The Ribbon Newsletter

Suzanne E. Fenton, Ph.D.
Reproductive Toxicology Division, U.S. Environmental Protection Agency

For nearly 20 years, the search has been on for environmental factors, specifically industrial chemicals, associated with the rising numbers of diagnoses of breast cancer in American women. There have been many attempts to isolate a specific class of compounds in our environment or even in the homes of women diagnosed with breast cancer that would help understand the exposures that either cause or make certain women more susceptible to the disease. Very little has been determined from these costly studies. Yet, judging from many studies in rodent models of human disease the reason may be related to the amount and timing of environmental exposures in comparison to the time of disease. In other words, the effect(s) of an environmental exposure may have begun during childhood or around the time of puberty, yet breast cancer typically manifests itself decades later.

Environmental chemicals that disrupt the normal signals that take place between a hormone and its receptor, or alter the amount of time or the concentration at which a hormone is active in the body, are commonly called endocrine disrupting compounds or EDCs. In recent years, we have learned a fair amount about the effects EDCs can have on the development of many male and female reproductive tissues. Most of the studies have employed high, non-environmental exposures of EDCs to demonstrate these effects. A series of rodent studies with bisphenol A, commonly used as an epoxy resin and in polycarbonate plastics and PVC pipes, demonstrated that this mildly estrogenic compound had effects in multiple reproductive tissues at low doses that were not repeatable at high levels of the compound. We now know that EDCs may have variable and sometimes dissimilar effects on reproductive tissues at high vs. low (more environmentally relevant) exposures. This paradox is called "hormesis." Hormesis, as defined by Wikipedia (http://en.wikipedia.org/wiki/Hormesis), is "the term for generally-favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses than in large doses." The mammary gland is one reproductive tissue in which hormesis has been proposed. Therefore, many of the toxicology studies that are performed in rodent models of human disease must perform a dose response of the EDC in question to categorize the high and low dose effects and at which exposure level(s) they are adverse (significantly affect development, growth, or survival of the next generation).

There are several other EDCs that have been shown to affect mammary gland growth at either high or low exposure levels. Table 1 summarizes those EDCs that have demonstrated early life effects on the development of the mammary gland (exposures took place before or around the time of birth or around the time of puberty), as well as those shown to have longer lasting effects (into adult life). The effects of these compounds are divided into two groups - either precocious development, that which is faster than normal, or those causing delayed development. The importance of these variant effects of EDCs lies in the amount of time that terminal end buds (TEB) are present in the gland. The TEB are tear-drop shaped structures that are heavily laden with dividing epithelial cells. TEBs are the branching and dividing points in the gland; much like the bulldozer that goes before the paver in making a new highway, these cells plow the way for a new network of epithelial ducts in the developing mammary gland. Much work in rodents, primarily led by the laboratories of Drs. Michael Gould (University of WI-Madison) and Jose and Irma Russo (Fox Chase Comprehensive Cancer Center, Philadelphia, PA), has proven that the TEB are susceptible to chemical carcinogens and the number of TEB exposed to the carcinogen is related to tumor risk (both in terms of numbers of tumors and the timing of tumor development). Precocious development of the TEB has been theorized to play a protective role in terms of mammary carcinogenesis. The sooner the TEB develop into adult structures, the sooner they are less susceptible to the effects of other environmental agents. However, in the case of delayed development, the TEB are present in the gland for longer periods of time, leading to increased susceptibility to the effects of environmental carcinogens.

Environmental chemicals that have demonstrated endocrine-related effects in animal models and also alter mammary gland development (precocious or delayed) are shown in Table 1. As described above, some of these compounds have divergent effects depending on the doses used and that is shown for those chemicals having both accelerated or delayed X's. Atrazine, a high use herbicide, is one compound that has been shown to have consistent effects at both high and low doses.

Recent work soon to be published in Environmental Health Perspectives (http://www.ehponline.org/docs/2006/9612/abstract.html), demonstrates that an exposure to a mixture of atrazine and its biological metabolites for only the last week of pregnancy can have long-lasting effects on the development of the mammary gland. What makes the effect of this mixture interesting is the finding that relatively low doses (only 100 times higher than the levels reported in some ground and surface waters) are able to evoke a delayed development. Other chlorotriazine herbicides break down to the same metabolites as atrazine and therefore this class of herbicides can be generally thought to have similar effects on the mammary gland. Another environmental compound found to dramatically delay mammary development is perfluorooctanioic acid (PFOA), sometimes found in consumer products that are non-stick, grease or water resistant, or weather proof, in addition to its uses as an emulsifier and insulator.

A recent report in Toxicological Sciences demonstrated that exposure to the compound during pregnancy resulted in halted mammary development in female mouse offspring and delayed lactation (White, et al. [2006]. Gestational PFOA Exposure of Mice is Associated with Altered Mammary Gland Development in Dams and Female Offspring. Toxicological Sciences 96, 133-144). Although the exposure level used in the study may seem small (5 mg/kg body weight), it was a great deal higher than the exposure levels in the U.S. population, even those in contaminated areas of Ohio and West Virginia.

Even though the number of EDCs known to alter mammary gland development is growing, the long-term consequences of the exposures early in life have not been as easy or quick to determine. Only a small handful of EDCs have been investigated for their early life effects and chemically-induced or spontaneous tumor formation. Further, only a small number of EDCs known to affect mammary gland development in the offspring have been investigated for the effects of those underdeveloped glands on future generations. The compounds for which adverse long-term outcomes have been described are listed in Table 1. Also, those chemicals for which effects are mediated via prenatal or neonatal exposure and are not repeatable if exposure occurs later in life are noted. The amount of information that has been gained over the last 10 years on the effects of EDCs on the mammary gland is impressive. However, very little can be concluded about exactly which classes of compounds epidemiologists could prioritize in search of candidates for breast cancer risk. There are several 2006 and 2007 references listed in Table 1 that bring even more information to the table about low dose effects and new compounds that may influence mammary gland development.

One problem hampering this field of research is the difficulty in getting funding for studies on the mechanisms used by environmental toxicants or food components in altering mammary gland and potential tumor development. The National Institute of Environmental Health Sciences (NIEHS) has recently posted a request for research proposals that would further address the role of developmental exposure on adverse mammary gland outcomes. The work funded by these grants and those funded in the Breast Cancer and the Environment Research Centers will help to expand our knowledge of environmental influences on breast cancer risk.

The information in this article has been subjected to review by the National Health and Environmental Effects Research Laboratory of the U.S. Environmental Protection Agency. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

Early Life Exposures to Environmental Compounds: Lessons Learned from Animal Models The Ribbon

Early Life Exposures to Environmental Compounds: Lessons Learned from Animal Models
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