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Environmental Factor, September 2015

Extramural papers of the month

By Nancy Lamontagne

Srp logo : Read the current Superfund Research Program "Research Brief". New issues are published on the first Wednesday of each month.

Epigenomic mapping of human tissues

As part of the National Institutes of Health Roadmap Epigenomics Program, an NIEHS grantee and colleagues produced a new atlas of human tissue epigenomes and found that DNA methylation varies greatly among the tissues.

Epigenetic changes influence gene expression without changing the genetic code. To understand the mechanisms involved in disease development, scientists must link genetic information, which is identical in most cells across the body, with epigenetic changes that can vary by tissue. As a starting point, the researchers created a baseline assessment of the epigenome, by conducting DNA sequencing of 18 tissue types from four people, and examining DNA methylation.

The researchers reported widespread differences in levels of methylation between tissues. Organs differed extensively in the degree of genome-wide methylation. For example, the pancreas had an unusually low level of methylation, while the thymus had high levels of methylation. As expected, methylation levels tended to be lower around areas of DNA that coded for genes expressed by the type of tissue analyzed. In other words, a cell from muscle tissue had less methylation near muscle-related genes. One surprising finding was that many tissues exhibited non-CG methylation, a type of methylation previously thought to be widespread only in the brain and stem cells.

CitationSchultz MD, He Y, Whitaker JW, Hariharan M, Mukamel EA, Leung D, Rajagopal N, Nery JR, Urich MA, Chen H, Lin S, Lin Y, Jung I, Schmitt AD, Selvaraj S, Ren B, Sejnowski TJ, Wang W, Ecker JR. Human body epigenome maps reveal noncanonical DNA methylation variation. Nature 523(7559):212-216.

DEHP replacements may also cause health risks

Potential health risks related to di-2-ethylhexylphthalate (DEHP) is leading manufacturers to switch to chemically similar di-isononyl phthalate (DINP) and di-isodecyl phthalate (DIDP) in products such as furnishings, cookware, and plastic food packaging. However, these replacements may also pose health risks in children, according to new research from an NIEHS grantee and colleagues.

The researchers published two studies that examined the effects of DINP and DIDP on 2009-2012 participants in the National Health and Nutrition Examination Survey (NHANES), a program of studies designed to assess the health and nutritional status of adults and children in the United States.

One study examined participants ages 6 to 19 and found a significant association between high blood pressure and the presence of DINP and DIDP urinary metabolites. The other study examined participants 12 to 19 years old, and revealed a link between DINP and DIDP concentrations and increased insulin resistance. Specifically, 34.4 percent of the adolescents with the highest DINP metabolite urinary levels showed insulin resistance, compared to 23.4 percent of the adolescents with the lowest levels of DINP. Similarly, for DEHP, 37.7 percent of study participants with the highest levels had insulin resistance, compared to 20.5 percent with the lowest DEHP levels.

CitationTrasande L, Attina TM. 2015. Association of exposure to di-2-ethylhexylphthalate replacements with increased blood pressure in children and adolescents. Hypertension 66(2):301-308.

Attina TM, Trasande L. 2015. Association of exposure to di-2-ethylhexylphthalate replacements with increased insulin resistance in adolescents from NHANES 2009-2012. J Clin Endocrinol Metab 100(7):2640-2650.

Living close to hydraulic fracturing associated with more hospitalizations

Researchers from two NIEHS Environmental Health Science Core Centers found that hospitalizations for heart conditions, neurological illness, and other health problems were higher among people living near unconventional gas and oil drilling sites, also known as hydraulic fracturing or fracking sites, in Pennsylvania. The work points to a need for more research to determine the reason for the increased hospitalization rates.

From 2007 to 2011, the researchers examined the link between drilling well density, or the number of wells within a square kilometer, and health care use by zip code in three northeastern Pennsylvania counties. Bradford and Susquehanna Counties experienced a significant increase in drilling activity during this time period, while Wayne County acted as the control because of a ban on drilling. Examining 198,000 hospitalizations, including multiple hospitalizations for the same person, the researchers found an association between 25 specific medical categories and patients' proximity to active wells.

The analysis showed that the number of people hospitalized for cardiology and neurology health problems was significantly higher in areas closer to active wells. Specifically, the rates of cardiology hospitalizations were significantly associated with number of wells per zip code (p<0.00096) and wells per square kilometer (p<0.00096) while neurology inpatient hospitalizations were significantly associated with wells per square kilometer (p<0.00096). Hospitalizations for skin conditions, cancer, and urology problems were also associated with the proximity of dwellings to active wells. The authors say that more studies are necessary to compare toxicant exposure to number of wells.

CitationJemielita T, Gerton GL, Neidell M, Chillrud S, Yan B, Stute M, Howarth M, Saberi P, Fausti N, Penning TM, Roy J, Propert KJ, Panettieri RA Jr. 2015. Unconventional gas and oil drilling Is associated with increased hospital utilization rates. PLoS One. 10(7):e0131093. (Story)

Researchers identify pathway that can halt fibrosis progression

Research, funded in part by NIEHS, has identified a molecular pathway that can be targeted to stop pulmonary fibrosis, a progressive and fatal disease that causes damage and scarring in lung tissue. Understanding the molecular mechanisms involved in pulmonary fibrosis may help lead to treatments that prevent or halt the disease.

Although scientists don’t fully understand the mechanisms involved in pulmonary fibrosis, they do know that reactive oxygen species play a critical role, and that pulmonary macrophages help regulate how the body responds to lung injury. Previous studies have found that the mitochondrial production of hydrogen peroxide by pulmonary macrophages is directly linked to pulmonary fibrosis, and that the small GTP-binding protein, Rac1, directly mediates the hydrogen peroxide production. Since the protein modification process known as geranylgeranylation is required to activate Rac1, the researchers hypothesized that interrupting this protein modification might halt the production of oxidative stress and fibrosis.

Results from cell and mouse experiments showed that targeting the isoprenoid pathway by using digeranyl bisphosphonate to impair geranylgeranylation lessened mitochondrial import of Rac1, mitochondrial oxidative stress, and the progression of the fibrotic response to lung injury.

CitationOsborn-Heaford HL, Murthy S, Gu L, Larson-Casey JL, Ryan AJ, Shi L, Glogauer M, Neighbors JD, Hohl R, Brent Carter A. 2015. Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis. Free Radic Biol Med 86:47-56.

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

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