Environmental Factor – October 2020: Extramural Papers of the Month – Environmental Factor Newsletter

Extramural Papers

Extramural By Megan Avakian

Exposure to per- and polyfluoroalkyl substances (PFAS) in the womb may increase liver injury risk in children, according to NIEHS-funded researchers. This study is the first to examine the impact of early life exposures to a PFAS mixture on child liver injury. PFAS, a large group of synthetic chemicals found in a variety of consumer products, have been linked to immune dysfunction, altered metabolism, brain development, and certain cancers.

The study used data from 1,105 mothers and their children enrolled in the Human Early-Life Exposome, or HELIX, study in Europe. The researchers measured blood levels of six PFAS chemicals in pregnant mothers and assessed liver enzyme and metabolite levels in their childrens serum at age 6 to 9 years.

Using computational modeling, they found that higher exposures to PFAS during pregnancy were associated with higher liver enzyme levels in children, which are biomarkers of nonalcoholic fatty liver disease (NAFLD). The researchers also identified a profile for children at high risk for liver injury, characterized by high prenatal PFAS exposures and increased serum levels of compounds related to amino acid and lipid metabolism.

Because the prevalence of NAFLD in children is rapidly increasing and PFAS can cross the placenta to reach the fetus early in development, these results may provide new opportunities for liver injury prevention starting early in life, say the authors.

Citation:Stratakis N, Conti DV, Jin R, Margetaki K, Valvi D, Siskos AP, Maitre L, Garcia E, Varo N, Zhao Y, Roumeliotaki T, Vafeiadi M, Urquiza J, Fernandez-Barres S, Heude B, Basagana X, Casas M, Fossati S, Grazuleviciene R, Andrusaityte S, Uppal K, McEachan RRC, Papadopoulou E, Robinson O, Haug LS, Wright J, Vos MB, Keun HC, Vrijheid M, Berhane KT, McConnell R, Chatzi L. 2020. Prenatal exposure to perfluoroalkyl substances associated with increased susceptibility to liver injury in children. Hepatology; doi:10.1002/hep.31483 [Online 1 August 2020].

Consuming omega-3 fatty acids may protect against air pollution-associated brain shrinkage in older women, according to a recent NIEHS-funded study. Omega-3 fatty acids are found in fish and play an important role in maintaining brain structure and function during aging.

The researchers used magnetic resonance imaging (MRI) to study the brains of 1,315 U.S. women aged 65 to 80 years and assessed levels of omega-3 fatty acids in their blood. The women were enrolled in the study between 1996 and 1999 and underwent MRI between 2005 and 2006. Using geocoded participant addresses and data from a national network of air monitors, the researchers estimated each womans average exposure to fine particulate matter (PM2.5) three years before MRI.

Women with higher blood levels of omega-3 fatty acids had larger volumes of white matter in their brains. Women living in locations with higher PM2.5 had significantly less white matter in their brains, but damage potentially caused by PM2.5 was greatly reduced in women with high blood levels of omega-3 fatty acids. White matter loss in the brain may be an early marker of Alzheimers disease.

According to the authors, these findings suggest that omega-3 fatty acids could contribute to the healthy aging of white matter and protect against the harmful effects of air pollution on the brain.

Citation:Chen C, Xun P, Kaufman JD, Hayden KM, Espeland MA, Whitsel EA, Serre ML, Vizuete W, Orchard T, Harris WS, Wang X, Chui HC, Chen JC, He K. 2020. Erythrocyte omega-3 index, ambient fine particle exposure, and brain aging. Neurology 95(8):e995e1007.

Air pollution may play a role in the development of cardiometabolic diseases like diabetes, with effects comparable to eating a high-fat diet, say NIEHS grantees. Importantly, effects were reversed when air pollution exposure stopped.

Using male mice, the researchers compared three groups: a control group that received clean filtered air; a group exposed to concentrated PM2.5 air pollution; and a group that received clean filtered air but were fed a high-fat diet. After 14 weeks, they measured cardiometabolic disease risk factors, such as insulin resistance and glucose levels. They also assessed epigenetic changes, or chemical tags that attach to DNA and affect gene expression.

Being exposed to air pollution was comparable to eating a high-fat diet. Mice in both the air pollution and high-fat diet groups had impaired insulin resistance, high glucose, and reduced metabolism. In both groups, these effects were associated with epigenetic changes that resulted in altered expression of genes related to metabolism and circadian rhythm. Once air pollution was removed from the environment, mice showed improved metabolic health and epigenetic changes were reversed within eight weeks.

The study suggests that cardiometabolic health effects of air pollution are reversible, and the researchers call for studies in humans to verify their findings. If confirmed, results may have important implications for interventions to reduce air pollution.

Citation:Rajagopalan S, Park B, Palanivel R, Vinayachandran V, Deiuliis JA, Gangwar RS, Das LM, Yin J, Choi Y, Al-Kindi S, Jain MK, Hansen KD, Biswal S. 2020. Metabolic effects of air pollution exposure and reversibility. J Clin Invest; doi:10.1172/JCI137315 [Online 11 August 2020].

NIEHS grantees discovered how the shape of the muscles in the heart affect heart performance and heart failure. The study focused on a network of muscle fibers, called trabeculae, that form complex geometric patterns on the inner surface of the heart. Trabeculae are important for heart development, but until now, their function in adults has been unknown.

The research team primarily used data from the UK Biobank study, which includes individuals from the United Kingdom aged 40 to 69 years at enrollment. They used artificial intelligence to analyze the complexity of trabeculae structure in more than 18,000 MRI scans of the heart. Using genome-wide association analysis, they identified 16 DNA regions linking trabeculae complexity and heart function. Further analysis revealed that DNA regions linked with lower trabeculae complexity were associated with increased susceptibility to heart disease and heart failure.

Using computer simulations to model how trabeculae complexity affects heart function, the researchers found that as complexity increased, so did measures of heart performance. Study participants with higher trabeculae complexity had more efficient blood flow from the heart, confirming simulation results and suggesting that trabeculae increase the hearts ability to contract and pump blood to the body.

Taken together, the authors say findings support a previously unknown role for trabeculae in the adult heart, identify DNA regions that regulate trabeculae complexity, and reveal a causal relationship between trabeculae complexity and heart disease.

Citation:Meyer HV, Dawes TJW, Serrani M, Bai W, Tokarczuk P, Cai J, de Marvao A, Henry A, Lumbers RT, Gierten J, Thumberger T, Wittbrodt J, Ware JS, Rueckert D, Matthews PM, Prasad SK, Costantino ML, Cook SA, Birney E, O'Regan DP. 2020. Genetic and functional insights into the fractal structure of the heart. Nature 584(7822):589594.

(Megan Avakian is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)

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Environmental Factor - October 2020: Extramural Papers of the Month - Environmental Factor Newsletter