Cell interactions in spermatocyte apoptosis

Among their many unfortunate effects, heavy metals such as cadmium can impair male fertility. Whether oligospermia arises from environmental exposure to cadmium is unclear from epidemiological studies, but male rats treated with this metal reliably decrease their production of mature sperm. Ozawa et al. have found that this response reflects a complex interplay between the developing germ cells and the neighboring somatic cells. Leydig cells, endogenous producers of testosterone and other steroids in the testis, are particularly important in this reaction, because they induce heme oxygenase-1 (HO-1) expression in response to cadmium or other stressors. The enzymes HO-1 and -2 generate CO and biliverdin, starting from the ferric protoporphyrin IX, an iron-complexed form of heme. The authors show that inhibition of HO activity prevents germ cell apoptosis in cadmium-treated animals but that treatment with dichloromethane, which replaces the missing CO, restores this response. Hence, they argue, CO generated within the Leydig cells reaches the developing spermatocytes and causes them to undergo Fas-dependent apoptosis, rather than meiosis. Interestingly, treatment with dichloromethane alone does not cause apoptosis, suggesting that some other aspect of heavy metal toxicity is required for the response. Germ cells apparently die prior to meiosis, since the Fas ligand protein is induced specifically in diploid and tetraploid cells but is not found at heightened levels in the surviving population of haploid spermatids, and the latter cells do not show nuclear condensation or fragmentation, the usual hallmarks of apoptotic cells. The authors suggest that, even in unstressed animals, Leydig cell HO-1 and CO accumulation around germ cells may contribute to a background level of spermatocyte apoptosis in unstressed animals. If so, the same pathway may well be implicated in other forms of oligospermia and male infertility.


Contact: John Ashkenas
Journal of Clinical Investigation

Page: 1

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