Papers of the Month
By Nancy Lamontagne
Researchers discover new diet-toxicant interaction
An NIEHS grantee and colleagues have identified a new interaction that may link exposure to polychlorinated biphenyls (PCBs) with cardiovascular disease. Although their manufacture and use are now banned in the United States, PCBs break down slowly, so they remain in the environment for long periods of time.
Scientists are only just beginning to understand the mechanisms that connect diet, exposure to environmental pollutants, and cardiovascular risk. To study these mechanisms, the researchers whether exposure to PCBs can lead to increased levels of trimethylamine N-oxide (TMAO). TMAO is produced when the body metabolizes certain foods, especially those derived from animals. Several large studies in humans have linked high levels of circulating TMAO with an increased risk for heart disease.
The researchers conducted studies in mice and found that several types of PCBs led to increased levels of a liver enzyme that generates TMAO. In addition, feeding dietary precursors of TMAO to mice that had been exposed to PCBs increased blood levels of TMAO.
Taken together, the new findings identify environmental pollutants as a previously unknown modulator of blood TMAO levels and raise the possibility that exposure to environmental pollutants, like PCBs, may contribute to variability in TMAO levels among people.
Petriello MC, Hoffman JB, Sunkara M, Wahlang B, Perkins JT, Morris AJ, Hennig B. 2016. Dioxin-like pollutants increase hepatic flavin containing monooxygenase (FMO3) expression to promote synthesis of the pro-atherogenic nutrient biomarker trimethylamine N-oxide from dietary precursors. J Nutr Biochem 33:145-153.
Living near hydraulic fracturing wells linked with more asthma attacks
New research, supported in part by NIEHS, showed that people with asthma living near bigger or larger numbers of active hydraulic fracturing natural gas wells in Pennsylvania were up to four times more likely to have asthma attacks than those who lived farther away.
For the study, the researchers analyzed health records of patients treated between 2005 and 2012 by a health care provider that served 40 counties in north and central Pennsylvania. The scientists identified more than 35,000 asthma patients between the ages of 5 and 90. After mapping where these patients lived, the team compared hydraulic fracturing well activity near the homes of patients who reported asthma attacks with those who had no attacks in the same year.
The researchers found an association between increased numbers of mild, moderate, and severe asthma attacks and living close to bigger or larger numbers of hydraulic fracturing wells, even after accounting for other factors that can worsen asthma. Asthma attacks occurred around wells throughout all four phases of well development — pad preparation; drilling; stimulation, or hydraulic fracturing; and production — but the risk increased the most during the production phase, which can last for many years.
Although it is not clear from the study why there were more asthma attacks closer to more or larger wells, the researchers said that air pollution and increased stress levels from the noise, traffic, and other community impacts associated with the industry could play a role.
Rasmussen SG, Ogburn EL, McCormack M, Casey JA, Bandeen-Roche K, Mercer DG, Schwartz BS. 2016. Association between unconventional natural gas development in the Marcellus shale and asthma exacerbations. JAMA Intern Med; doi: 10.1001/jamainternmed.2016.2436 [Online 18 July 2016].
Researchers uncover role of copper in prion protein misfolding
NIEHS grantees have discovered how copper ions cause prion proteins to misfold, which then seeds the misfolding and clumping of nearby prion proteins. They also established a link, at the molecular level, between copper exposure and prion protein neurotoxicity, providing insight into the role of metals in Alzheimer's, Parkinson's, and prion diseases, which all involve misfolding of proteins.
Prions are abnormal, pathogenic agents that can be transmitted. They can induce abnormal folding of prion proteins, which are found most abundantly in the brain. The abnormal folding of these proteins leads to brain damage and symptoms of neurodegenerative disease.
The researchers combined biophysical and neurotoxicological research approaches. They developed a technique that identified misfolded prion proteins with single-molecule sensitivity and used it to show that misfolding begins when copper ions bind to the unstructured tail of the protein. Using single-molecule force spectroscopy to measure the efficiency of prion protein clumping, they found that misfolded prion proteins stick together nearly 900 times more efficiently than normally folded proteins. They also studied brain tissue from mice and found that the copper-induced misfolding and clumping is associated with inflammation and damage to nerve cells in brain tissue. Overall, the findings identified the biophysical conditions and mechanisms for copper-induced prion protein misfolding, clumping, and neurotoxicity.
Yen CF, Harischandra DS, Kanthasamy A, Sivasankar S. 2016. Copper-induced structural conversion templates prion protein oligomerization and neurotoxicity. Sci Adv 2(7):e1600014.
Arsenic and chromium exposure associated with kidney injury biomarker in children
An NIEHS-funded study of children living in north-central Mexico found that higher levels of exposure to arsenic and chromium were associated with elevated levels of kidney injury molecule-1 (KIM-1). The new findings suggest that KIM-1 might serve as a sensitive biomarker for screening children for kidney damage induced by environmental exposures.
The researchers examined levels of arsenic, cadmium, chromium, fluoride, and lead in drinking water, urine, and blood samples of 83 children, ages 5 to 12, living in Villa de Reyes, Mexico. Exposure to these heavy metals early in life can have long-term health consequences.
The researchers found that levels of arsenic and chromium in the urine samples from the children were even higher than exposure limits set in the Biological Exposure Index, developed by the American Conference of Governmental Industrial Hygienists to assist in controlling potential workplace health hazards in adults. Although measurements of traditional biomarkers of kidney function were not elevated, KIM-1 was elevated in the children. KIM-1 is thought to be more sensitive and specific than other biomarkers of kidney injury and was recently qualified by the U.S. Food and Drug Administration for use in preclinical studies and on a case-by-case basis for clinical evaluation.
Cardenas-Gonzalez M, Osorio-Yanez C, Gaspar-Ramirez O, Pavkovic M, Ochoa-Martinez A, Lopez-Ventura D, Medeiros M, Barbier OC, Perez-Maldonado IN, Sabbisetti VS, Bonventre JV, Vaidya VS. 2016. Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1. Environ Res; doi:10.1016/j.envres.2016.06.032 [Online 14 July 2016].