Environmental Factor, August 2007, National Institute of Environmental Health Sciences
EPA Biologist Reviews Endocrine Disruptor Research
By Lillian Gu
On June 29 in Rodbell Auditorium, the Frontiers of Environmental Science Lecture Series featured a talk by biologist Suzanne E. Fenton, Ph.D., on "The Mammary Gland as a Sensitive Tissue for Detecting Effects of Environmental Components." The talk was hosted by Laboratory of Molecular Carcinogenesis Fellow Rosemarie Ramos, Ph.D. Fenton attracted a near-capacity crowd of NIEHS scientists who share her research interests in the effects of endocrine disrupting compounds (EDCs) on the reproductive health of mammals and their offspring.
The lecturer is a research biologist with the Environmental Protection Agency, where she and her group study prenatal and lactational EDC exposures and their effects on the development of the mammary gland. "The mammary is unique because it has periods of rapid growth," she explained, "and it also has periods of extensive differentiation, and it can switch back and forth between these throughout the life of the woman. That provides many opportunities for initiation of lesions and promotion of altered cells."
Fenton uses the rodent as a model in her studies because the mammary structure and development process are very similar to its human counterpart. The end points in her studies are significant alterations in mammary gland development and lactation - specifically, delays in vaginal opening, decreased ductal branching and delays in the differentiation of terminal end buds in mammary glands. She also looks at gene expression effects, increased mortality, decreased milk ingestion and developmental abnormalities in rodent dams and pups.
During her talk, Fenton focused on effects on the mammary gland of exposure to three EDCs, dioxin, atrazine and perfluorooctanoic acid (PFOA). She reported that while the dioxin exposure levels she used were quite high, the atrazine exposure levels that produced mammary effects in rodents were lower than the current NOEL, the no-observed-effect level. The PFOA levels used were only ten-fold that of the known human serum concentration, making the results of her studies (see text box) more relevant to human exposure levels.
According to Fenton, in addition to dioxin, atrazine and PFOA, which have demonstrated effects as endocrine disruptors, several other compounds are also suspected of altering mammary gland development, including bisphenol A, polychlorinated biphenyls and organochlorine. Because of the controversy surrounding these compounds, Fenton stressed the importance of including the study of mammary glands in puberty research. "By not collecting mammary tissue in the assays addressing pubertal endpoints following early EDC exposure," she argued, "we are slowing the process of determining which EDCs alter developing breast tissue."
Researchers should be aware of pitfalls in researching EDCs, Fenton noted. "Many studies are exposing the animals at the wrong time. Exposure in adult animals for all of the compounds that I talked about today has no effect on the mammary glands. Trying to correlate current exposures in women with their health effects is not getting us closer to the answers of what the environmental risks are for breast cancer."
As examples of better study design, Fenton pointed to two human studies that will track children's environmental exposures to various compounds and their development over many years, the NIEHS-funded multi-center breast cancer research studies and the National Children's Study. With this kind of design, she concluded, investigators may be more likely to determine whether the trans-generational effects demonstrated in rodent populations also are applicable to humans.
Highlights of Fenton's Rodent Studies
Dioxins are a persistent group of chemicals that are common byproducts of industrial processes. Fenton studies the specific dioxin known as TCDD, which she described as "a model compound, where we have substantial human information and rodent information."
Fenton found that exposure to TCDD on gestation day 15 delays vaginal opening, decreases ductal branching and delays the differentiation of terminal end buds in mammary glands. Effects also included a 100-fold increase in the expression of CYP1B1 and a ten-fold increase in CYP1A1, key detoxification enzymes in the cytochrome P450 family.
In her cross-fostering study of atrazine, a once widely used and still persistent herbicide, Fenton found that while either in utero or lactational exposure to atrazine were enough to alter mammary development, the most severe effects were seen in pups with both exposures. She found that a mixture of atrazine metabolites, which are not as well regulated as the compound itself, affected mammary gland development at significantly lower doses than previously seen - counter to the findings of large epidemiological studies that have failed thus far to find an association between atrazine exposure and breast cancer risk.
Perfluorooctanoic acid (PFOA)
PFOA is a very stable, high-use compound found in grease- and stain-proof materials such as mattresses, clothing and carpets. In the mouse model, Fenton found that both mammary gland development and gene expression in dams were delayed by PFOA exposure.
These developmental delays affected the epithelium and adipose content of breast tissue at normal lactation and weaning times. Altered spiking patterns for expression of lactoferrin, a protein with antimicrobial activity, left pups unprotected at a point in their development when they were most susceptible to infection.