Sex matters: exploring differences in responses to exposures. (NIEHS News).

Leading researchers across the spectrum of toxicology gathered at the NIEHS on 15 October 2002 for an in-depth roundtable discussion on the biology of sex differences in environmental health. Cosponsored by the NIEHS and the Society for Women's Health Research, an advocacy group located in Washington, D.C., the one-day conference examined how sex interacts with environmental exposures to yield sometimes-different health effects in men and women.

A primary goal of the conference was to outline how a person's sex influences his or her environmental health--teasing out how biological and societal differences in men's and women's lives impact their health. "Environmental health lies right in the middle of the great tangled hairball of research," says Sherry Marts, the society's scientific director. "Sex is a crucial biological variable that needs to be looked at at all levels and in all organ systems. Sex matters."

The conference was one of a series sponsored by the society to help establish an agenda for understanding the influence of sex and gender across the life sciences. The series expands on a 2001 Institute of Medicine report, Exploring the Biological Contributions to Human Health: Does Sex Matter?, which the society helped initiate and sponsor. Other series roundtables have addressed sex differences in cardiovascular health and disease, immunity and autoimmunity, and prenatal development. "We want to encourage that sex differences be part of research, all research, integrated into everything," explains society president Phyllis Greenberger.

Understanding Sex Differences

The first half of the October roundtable focused on traditional and newly developed scientific tools and how they can enhance understanding of sex-specific responses to environmental exposures. James Huff, an NIEHS senior investigator, discussed bioassays in chemical carcinogenesis. The picture is complicated. "Roughly half the chemicals we test have a tumor effect at one site in one sex in one species," Huff reported. Many cancer differences in animal bioassays, he said, likely reflect differences in the sex-hormonal biological context as it may be impacted by environmental exposures.

Although highly effective in developing preventive health strategies, animal-based bioassays also have weaknesses, especially the time and animal facility costs involved in whole-organism work. Expanding these assays to cover effects in both sexes would increase costs further by increasing the number of animals involved. However, these bioassays clearly signal sex differences in response to environmental exposures, and have led to better biologic understanding of such differences.

Mary Jane Cunningham, director of discoveries at Molecular Mining Corporation, a Kingston, Ontario-based data analysis and predictive modeling technology company, discussed methods that may overcome those barriers. She described gene expression microarrays and advanced data mining and analysis methods allowing rapid detection and comparison of the effects of environmental exposures. "It takes only three to four days to obtain the expression of ten thousand or more genes using arrays, and only a matter of minutes to analyze the data," she said. "These technologies are available now. However, when the cost of the arrays is reduced or [they] become more efficient, you can afford to allow for testing of both sexes." (Others are not so optimistic, however, and believe that microarray technologies will take enormous funding, resources, and time to develop and validate.)

Kent Hunter, an investigator at the National Cancer Institute, described work using quantitative trait genetics, a breeding approach that untangles processes controlled by multiple genes to elucidate how environmental factors can affect development of sex-specific cancers. He has found that how individuals differ in one trait--expression of the tumor suppressor Atm--may help determine whether breast cancer stays dormant or metastasizes. Complicating the picture is the fact that Atm is sensitive to caffeine, a common environmental exposure for both men and women. The interplay between environmental factors and individuals' genes is key, Hunter said: "The exposure is critical to development of disease. You can be susceptible to a disease, but if you're not exposed, you won't develop the condition."

Brent Palmer, a University of Kentucky associate professor of environmental biology, complicated the picture further with a discussion of endocrine disruption, showing that even without genetic factors, sexually distinct environmentally induced effects can propagate to subsequent generations. Endocrine disruptors, he said, can both mimic and thwart the actions of steroid sex hormones. These compounds can have profound effects, especially during critical periods of fetal and childhood development, because they mimic or antagonize the effects of sex hormones. Sexual development and adult fertility may be affected, as well as processes such as immune function and development of cancer. Further, because they can affect reproduction and germ cell development, their effects can be multigenerational, with germ cell damage in a parent emerging in later children.

Other discussion centered on the concept that genetics are involved in only 5% or less of cancers. Thus, says Huff, the environment represents a much greater determinant in environmentally associated disease.

Discussants agreed that there is no technology that will soon answer the question of how the sexes differ. Nevertheless, efforts should be made to evaluate the effect of environmental agents on both sexes, and to elucide the effects that environmental agents, including pharmaceuticals, have on sex-specific health problems.

How Sex Matters

The second half of the conference focused on specific diseases. Allen Silverstone, a professor of microbiology and immunology at the State University of New York/Upstate Medical University in Syracuse, highlighted immunostimulation and -suppression by environmental agents. Ellen Silbergeld, a professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, brought up the prospect of environmental factors as "coconspirators" in autoimmune disease--not causing diseases by themselves, but helping diseases arise when they otherwise might not. She gave the example of mercury, which accelerates the development of lupus erythematosus, a disease that occurs 8-10 times more often in women than in men. In mouse studies, the metal stimulated the disease even when present at concentrations 50- to 100-fold lower than those typically judged toxic.

Mary Beth Martin, a Georgetown University Medical Center associate professor of oncology, examined the role of cadmium as an estrogen mimic that can activate sex hormone receptors. Bernard Weiss, a professor of environmental medicine at the University of Rochester School of Medicine, rounded out the session with comments on the cognitive and behavioral consequences of environmental exposures, particularly metals. Even without toxic exposures, males and females behave and perform differently on many tasks, and men's and women's brains are anatomically distinct, he said.

"Experimenters for the most part have not tended to ask why [these differences occur]," Weiss said. "It's astonishing when you realize that women suffer from clinical depression at two to three times the rate of males." To begin sorting out how toxic exposure can affect behavior, Weiss is studying the effect of endocrine disruptors on wheel-running in rats. Running in a wire wheel is a behavior both male and female rats enjoy, as judged by their willingness to seek it as a reward. Wheel-running varies with the estrous cycle in female rats; they run more as their estrogen levels rise, and their running patterns change on exposure to endocrine disruptors.

Although it is clear that men and women often respond differently to toxicants, the discussants agreed that predicting just how the sexes will respond, and when they will respond differently, has not proved simple because, Silverstone said, of the limited amount of data at this time. One approach to improving understanding of critical differences between the sexes would be to ask that grant makers require researchers to include both sexes in both basic experimental research and animal studies. "It's only been recently that when you're doing human NIH research with institutional review board approval you've had to include women," Silverstone said. Animals studies do not yet even have the same requirement.

The researchers agreed that bringing together insights from a broad group of sciences and scientists is key to better understanding sex differences, despite barriers to collaborative science, including a tax in which grant overhead is collected by each of the institutions involved in a collaborative project. Fundamental needs include more funds and more personnel to invest in whole-organism approaches and translation of laboratory results into medical practice. "We need to know in terms of clinical care what works and what doesn't," Greenberger said. "There's plenty we don't know about women. There's plenty to be learned."