RESEARCH OBJECTIVES Background Many industrial and environmental chemicals mimic, antagonize, or indirectly alter the activity of hormones, particularly steroid hormones. These chemicals have been classified as "endocrine disruptors" because they may bind to the estrogen and/or other hormone receptors, either imitating the action of the hormone or blocking its activity. These chemicals impact endocrine glands and other target organs that depend on the endocrine system for regulation. Endocrine disruptors that have been identified are commonly found in the environment include a variety of herbicides, fungicides, insecticides, nematocides and industrial chemicals such as dioxin, polychlorinated biphenyls (PCBs), and other chlorinated compounds. Some of these chemicals have been shown to be weakly estrogenic, antiestrogenic, antiandrogenic, or effect thyroid hormone function. Exposure to these compounds prenatally or in early postnatal life can disturb the development of the endocrine system and organs that respond to hormonal signals in animals. Women, who were exposed to these chemicals during early development, neonatally, or later in life may have increased risk of endocrine dysfunction leading to infertility, fibroids, endometriosis, early menopause, osteoporosis, autoimmune diseases, and breast and other cancers. Exposure to exogenous sources of estrogens and other endocrine altering chemicals may also occur during critical biological periods, such as puberty and the childbearing years. Exposures at these times may be related to changes in reproductive capacity and an increase in adverse women's health conditions in later life. Untangling issues related to the timing of exposure are especially important to understand the mechanism of action of these compounds and their cellular effects during critical periods of a female's development. Women may be exposed to exogenous sources of estrogens through the use of pharmaceuticals containing synthetic estrogens, in the workplace, through environmental contamination from industrial or agricultural processes, and dietary exposures from consuming contaminated fish or vegetable sources of phytoestrogens. Organochlorine compounds are ubiquitous in the environment and their biologically persistent nature makes their presence a potential hazard for a long time period. Body stores of compounds such as DDT and dioxins accumulate in adipose tissue, have long biological half lives and may be active in the body for more than 20 years. In the exposed pregnant woman, endocrine disrupting chemicals can be passed through the placenta, exposing the fetus, or may be expressed in human milk through breast feeding, exposing the neonate to significant levels of these chemicals. National surveys of pollutants in human milk document the presence of pesticides and chemicals such as dioxins. Exposures to certain pesticides have been shown to shorten the period a woman is able to lactate. Exposures during critical developmental periods during gestation may affect the development of the nervous, endocrine and immunologic systems in the fetus and may impact on the regulation of various physiologic processes within the neuro endocrine axis. Birth defects such as cleft palate and malformations in genitalia may be more common after exposures during gestation to these agents. Abnormalities of growth and development have been reported in cohorts of children accidentally exposed in utero to endocrine disrupting chemicals in Japan and Taiwan. It is not clear whether these chemicals are exhibiting direct neurotoxic and immunotoxic effects or whether these effects are mediated by alterations in the endocrine system. More research is clearly needed to clarify these pathways. In certain ethnic groups, such as some Native American populations where fish eating predominates, pregnant women consuming contaminated fish have substantial exposures to organochlorine compounds that they pass on to the fetus. It will be important to determine the health status of women and their offspring ingesting these contaminants and to follow up the children for future disease risk. Research Goals The goals and scope of this initiative are twofold. The first is to encourage and support mechanistically based research on the health effects of endocrine disruptor concentrations that are commonly found in the environment. Research would be encouraged to define the action of these chemicals on the reproductive, immune, and nervous systems during critical periods of exposure (in utero, neonatal, pubertal, reproductive aged adult, post menopausal) concentrating primarily on women's health. Experimental work on the cellular, molecular, genetic, and systemic effects of exposures are appropriate. The second area of emphasis is to examine emerging hypotheses in human populations that complement the recent findings in the laboratory and in wildlife. Emphasis should be placed on development and validation of methods to precisely measure these exposures in human populations. For the purpose of this RFA, endocrine disruptors are defined as those chemicals that mimic or antagonize directly or indirectly an endocrine system. Examples include, but are not limited to, estrogenic pesticides, naturally occurring phytoestrogens, and pesticides or industrial chemicals with antiestrogenic or antiandrogenic activity. This RFA is not intended to support research that primarily focuses on the health effects of the use of oral contraceptives or menopausal replacement hormones. Toxicologic testing of endocrine disruptors using bioassays or alternative methods, which are necessary for regulatory purposes, will be considered nonresponsive to this RFA. Research on the role of endocrine disruptors in breast cancer development is also not a focus of research in this RFA. Support for research on breast cancer is being provided under the National Action Plan for Breast Cancer, grants from the Department of Defense and other National Cancer Institute and NIEHS initiatives. Areas of research that are encouraged include, but are not limited to: o Studies of the effects of endocrine disrupting chemicals on the following health endpoints. Health effects pertinent to reproduction would include endocrine dysfunction, infertility, endometriosis, pregnancy outcomes, and lactation. Health effects pertinent to women's health would include fibroids, early menopause, osteoporosis, autoimmune diseases, and gynecologic cancers. Of particular interest are studies that focus on exposures during critical periods of development. The development and validation of biomarkers of endocrine disrupting exposure and early health effects are encouraged. o Research that clarifies the transgenerational effects of in utero and neonatal/early postnatal effects of endocrine disrupting chemicals. This would include the occurrence of birth defects, perturbations of growth and development, precocious puberty in young offspring and functional changes that are detected in later life.