Effect of Environmental Exposures on the Egg Fertilizing Ability of Human Sperm

Our goal is to understand how environmental and occupational exposures to heavy and
transition metal ions injure the human male reproductive tract.

The American Urological Association and the American Society for Reproductive Medicine
report that ~15% of couples (i.e., more than 6.1 million people in the U.S.) experience
infertility at some time. The male is responsible for infertility of 20% of these couples
and contributes to the infertility of another 30-40%. However, the cause(s) of male
infertility in many cases is unknown. Our data suggest that lead exposures (in the air, in
food and in drinking water) underlie a significant fraction of "unexplained" male
infertility. We found that blood and seminal plasma lead levels were elevated in 22% of
normospermic males from couples seeking infertility treatment, in 29% of semen donors
participating in an artificial insemination program and in 23% of unselected semen donors
answering an advertisement for research participation. These elevated lead levels were
associated with decreased sperm fertility potential in IVF, in artificial insemination and
in pregnancy by coitus. The negative effects of lead on sperm function was correlated with
expression of specific forms of sperm ion channels (metal binding proteins that allow lead
to enter cells), suggesting that such proteins serve as markers for susceptibility or
resistance to the reproductive toxic effects of lead. Further, in cases in which human male
lead levels changed markedly over time, there were corresponding changes in sperm ion
channel, sperm function and sperm fertility potential. These changes were linked to changes
in calcium modulated processes in human testis biopsies obtained from infertility patients
and could be mimicked in testes of rats experimentally fed lead.

In the current study, we plan to identify changes in gene expression important to the
production of the infertile state by comparing the genes expressed in the testis of control
and lead exposed rats which are resistant or susceptible to lead. These findings will help
to explain how lead exposure kill cells within the testis. We will then determine whether
the same changes occur in human testis biopsies and ejaculated sperm from infertile males
with high body burdens of lead. The expected outcome of this study is the identification of
a possible mechanism explaining male infertility associated with low sperm counts or
idiopathic male infertility, tools for diagnosis of male infertility and the hope for
rationale treatment.

- Otherwise healthy men seeking fertility evaluation, without history of urologic
infections or varicocele.

- Non-smokers.

- Occupationally exposed to lead or not exposed to lead.

- Otherwise healthy men undergoing testis biopsy for clinical assessment of
spermatogenesis or for sperm retrieval prior to an attempt at assisted reproduction.

- Otherwise healthy men providing semen specimens for clinical analysis prior to an
attempt at assisted reproduction.