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DERT Papers of the Month

By Jerry Phelps
July 2006

Estrogenic Compound in Plastic Linked to Prostate Cancer

Bisphenol A, a common chemical found in many types of plastic, permanently alters genes and leads to prostate cancer according to a new study published in the June 1 edition of Cancer Research. These results represent the first evidence that early exposure to low doses of environmental estrogens during prostate development in the male fetus may result in prostate cancer later in life.

A research team led by Gail Prins, an NIEHS grantee, exposed pregnant female rats to low doses of either estrogen or bisphenol A during the development period corresponding to the second and third trimesters of human pregnancy. They found that this early exposure predisposed the male offspring to precancerous lesions of the prostate gland later in life.

The researchers determined that the early estrogenic exposures caused these effects through a process known as epigenetic reprogramming. Epigenetics is the study of heritable changes in gene function that occur without a change or mutation in the DNA sequence. They found that methylation of the gene coding for the enzyme phosphodiesterase 4 permanently altered its expression in prostate tissue. Normally, this gene is expressed at very low levels in adult mammals, but after early exposure to the estrogenic compounds, the animals continued to have high levels of expression of the gene in their prostate glands throughout their lives. In additional studies using cell cultures, high levels of gene expression were also found in prostate cancer cell lines.

The authors point out that application of these findings to human prostate cancer requires additional studies. However, since the methylation of the gene can be found before any disease has occurred, it may be useful as an early biomarker and provide a means for the early identification of men at risk for prostate cancer.

Citation: Ho SM, Tang WY, Belmonte de Frausto J, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res. 2006 Jun 1;66(11):5624-32.

Oral Contraceptives Affect Asthma and Wheeze

Oral contraceptive used by young women may influence the occurrence of asthma and wheezing, according to research from the University of Southern California Keck School of Medicine. Oral contraceptive use was associated with about an 80 percent reduction in wheezing, in women with a history of asthma; however, in women without asthma, oral contraceptive use was associated with a 75 percent increase in the prevalence of wheeze.

Previous research by this group and others showed that sex steroid hormones may play a role in asthma.

To expand on this body of research, this NIEHS-supported team conducted an epidemiologic study in a population of 905 women aged 13-28. The results were variable depending on the whether women had a history of asthma.

The age at which girls reach puberty has been declining in the same time period that asthma prevalence has been increasing. The authors conclude that "sex hormones may play an important role in asthma occurrence." Oral contraceptive use and asthma are common among young women; therefore, these findings are likely to have public health implications. The authors also suggest that clinicians may want to inform young women about the potential effects of oral contraceptive use on asthma-related respiratory symptoms.

Citation: Salam MT, Wenten M, Gilliland FD. Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women. J Allergy Clin Immunol. 2006 May;117(5):1001-7.

Toll-like Receptor 4 Reduces Chronic Airway Inflammation

NIEHS scientists and colleagues at Duke University report progress in understanding the complex relationship between asthma and air-way inflammation associated with exposure to endotoxin. This research was published in the May 15 edition of the Journal of Immunology. The research model employed in their study will be useful in further understanding the regulation of allergic airway inflammation and "should facilitate the development of novel therapies to treat asthma by augmenting natural regulatory mechanisms."

Endotoxin, also known as lipopolysaccharide, is a component of the cell walls of gram-negative bacteria and is commonly found in household dust. Exposure to endotoxin has been shown to exacerbate asthma; however, exposure early in life has also been shown to be protective against the development of asthma. The latter finding is a component of a controversial theory known as the "hygiene hypothesis," which states that an excessively clean environment in early childhood may predispose some people towards asthma, allergies and autoimmune diseases.

The researchers exposed normal mice and mice lacking the gene for the toll-like receptor 4 (tlr4) to the chicken egg protein albumin containing small amounts of endotoxin and studied allergic responses. Results showed similar responses for both kinds of mice after short-term exposures. However, the tlr4-deficient mice showed much stronger pulmonary allergic responses compared with the normal mice when the allergic challenges lasted for greater than one week.

These findings demonstrate that tlr4 signaling is necessary to regulate inflammatory responses to ongoing allergic challenges. The investigators conclude that their work supports previous epidemiologic findings that "low doses of endotoxin, particularly in childhood, protect against developing asthma later in life.

Citation: Hollingsworth JW, Whitehead GS, Lin KL, Nakano H, Gunn MD, Schwartz DA, Cook DN. TLR4 signaling attenuates ongoing allergic inflammation. J Immunol. 2006 May 15;176(10):5856-62.

Quality of Sperm Declines as Men Age

New research suggests that as men age they may have more difficulty fathering children. Like women, the study also suggests that some men who wait to become fathers are slightly more at risk for passing on certain rare diseases.

Obstetricians and gynecologists have long known that as women age they have more trouble conceiving, their risk of miscarriage increases, as does the risk of having children with Down Syndrome or other genetic defects.

This study suggests that men too have a "biological clock," but one that causes a more gradual change in fertility. Both men and women have postponed parenthood in the past several decades. Fatherhood for men aged 35-49 has increased 40 percent while there has been a decline in births involving men under age 30.

The authors caution that their findings are preliminary and are based on a small number of tests in a small population of men. The study enlisted 97 men ages 22-80 and was funded by NIEHS. This research team previously reported that as men age, their sperm counts decline and their sperm become less active. Increased age of the men was not associated with the same genetic defects seen in older women. For instance there was no increased risk of fathering a child with Down Syndrome, but some older fathers did have an increased risk of having children with dwarfism and according to the published results, "a small fraction of men are at increased risk for transmitting multiple genetic and chromosomal defects.

Citation: Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, Glaser RL, Pearson FS, Evenson D. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci U S A. 2006 Jun 9.



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