Working for women's health.

Women's health is an area that is gaining increasing attention with the realization that men's and women's bodies don't just look different-they also react differently to environmental agents. Barbara J. Davis, head of the Female Reproductive Pathology Group and now acting chief of the newly created Laboratory of Women's Health, is leading women's health studies at the NIEHS. Over the course of her 10 years at the institute, Davis has concentrated her efforts on studying ovarian toxicity and its relationship to the environment. The ramifications of infertility stretch further than just whether a woman can bear children. For instance, in addition to making a woman less likely to conceive, persistently lower estrogen concentrations have been shown to contribute to osteoporosisf and heart disease. Davis urges a broad pe spective in looking at women's health, perspective that takes into account not jut the primary effects but also the secondaijr and tertiary effects of a particular exposure. Davis's strategy has been to develop rodent models that mimic the human men-strual cycle so that she can study the effects of chemical exposures over several iterations of a hormonal cycle. Rather than inundate the model with a chemical that totally shuts down the reproductive system, she says, she leaves the reproductive system intact so as to study the long-term effects of certain exposures. Davis feels that the cyclical approach taken toward women's diseases could also be applied to male-specific hormone-related diseases such as prostate cancer. The Female Reproductive Pathology Group provides support for reproductive toxicity studies conducted by the National Toxicology Program. The group studies the pathophysiology of ovarian dysfunction and cancer in women and rodents caused by chemical exposures, and seeks to identify ovarian target cells as well as the biochemical and molecular mechanisms by which both synthetic and naturally occurring environmental chemicals cause ovarian dys-function or cancer. Both in vivo and in vitro models are used in this work. The group is also working to determine the role of key genes and signaling molecules in ovarian cell growth, differentiation, and physiology, and to understand how to modify these pathways to prevent or lessen the chance of ovarian dysfunction and cancer. The Laboratory of Women's Health is expected to carry those studies a step fur-ovaries to ovulate-without this cue, the ther, extending them into the realm of direction never comes and the rodents fail human exposure. to ovulate. Nevertheless, egg follicles are Ovarian …

Women's health is an area that is gaining increasing attention with the realization that men's and women's bodies don't just look different-they also react differently to environmental agents. Barbara J. Davis, head of the Female Reproductive Pathology Group and now acting chief of the newly created Laboratory of Women's Health, is leading women's health studies at the NIEHS. Over the course of her 10 years at the institute, Davis has concentrated her efforts on studying ovarian toxicity and its relationship to the environment.
The ramifications of infertility stretch further than just whether a woman can bear children. For instance, in addition to making a woman less likely to conceive, persistently lower estrogen concentrations have been shown to contribute to osteoporosisf and heart disease. Davis urges a broad pe spective in looking at women's health, perspective that takes into account not jut the primary effects but also the secondaijr and tertiary effects of a particular exposure.
Davis's strategy has been to develop rodent models that mimic the human menstrual cycle so that she can study the effects of chemical exposures over several iterations of a hormonal cycle. Rather than inundate the model with a chemical that totally shuts down the reproductive system, she says, she leaves the reproductive system intact so as to study the long-term effects of certain exposures. Davis feels that the cyclical approach taken toward women's diseases could also be applied to male-specific hormone-related diseases such as prostate cancer.
The Female Reproductive Pathology Group provides support for reproductive toxicity studies conducted by the National Toxicology Program. The group studies the pathophysiology of ovarian dysfunction and cancer in women and rodents caused by chemical exposures, and seeks to identify ovarian target cells as well as the biochemical and molecular mechanisms by which both synthetic and naturally occurring environmental chemicals cause ovarian dysfunction or cancer. Both in vivo and in vitro models are used in this work. The group is also working to determine the role of key genes and signaling molecules in ovarian cell growth, differentiation, and physiology, and to understand how to modify these pathways to prevent or lessen the chance of ovarian dysfunction and cancer. The Laboratory of Women's Health is expected to carry those studies a step furovaries to ovulate-without this cue, the ther, extending them into the realm of direction never comes and the rodents fail human exposure.
to ovulate. Nevertheless, egg follicles are l t wtwo found that the chemicals elevated proges-",classes thylterone production in both rat and human e -baseoa used cells. In the rats, the chemicals also inhibitto mlasticlefa SQk t hey are ed ovulation. Davis and colleagues specucoritained in cosm ts suc as nail late that the chemicals may cause the same polish and in paints, varnshes, or y plaseffect in humans.
tic that needs to be flexible. Ethyleye-based glyc I~t hers' rimarily used as olvents an fart be foun in s, varnis s, and d, ing chemicals. They artalso uged in t semiconiuctor industry. '-Ph, route of e osure for tpes of chemk-cals inay dermal or inhaIinal. People aredlso e sed to phthalates orally as they t~ach & plastic products into food.
avis says the data are not yet avAlable to ( termine whether exposure to%these chem s constitutes a ajor htalt concern. phthalates rep esent f the largest ass of syntheti ompo s produced, e need to be aw re of the potential he h effect and de rmine h w they act ani to what extent people re ly are expos ," she says. are only tting those ata now. The investigators were able to determine that mice that lacked COX-2 failed to ovulate and had abnormal implantation and decidualization responses (the uterine changes that allow for implantation), whereas the COX-1-deficient mice were fertile. The studies also showed that the COX-1-deficient mice exhibited aberrant estradiol production and indicated that both prostaglandins and estradiol are necessary for normal delivery. Finally, the studies showed for the first time that ovulation can be Volume 108, Number 1, January 2000 * Environmental Health Perspectives A 18 evv-. LLI t) amm ME AR NIEHS News restored in COX-2-deficient mice by simultaneous treatment with gonadotropins and either the prostaglandin synthase PGE2 or the cytokine interleukin-1 P, which may provide a clue to future infertility treatments. These studies suggest that, contrary to traditional belief, it is COX-1 and not COX-2 that produces the prostaglandins that are necessary for boosting ovarian estradiol production, and that estradiol levels then determine the production of COX-2-related prostaglandins. Future studies will evaluate specific chemicals and their effect on ovarian function and interaction with prostaglandin pathways.

