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Environmental Factor, September 2012

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Fenton examines effects of exposure to endocrine disrupting chemicals

By Sonika Patial

Ken Korach, Ph.D., and Suzanne Fenton, Ph.D.

Fenton joined lecture co-host Korach following the seminar. Korach is head of the NIEHS Laboratory of Reproductive and Developmental Toxicology and lead researcher in the Receptor Biology Group. (Photo courtesy of Steve McCaw)

Suzanne Fenton, Ph.D. and David Malarkey, D.V.M., Ph.D.

Fenton and David Malarkey, D.V.M., Ph.D., discussed the results of her group’s recent studies. Malarkey is the group leader and head pathologist in the NTP Pathology Group, which is an important contributor in NTP two-year rodent studies. (Photo courtesy of Steve McCaw)

A capacity audience filled the NIEHS Executive Conference Room Aug. 7 to hear Suzanne Fenton, Ph.D., discuss “Mammary Gland as a Sensitive Target Tissue for Endocrine Disruption.” Fenton’s talk was hosted by NIEHS lead researchers Ken Korach, Ph.D., and John Cidlowski, Ph.D., as part of the monthly NIEHS Receptor Mechanisms Discussion Group Series.

Fenton, a group leader in the NIEHS NTP Labs, utilizes rodent models to examine the effects of prenatal and lactational exposure to endocrine disrupting chemicals (EDCs) on mammary gland development and later life disease. EDCs are substances in the environment that interfere with the synthesis, metabolism, and action of natural hormones present in the body that are responsible for several normal functions, such as development, reproduction, and metabolism.

Fenton presented findings from recent studies by her group and underscored the importance of evaluating mammary tissue following exposures during critical periods in mammary gland development. She raised the issue that breast cancer incidence and rates of precocious breast development in girls have not decreased, and that unidentified environmental factors may play important roles.

“There is an urgent need to perform evaluation of mammary glands at low dose exposures as well as during critical periods in mammary gland development,” Fenton explained. “The general trend is towards identifying chemicals that can be potential carcinogens,” she added. “However, there is also a need to identify chemicals or compounds that alter susceptibility.”

Mammary gland development is sensitive to environmental influences

Fenton specifically presented her findings on the effects of three different EDCs on mammary gland development — dioxin or TCDD, a combustion by-product and known human carcinogen; the high use herbicide atrazine; and the industrial surfactant perfluorooctanoic acid (PFOA).

Fenton’s findings highlighted the importance of exposure to environmental contaminants during fetal and neonatal developmental periods on latent mammary effects. According to Fenton, the fetal and neonatal developmental period is a particularly sensitive time in development when external environmental contaminants can disrupt active mammary branching, signaling mechanisms, and tissue remodeling processes.

For example, a single prenatal exposure to TCDD in female rats a week before birth induces significant gene induction and drastic and persistent delay in mammary gland differentiation. These defects include decreased ductal branching and delayed migration of epithelial cells to the fat pads of mammary tissue. Similarly, prenatal exposure of rats to atrazine for three days during the later stages of pregnancy triggered persistent delays in mammary gland development. Interestingly, rats exposed for five days also showed a delayed vaginal opening, a pubertal change lacking in rats exposed for only three days.

Fenton’s group also found that rats exposed for five days to atrazine metabolite mixtures (AMM) at doses 10-1000 times lower than atrazine by itself also showed abnormal mammary gland development. These findings suggest that atrazine metabolites are biologically active, which is important from the standpoint that atrazine normally exists in nature in a mixture form and that the effects of a mixture may be much more drastic than the effects of pure atrazine.

PFOA exposure either during lactation or through the intra-uterine route also led to delayed mammary gland development. This delay was visible as early as birth and has been found to extend into adulthood. In PFOA studies, the lowest doses that were tested produced blood levels in mice similar to the levels seen in humans in PFOA-contaminated areas in Ohio and West Virginia.

Fenton concluded that low dose, biologically relevant exposures to EDCs may cause long-lasting effects in sensitive tissues, such as the mammary gland. For example, PFOA exposure induced stromal hyperplasia at 18 months in mouse mammary glands, an effect that is hypothesized to increase susceptibility for tumor growth in rodents and humans. Those effects were also detected in young adult mice.

(Sonika Patial, D.V.M., Ph.D., is a fellow in the Laboratory of Signal Transduction at NIEHS)

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