**2.9 Potential information from genetics to advance epidemiologic studies**

If epidemiologic studies could identify genetic-toxicant interactions by comparing the prevalence of a particular genetic marker (polymorphism) or a group of markers in affected and unaffected populations, this information could be used to target environmental, behavioral, or medical interventions (Khoury 1997). Ultimately, validation of genetic testing to link a particular genotype with exposure to a specific chemical to the increased prevalence of a particular reproductive disorder would require epidemiologic confirmation (Khoury & Dorman 1998).

#### **2.10 Communication**

An essential component of future reproductive studies will be improved communication. Because of the complex mechanisms involved in reproductive research, collaboration across scientific disciplines must be conducted. In addition, notification of research results and recommendations must be communicated to workers and the affected public in a manner that is timely, accessible, and easily understood. A primary goal of reproductive research is to reduce the high percentages of adverse outcomes such as infertility, pregnancy loss, and congenital malformations. Although certain limitations exist that are unique to reproductive research, many advances in technology and methodologies have been recently developed that will aid researchers in their efforts to *a*) understand mechanisms by which toxicants

Environmental Toxicants Induced

**3.2 Epidemiologic approaches** 

Male Reproductive Disorders: Identification and Mechanism of Action 499

effects appear, researchers can go back and administer a dose during that critical period of development to refine knowledge about how such problems occur. Early developmental end points measurable in animal research include anogenital distance at birth, testis position, genital malformations, secondary sex characteristics, and serum hormone levels. Acute short-term exposures, on the other hand, can be useful for identifying critical windows of exposure. Acute exposures followed over time can help identify the pathogenesis of a lesion, isolate the cell type that is susceptible to damage (germ cells, spermatocytes, or spermatid), and determine genetic effects, including the repair capability of affected genes. Serial sacrifice studies are best used for identifying the earliest detectable pathologic changes in target organs, cells, or processes. Multigeneration studies, in particular continuous breeding studies, yield the most thorough assessment of the many

Epidemiologic methods for assessing the impact of hazardous substances on male reproductive health include *a*) questionnaires to determine reproductive history and sexual function, *b*) reproductive hormone profiles, and *c*) semen analysis. The choice of appropriate methodologies to study the effects of reproductive toxicants is predicated on the investigators' understanding of several factors: the nature of the exposed population; the source, the levels, and the known routes of exposure; the organ systems in which a toxicant exerts its actions; the hypothesized mechanisms of a toxicant's actions; and the techniques available to assess the effects of toxicants in the relevant organ systems (Wyrobeck et al., 1997). **Table 2** outlines the methods currently available for assessing the principal targets of male reproductive toxicants in humans--the testes, the accessory sex glands, the neuroendocrine system, and sexual function. Researchers and clinicians interested in male reproductive health and fertility are using increasingly sophisticated methods adapted from the fields of assisted reproductive technology and reproductive toxicology, including assays of sperm function, genetic integrity, and biomarkers of DNA damage. For population-based studies involving occupational groups or communities with environmental exposures, issues related to the cost, validity, precision,

The testis, the site of sperm cell production and the target organ for genetic damage, is most often studied. To establish the extent of toxicity to the testis, researchers can measure the size of the testis, obtain a semen sample, or take a testicular biopsy. Standard semen analyses (including semen volume, sperm concentration, total sperm count, motility, and morphology) have been the primary research tools for studying the effects of toxicants on the male reproductive system. Epidemiologic studies have successfully utilized semen quality as a marker of fertility (Fisch et al., 1997). The uncertainties associated with traditional semen measures have led to the recent development of assays of sperm function and genetic integrity; these assays may prove more sensitive and more specific reflections of toxicant-induced effects (e.g., aneuploidy or reduced sperm motility) in individuals (Martin et al., 1997). However, The accessory sex glands, which include the epididymis, prostate, and seminal vesicle, may also be targets of toxicants (Schrader, 1997). Ethylene dibromide is one substance that affects the accessory sex glands after occupational exposure. Alterations in sperm viability, as measured by eosin stain exclusion or by hypo-osmotic swelling or alterations in sperm motility variables, suggest a problem with the accessory sex glands. Biochemical analysis of seminal plasma provides insights into glandular function by

complex processes that result in reproductive and developmental toxicity.

and utility of these methods must be carefully considered.

exert their effects, *b*) identify populations at risk, and *c*) evaluate reproductive and developmental hazards to improve public health.
