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Extramural Papers of the Month

By Jerry Phelps
June 2010

New Concerns About Radiation and Breast Cancer

New research findings, funded in part by NIEHS, suggest that ionizing radiation exposure not only produces mutations that lead to cancer, but also changes the microenvironment of cells so that future cells are more likely to become cancerous.

Researchers used non-lethal but substantial doses of radiation much higher than what a woman would be exposed to during a mammogram, but approaching levels used in CT scans or radiotherapy.

Human mammary epithelial cells were used in the experiments. These cells line breast ducts where most breast tumors originate. They typically divide 5-20 times in culture. However, a variant phenotype of cells capable of dividing for many weeks spontaneously arises. Typically the variant phenotype lacks a tumor-suppressor protein called p16 and is much more susceptible to malignancy.

The experiments consisted of growing cell cultures from normal breast tissue for about one week. Then some of the cells were irradiated with a single low-to-moderate dose. Four to six weeks later, most of cells in both the irradiated and non-irradiated culture dishes had stopped dividing. However, the daughters of the irradiated cells formed larger and more numerous patches of cells with the variant phenotype.

The researchers conclude that the radiation exposure promoted the growth of pre-cancerous cells by making the environment that surrounds the cells more hospitable to their continued growth.

Citation: Mukhopadhyay R, Costes SV, Bazarov AV, Hines WC, Barcellos-Hoff MH, Yaswen P. ( Exit NIEHS 2010. Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies. Breast Cancer Res 12(1):R11.

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Age Dependent Decrease in DNA Methylation Linked to Autoimmune and Heart Disease

A research team at the University of Michigan Geriatrics Center reports that T cell methylation patterns are more sensitive to low folate and methionine nutritional levels in older as compared to younger individuals, causing aberrant gene expression related to autoimmunity and cardiovascular disease. These findings suggest that attention to proper nutrition, especially folate and methionine intake, may be particularly important in older people.

The laboratory that conducted this research studies the role that DNA methylation and chromatin structure play in regulating immune and cellular function, and how changes in chromatin structure contribute to problems characterizing automimmune diseases and aging. T cell DNA methylation levels are known to decline with age. This leads to the activation of genes implicated in lupus-like autoimmunity and acute coronary syndromes. The cellular mechanisms responsible for the decrease in methylation are not known. However, maintenance of methylation is dependent on dietary micronutrients, including folate and methionine, and is also affected by homocysteine levels.

T lymphocytes from healthy individuals aged 22-81 cultured with low folate, low methionine, or high homocysteine showed demethylation and increased expression of two genes associated with autoimmunity and coronary disease. These changes were seen in the cultures from subjects beginning at age 50 and the effects increased with age.

Citation: Li Y, Liu Y, Strickland FM, Richardson B ( Exit NIEHS. 2010. Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp Gerontol 45(4):312-322.

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Prenatal Exposure to Phthalates Is Associated with Reduced Masculine Behavior in Boys

A team of investigators led by University of Rochester researcher Shanna Swan, Ph.D., reports for the first time that prenatal exposure to phthalates causes reduced masculine behavior in boys. This finding adds to the growing list of health effects associated with phthalates and other endocrine-disrupting compounds found in plastics.

Mothers whose urine had been analyzed for phthalates in mid-pregnancy completed a questionnaire that included the Pre-School Activities Inventory used to assess gender differences in play behavior. The results show that concentrations of dibutyl phthalate and diethylhexyl phthalate metabolites in the mothers' urine samples were statistically associated with decreased masculine play behavior in boys who were an average of 5 years old at the time of the assessment. There were no strong associations for any other phthalate metabolites, nor were there any associations with girls' play behavior.

These data suggest that in utero exposure to antiandrogenic phthalates may be associated with less masculine behavior in boys. Although based on a relatively small sample (N=74 boys), the overall findings exhibit concern that environmental chemicals have the potential to alter androgen-responsive neurologic development in humans.

Citation: Swan SH, Liu F, Hines M, Kruse RL, Wang C, Redmon JB, et al ( Exit NIEHS. 2010. Prenatal phthalate exposure and reduced masculine play in boys. Int J Androl 33(2):259-269.

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Meta-Analysis Confirms Greater Asthma Risk from Asthmatic Mothers than Fathers

Results from a meta-analysis and systematic review of 33 studies published from 1966 to 2009 confirm that maternal asthma imparts a greater risk of offspring asthma than does paternal asthma. Many of the studies had reached this conclusion independently. However, there were some studies that reached the opposite conclusion. Given this disparity, the research team conducted the meta-analysis to determine the authenticity and size of the maternal effect.

These studies involved greater than 250,000 participants. The final conclusion is that children with asthmatic mothers were 3.04 times more likely to develop asthma than those with non-asthmatic mothers. Children with asthmatic fathers were 2.44 times more likely to develop the disease. The statistical significance of the trend disappeared with analysis of the studies in which asthma was diagnosed by a physician and when the children in the studies were 5 years or older. However, in all analyses, the trend that maternal asthma imparted a greater risk than paternal asthma remained the same.

The findings from this analysis are consistent with animal studies demonstrating that maternal exposures can induce asthma susceptibility in offspring, supporting the notion that additional research is necessary to elucidate the mechanism for this maternal effect.

Citation: Lim RH, Kobzik L, Dahl M ( Exit NIEHS. 2010. Risk for asthma in offspring of asthmatic mothers versus fathers: a meta-analysis. PLoS One 5(4):e10134.

(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training.)

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