Superfund Research Program
Stage-specific Actions of Cadmium During Spermatogenesis
Spermatogenesis is an essential part of human reproduction. This dynamic process produces millions of sperm per day in a healthy man to support the continuity of life. Even with this robustness, sperm production is vulnerable to disruption by certain chemicals. Some controversial evidence even suggests that chemical contaminants in the environment may be contributing to a decrease in average sperm counts. Understanding whether environmental contaminants actually do interfere with sperm production is important in light of research that suggests male infertility may be increasing and knowing that the cause of infertility cannot be definitively identified for approximately 30 percent of infertile men.
However, the complexity of spermatogenesis makes it a difficult process to study cause-effect relationships. Many individual hormonal, biochemical and cellular events take place during the production of sperm. Among other steps this process includes several stages in which germ stem cells give rise to daughter cells that sequentially differentiate into highly specialized sperm cells. Spermatogenesis also involves several cell types found only in the testis, such as the Sertoli cell, which produces a number of proteins critical to successful sperm production. Pinpointing sensitive stages, cell types, and cellular targets has been very difficult in commonly used mammalian models, which have a very complex testicular organization.
Knowing that the stages of spermatogenesis are fundamentally conserved in all vertebrates, researchers at Boston University have been exploring the use of a nonmammalian model -- the spiny dogfish shark (Squalus acanthias) -- for its use in studying toxicant effects on sperm production. Taking advantage of the simpler testicular organization of sharks, the scientists recently showed that the spiny dogfish shark is a useful model for analysis of toxicant accumulation and effects during spermatogenesis.
A distinct advantage of using this model is the relatively simple organization of the shark testis. In the spiny dogfish shark spermatogenesis occurs in enclosed follicle-like structures called spermatocysts, which are not only fairly easy to isolate and manipulate, but are also organized such that the consecutive stages of spermatogenesis are arranged in a linear order within the shark testis. Thus, the developmental stages of germ cells are clearly separated and organized in the shark, features that facilitate stage-by-stage analysis of toxicant effects on sperm production. In contrast, the organization of mammalian germinal units are highly irregular making them difficult to isolate and use for investigating chemical effects.
The objective of recent studies was to identify the stages, cells and biological processes specifically targeted by cadmium -- a known spermatotoxicant -- during spermatogenesis. With its long biological half-life, cadmium is a good example of a trace environmental contaminant with potential for cumulative toxicity. Cadmium enters the environment from mining, burning coal, and many industrial processes including electroplating and battery manufacture. Fish, plants, wildlife and humans readily take up cadmium, which can build up in organisms from many years of low level exposure.
Both in vivo and in vitro studies were conducted to analyze the uptake, accumulation and effects of cadmium. Analysis of radiolabeled cadmium in vivo revealed cadmium toxicity is specific to certain stages and cell types. A great proportion of the radiolabeled tracer was detected in regions of the testis containing premeiotic germ cells, while very little was found in testicular regions containing germ cells at more mature stages. In addition, cadmium was found to increase apoptosis (cell death) in germ cells in premeiotic stages, but not Sertoli cells in the same stages or germ cells or Sertoli cells in meiotic or postmeiotic stages. Moreover, results showed that even transient exposure to low levels of cadmium can reduce the number of germ cells progressing into meiosis.
Based on these findings and in vitro studies, the researchers conclude that cadmium acts as a spermatotoxicant by preferential accumulation during early developmental stages of spermatogenesis. By reducing the number of spermatogonia that advance to meiosis and mitosis, cadmium has profound effects on all subsequent stages of spermatogenesis and on ultimate sperm production.
The in vivo accumulation and effects of cadmium are reproducible in vitro when culture conditions are optimized for growth and survival. Thus, the in vitro studies showed that isolated, staged spermatocysts may be useful for screening and mechanistic analysis of other spermatotoxicants.
Information concerning the risks of environmental contaminants to male reproductive health is very limited and for many chemicals, nonexistent. In addition to advancing our understanding of the risks of cadmium exposure to male fertility, these studies are significant for demonstrating the utility of this nonmammalian vertebrate model for evaluating other potential or known spermatotoxicants.
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To learn more about this research, please refer to the following sources:
- Betka M, Callard GV. 1999. Stage-dependent accumulation of cadmium and induction of metallothionein-like binding activity in the testis of the dogfish shark Squalus acanthias. Biol Reprod 60(1):14-22. PMID:9858481
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