Reproductive toxicology: current and future directions¹

Abstract

During the 20th century, there has been an increased risk from environmental by-products that may be harmful to reproductive function in humans. Therefore, as the 21st century begins, it is appropriate to evaluate future directions within the field of reproductive toxicology. This commentary identifies several approaches and developing technologies that would help research continue in a meaningful direction. Four areas for development are suggested, and selected examples of research involved in those areas are discussed: (1) Translational applications: workplace exposures thought to cause infertility in men (1,2-dibromo-3-chloropropane, DBCP) and menstrual disturbances in women (2-bromopropane, 2BP) are given as examples of human effects that have prompted animal studies. (2) Exposure paradigms: extrapolating dosing in animals to exposures in humans becomes complex. Two examples of surprising findings using lower doses are cited: ovotoxicity caused by polycyclic aromatic hydrocarbons (PAHs), and disrupted sexual differentiation caused by the fungicide vinclozolin. (3) Gender differences: predicting variable risk between women and men requires investigation of the effects of reproductive toxicants in both genders. The phthalates provide a good example for this comparison. Whereas di-(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant working by similar mechanisms in males and females, di-n-butyl phthalate (DBP) produces developmental effects in males and reproductive tract effects in females. (4) Endocrine disruptors: recent research has identified environmental chemicals that disrupt reproductive processes by altering the actions of endogenous steroid hormones. The endocrine disruptor issue is discussed in terms of evaluation of the actual risk these chemicals may pose in humans.

Introduction

The basic reproductive unit is composed of the mother, father, and offspring. Homeostatic maintenance of a species requires proper development and function of the reproductive systems in all three. The world experienced an explosion of technological and industrial advancement during the 20th century. Along with this, however, has come an increased risk from environmental by-products of those advancements. Therefore, disruptions these exposures might cause in the balance of the reproductive unit have caused increasing concern. Because of the complexity of regulation in each component within the reproductive unit, the field of reproductive toxicology has evolved with relative slowness.

In the mid-1970s, research in the field was conducted largely by governmental regulatory agencies and industry, and the data generated was fairly descriptive as biological endpoints were identified [1]. During the 1980s, a great deal of information was generated that provided a descriptive database from which working hypotheses could be generated for the development of mechanistic studies. The field of reproductive toxicology was to be impacted significantly in the mid-1990s, with the advent of the endocrine disruptor issue. This not only greatly increased the number of researchers interested in the impact of the environment on reproductive function, but also served to temporarily distract the field by narrowing its focus to only those chemicals that can specifically “mimic” the actions of endogenous steroid hormones, specifically xenoestrogens and xenoandrogens. As we begin the 21st century, therefore, it is an appropriate time to evaluate the field as to “where we are” and “where we want to go.” This commentary will discuss the field of reproductive toxicology as it encompasses environmental factors that impact reproductive function, by whatever mechanism. By taking this approach, endocrine disruptors also fall within this broader scope.