Pesticide Exposures
Along with Bob Chapin of the Reproductive Toxicology Group within the NIEHS Laboratory of Toxicology, Davis has studied the effects of pesticide exposures on juvenile and adult rodents. In a paper published in the November 1997 issue of Fundamental and Applied Toxicology, for instance, the pesticide methoxychlor was shown to cause ovarian dysfunction resulting in reduced estrous levels of follicle-stimulating hormone at all dosages and reduced estrous progesterone levels at some dosages. Davis has also studied the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin), which has been shown to promote ovarian tumors in female rats, and nitrofurantoin, an antibiotic used for urinary tract infections that has been associated with ovarian cancer in rodents, although not in humans.
Davis and colleagues are currently working to understand how TCDD causes tumors to develop and whether women may be at risk from these exposures. One possible connection between the rodent and real human exposure is that the type of ovarian tumor induced by TCDD in the rats in Davis's experiments is the same histological subtype as that found in one young woman who had been exposed to dioxins during a 1976 industrial accident in Seveso, Italy. "Because this subtype of ovarian tumor is indeed rare and because tumors of any kind are rare at such a young age in women, it is possible that the appearance of the tumor in the Italian woman was related to the exposure," says Davis. "It is also possible this finding could have been a random and unrelated event. We clearly need to investigate and distinguish these possibilities." The Laboratory ofWomen's Health he goals," says Davis, "is to get slational work underway. We're ,ing that gap between toxicologiand human exposure." cally, the lab will build on work Roger Wiseman, a senior staff the lab's Comparative Carcino-)up, have already started with the ,er susceptibility genes Brcal and hey relate to breast and ovarian )espite the gene's name, Brcal are also known to increase cancer ity in the ovaries.) The lab will id its focus and search for key signaling processes in the reprod immune systems and strive to ; environmental stresses and toxir those processes and genes. ors will study ovarian function zgnancy and childbirth, ovarian cancer, breast cancer, uterine leiomyomas (fibroid cysts), and autoimmune diseases. g-Ultimately, the lab's researchers hope to reduce the burden of environmentally related diseases in women through the combined effort and expertise of geneticists, endocrinologists, immunologists, pathologists, and epidemiologists. To that end, Davis emphasizes the idea of a "virtual lab" in which scientists will have free and constantly updated access to an ever-expanding body of data and knowledge to be used as stepping stones and building blocks in collaborative research efforts. "We need to always be ready to evolve as we understand new concepts, Davis says.