State 4) decreased from 1.82 to 1.06 at 0.08 mM lead acetate. The effect of lead acetate on oxidative phosphorylation suggests that the mitochondria may be the direct target of lead. Alternatively, lead may disrupt the calcium second messenger system in the cell. Because of the similarity of lead and calcium, lead may affect the metabolism of Sertoli cells by affecting rate-controlling enzyme activities in the cells by changing their state of phosphorylation. Lead was shown to bind to calmodulin and to increase the phosphorylation of three Sertoli cell proteins. It is proposed that lead produces this effect by mimicking calcium, at least in part, or by disturbing calcium homeostasis. Lead was also shown to decrease lactate utilization by germ cells without affecting their viability. This also suggests that lead affects the integrity of mitochondrial structure and/or function.