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Environmental Factor, April 2015

Extramural papers of the month

By Nancy Lemontagne

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Roadmap epigenomics program maps more than 100 types of cells and tissues

Researchers supported by the National Institutes of Health Common Fund Roadmap Epigenomics Program, which is co-led by NIEHS, have mapped the epigenomes of more than 100 types of human cells and tissues. This information can help scientists understand how changes to the genome and epigenome can lead to conditions such as Alzheimer’s disease, cancer, asthma, and fetal growth abnormalities.

Epigenetic changes are chemical modifications to DNA that alter how genes are expressed, without changing the genetic code. The epigenome contributes to unique gene expression and biological functions, and thus, unlike the genome, can vary among different cells and tissues. To better understand how the epigenome contributes to cell function as well as human disease, the researchers integrated information about histone marks, DNA methylation, DNA accessibility, and RNA expression to produce high-resolution maps of gene regulatory elements across 127 reference epigenomes — 111 from the Roadmap Epigenomics Program and 16 from the Encyclopedia of DNA Elements project — spanning diverse cell and tissue types.

The resulting comprehensive catalog of epigenomic data provides a first-of-its-kind resource that will help researchers make direct comparisons across cell types and tissues. The researchers expect that the data, which is freely available, will be of broad use to scientists for studies of gene regulation, cellular differentiation, genome evolution, genetic variation, and human disease. More than 20 additional papers, published in Nature and Nature-associated journals, show how these maps can be used to study human biology.

CitationKundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang XIntegrative analysis of 111 reference human epigenomes. 2015. Nature 518(7539):317-330. (See story.)

Pesticide exposure linked with ADHD behaviors in mice and people

NIEHS-funded research in humans and mice provides new evidence that early exposure to the commonly used pyrethroid pesticide, deltamethrin, may be a risk factor for attention-deficit hyperactivity disorder (ADHD).

Although there is strong scientific evidence that genetics plays a role in susceptibility to ADHD, no single gene has been linked to a significant percentage of cases, leading scientists to believe that environmental factors may also contribute to development of the disorder. To mimic exposures in pregnant women, the researchers exposed female mice to deltamethrin during pregnancy and lactation. The pups exhibited features of ADHD, including hyperactivity, impulsive behavior, and problems with working memory and attention. Similar to what is seen in children with ADHD, the male mice were more affected than females. And ADHD-like behaviors in the mice lasted through adulthood, even though the pesticide could no longer be detected in their systems. The researchers also observed increased dopamine transporter and receptor levels in the pups, which they say are likely to be responsible for the ADHD-like behaviors.

The researchers also looked at pyrethroid pesticide exposure in children, using data from the National Health and Nutrition Examination Survey. An analysis of health care questionnaires and urine samples from 2,123 children and adolescents revealed that children with higher pyrethroid pesticide metabolite levels in their urine were more than twice as likely to be diagnosed with ADHD.

CitationRichardson JR, Taylor MM, Shalat SL, Guillot TS 3rd, Caudle WM, Hossain MM, Mathews TA, Jones SR, Cory-Slechta DA, Miller GW.2015. Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder. FASEB J; doi:10.1096/fj.14-260901fj [Online 28 January 2015].

Mercury may be linked with autoimmune disorders

NIEHS grantees report an association between exposure to methylmercury — even at levels generally considered safe — and the development of autoimmunity, which can sometimes lead to an autoimmune diseases, such as inflammatory bowel disease, lupus, rheumatoid arthritis, and multiple sclerosis.

Autoimmunity occurs when the immune system begins treating normal proteins in the body as if they are foreign invaders. To study mercury’s effects on autoimmunity, the researchers analyzed data from 1,352 women ages 16-49 who participated in the National Health and Nutrition Examination Survey from 1999 to 2004. They assessed mercury levels based on hair and blood samples, which can be used to track organic mercury, or methylmercury, exposure, as well as urine samples, which can be used to track inorganic mercury.

Tests revealed the presence of antinuclear antibodies (ANA), a marker of autoimmunity, in 16 percent of the study participants. The researchers found an association between ANA levels and mercury levels in hair and blood, but not urine, after adjusting for confounders. The association was strongest for the women with the highest ANA levels. However, even at low methylmercury levels — less than 0.37 parts per million hair mercury and less than one microgram per liter blood mercury — the researchers observed a dose-response relationship. The researchers note that these levels are in the range that regulatory agencies generally consider safe for women of childbearing age.

The new findings point to the need for further investigation into the relationship between methylmercury and autoimmune conditions.

CitationSomers EC, Ganser MA, Warren JS, Basu N, Wang L, Zick SM, Park SK. 2015. Mercury exposure and antinuclear antibodies among females of reproductive age in the United States: NHANES. Environ Health Perspect; doi: 10.1289/ehp.1408751 [Online 10 February 2015].

Parental smoking during pregnancy linked with later diabetes in children

A study, funded in part by NIEHS, found that women with parents who smoked during pregnancy had an increased risk  for developing diabetes as adults, independent of their birth weight and current body mass index (BMI).

The researchers analyzed data from 1,801 daughters of women who participated in the Child Health and Development Studies, an ongoing project of the Public Health Institute. The daughters, ages 44-54 years old at the time of analysis, were two to three times more likely to have diabetes as adults if their mothers smoked while pregnant. The association remained after adjustment for parental race, diabetes, and employment. Dads who smoked while their daughter was in utero also contributed to an increased diabetes risk for their child, but to a lesser extent than the mothers. The effect of parental smoking was unchanged when adjusted for daughters’ birth weight and current BMI, both of which are risk factors for diabetes.

The data set was originally collected to study early risk of breast cancer, which is why sons are not included. The results provide further evidence that pregnant women should avoid smoking or being around cigarette smoke.

CitationLa Merrill MA, Cirillo PM, Krigbaum NY, Cohn BA. 2015. The impact of prenatal parental tobacco smoking on risk of diabetes mellitus in middle-aged women. J Dev Orig Health Dis; doi:10.1017/S2040174415000045 [Online 10 February 2015].

(Nancy Lamontagne is a science writer with MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)



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