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Extramural papers of the month

By Jerry Phelps
September 2010

Polyfluoroalkyl chemicals linked to ADHD

NIEHS-funded researchers report finding a link between exposure to polyfluoroalkyl chemicals (PFCs) and attention deficit hyperactivity disorder (ADHD) in children.

PFCs are highly stable compounds used in a variety of industrial and commercial applications, such as stain resistant coatings, food packaging, fire-fighting foams, and non-stick surfaces for cookware. The research team used data from the National Health and Nutrition Examination Survey (NHANES) to compare PFC levels in blood samples taken from 571 children ranging in age from 12 to 15. Forty-eight of the children were reported to have ADHD. An earlier report of NHANES data suggests that more than 98 percent of the US population has measureable amounts of PFCs. Because of the compounds' stability, it can take years for PFCs to be eliminated from the body.

Other research suggests that PFCs may be developmental neurotoxicants. In vitro studies show the compounds affect nerve cell differentiation, and in utero rodent studies linked PFCs to reductions in thyroid hormone, which is known to regulate brain development.

The authors are careful to point out that, at the present time, there is no evidence that PFCs cause ADHD. But given the persistence and prevalence of these compounds in the environment, further investigation into whether PFCs cause ADHD and other behavioral disorders is merited.

Citation: Hoffman K, Webster TF, Weisskopf MG, Weinberg J, Vieira VM. ( Exit NIEHS 2010. Exposure to polyfluoroalkyl chemicals and attention deficit hyperactivity disorder in U.S. children aged 12-15 years. Environ Health Perspect. Epub ahead of print.

Circadian clock in pancreas linked to diabetes

New research by NIEHS grantees at Northwestern University published in the prestigious journal Nature , reports that the circadian clock in pancreatic islet cells regulates the production of insulin. If the clock or, more specifically, the genes that regulate it are faulty, the result is diabetes.

The researchers report the insulin-secreting beta cells have their own dedicated clock, which regulates the behavior of genes and proteins involved in insulin production and secretion on a 24-hour cycle. The researchers created transgenic mice with the clock genes knocked out. The animals developed impaired glucose tolerance, had abnormally low levels of insulin, and went on to develop diabetes.

The team concludes that the variation seen in insulin secretion in humans and susceptibility to diabetes are likely related to the clock mechanism. They report an association between the changes of the cycling of the clock within the pancreas itself and disease. They plan to continue research in this area to determine if the clock can be modulated, which may lead to a better understanding of circadian rhythm or better treatments for diabetes.

Citation: Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, et al. ( Exit NIEHS 2010. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466(7306):627-631.

In utero BPA exposure leads to epigenetic alterations

Researchers at the Yale University School of Medicine report that in utero exposure to bisphenol-A (BPA) causes diminished methylation of the estrogen response element of the Hoxa10 gene. This finding suggests that permanent epigenetic alteration of estrogen response element sensitivity to estrogen may be a general mechanism by which endocrine disrupting chemicals exert their actions.

BPA is a known endocrine-disrupting chemical. It binds to the estrogen receptor, tricking the cells' machinery into thinking they are being signaled by estrogen to act in a prescribed manner. The Hoxa10 gene is a homeobox gene that controls uterine growth and development. A homeobox is a DNA sequence found in genes that are involved in the regulation of patterns of development. These sequences are found in animals and plants.

In this study, pregnant mice were treated with BPA. Hoxa10 and protein expression were increased by 25 percent in the reproductive tracts of mice exposed in utero. DNA methylation of Hoxa10 was significantly reduced in both the promoter and intron regions of the gene after BPA exposure. The decrease in methylation led to an increase in binding of the estrogren receptor alpha to the estrogen response element of the gene.

Citation: Bromer JG, Zhou Y, Taylor MB, Doherty L, Taylor HS. ( Exit NIEHS 2010. Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J 24(7):2273-2280.

Vitamin A treatment and lung disease in preterm lambs

Neonatal Chronic Lung Disease (CLD) often occurs in premature babies who are chronically maintained on mechanical ventilation until their lungs have developed enough to breath normally. The disease is characterized by incomplete development of the lungs and a thickening of lung tissues. Even with improved procedures for ventilation, neonatal CLD continues to be a major cause of mortality and long-term morbidity in premature infants. Administration of vitamin A has improved the respiratory outcome of premature infants, but there is little information to suggest the mechanisms by which this occurs.

A multidisciplinary team of researchers from Utah, California, Pennsylvania, and Texas reports that a variety of growth factors and cellular components are modulated by vitamin A administration in premature lambs managed with mechanical ventilation. Gene expression of tropoelasatin and deposition of elastin was decreased in treated lambs, while vascular endothelial and other growth factors were increased.

The researchers conclude that vitamin A treatment partially improves lung development in chronically ventilated preterm neonates by modulating these factors. They speculate that treatment approaches that could potentially enhance these effects may lead to more complete alveolar development and capillary growth, such that gas exchange will be improved in premature infants.

Citation: Albertine KH, Dahl MJ, Gonzales LW, Wang ZM, Metcalfe D, Hyde DM, et al. ( Exit NIEHS 2010. Chronic lung disease in preterm lambs: Effect of daily vitamin A treatment on alveolarization. Am J Physiol Lung Cell Mol Physiol 299(1):L59-L72.

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

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