Papers of the Month
By Sara Mishamandani Amolegbe
Genetic and environmental factors influence autism-associated genes
NIEHS grantees discovered how independent genetic and environmental factors can affect a larger set of genes important to brain development and autism spectrum disorders (ASD). The findings showed how some genes linked to ASD might be altered because of a specific genetic mutation combined with exposure to polychlorinated biphenyl (PCB) 95, a widespread environmental contaminant and neurotoxicant.
The researchers studied the combined effects of PCB 95 and chromosomal duplications, which are genetic mutations that can arise from errors in DNA replication and repair. Duplication of genetic material in chromosome 15, or Dup15q, has been previously associated with ASD. By studying brain samples with and without this chromosomal duplication, the researchers identified thousands of variations that affected genes. Many of the variations are related to differences in DNA methylation, the process by which molecules are added to regions of DNA to control whether a gene is expressed.
The researchers exposed cells with Dup15q and normal cells to PCB 95 to discern whether the genetic or the environmental factor was linked to variations in ASD-associated genes. They found that 65 percent of genes with reduced DNA methylation in the samples exposed to PCB 95 were also affected by Dup15q. They also found that the cells with a combination of Dup15q and PCB 95 exposure had unique genetic variations that were not seen when the two factors were studied separately.
The findings provide new evidence that environmental factors can influence the function of genes linked to ASD by altering DNA methylation. The work also points to ASD-related genes that may be possible drug targets or potential markers for predicting autism earlier.
Dunaway KW, Islam MS, Coulson RL, Lopez SJ, Vogel Ciernia A, Chu RG, Yasui DH, Pessah IN, Lott P, Mordaunt C, Meguro-Horike M, Horike SI, Korf I, LaSalle JM. 2016. Cumulative impact of polychlorinated biphenyl and large chromosomal duplications on DNA methylation, chromatin, and expression of autism candidate genes. Cell Rep 17(11):3035−3048.
Manganese exposures may worsen parkinsonism in welders
Welders exposed to manganese may develop Parkinson’s disease-like symptoms, and the symptoms may get worse the more they are exposed, according to NIEHS-funded researchers. A study of Midwestern workers over 10 years linked the progression of movement abnormalities seen in Parkinson's disease, or parkinsonism, to cumulative exposure, even at manganese levels below the regulatory limit.
Researchers examined 886 workers at two shipyards and a heavy machinery fabrication shop, looking for movement disorders associated with Parkinson’s disease. For up to 10 years after the initial assessments, 398 workers had follow-up examinations. Researchers estimated exposure to manganese through a questionnaire about the workers’ job types and length of time on the job. The team reported that the average exposure to manganese was equivalent to 0.14 milligrams of manganese per cubic meter. Throughout the study, approximately 15 percent of the workers received motor scores that indicated they had parkinsonism.
The researchers found that Parkinson’s disease-like symptoms got worse the more the welders were exposed over time. Symptoms included slowness of movement in the arms and hands, stiffness in arms and legs, speech problems, and reduced facial expressions. According to the authors, each additional year of manganese exposure might increase the risk of parkinsonism, even when concentrations of manganese were below regulatory levels.
Based on their findings, the researchers emphasized the need for more stringent workplace monitoring of manganese exposures, greater use of personal protective equipment and ventilation, and systematic worker assessment.
Racette BA, Searles Nielsen S, Criswell SR, Sheppard L, Seixas N, Warden MN, Checkoway H. 2016. Dose-dependent progression of parkinsonism in manganese-exposed welders. Neurology 88(4):344−351.
DNA repair pathways help cells tolerate trace levels of hexavalent chromium
NIEHS grantees identified DNA repair pathways that help cells tolerate small amounts of hexavalent chromium, a contaminant found at hazardous waste sites across the U.S., which is also a public health concern in drinking water.
Although inhaled hexavalent chromium is classified as a known human carcinogen, whether hexavalent chromium can cause cancer through ingestion is still open to debate. To investigate this, researchers analyzed how cells respond to hexavalent chromium by examining DNA damage response. They screened a variety of cells with different gene mutations to see which DNA repair genes and pathways are necessary for cells to survive exposure to hexavalent chromium.
The researchers found that DNA repair pathways are critical for cells to tolerate DNA damage caused by trace amounts of hexavalent chromium. They also identified four key components of DNA repair proteins that are responsible for rescuing cells from DNA damage.
They discovered that DNA damage was dependent on both the level of hexavalent chromium and the length of exposure. The team reported a 300-fold decrease in DNA damage response when the exposure to hexavalent chromium was shortened from 3 days to 10 minutes. Hexavalent chromium moves quickly through the digestive tract of animals that drink contaminated water. This could explain why previous studies in rodents have shown that hexavalent chromium ingestion is only carcinogenic at very high concentrations.
Tian X, Patel K, Ridpath JR, Chen Y, Zhou YH, Neo D, Clement J, Takata M, Takeda S, Sale J, Wright FA, Swenberg JA, Nakamura J. 2016. Homologous recombination and translesion DNA synthesis play critical roles on tolerating DNA damage caused by trace levels of hexavalent chromium. PLoS One 11(12):e0167503.
The mechanisms of PM2.5 influence on insulin resistance
NIEHS grantees found that short-term exposure to particulate matter smaller than 2.5 micrometers (PM2.5), a common air pollutant, can induce oxidative stress in the lungs. This oxidative stress may, in turn, trigger vascular insulin resistance, a critical factor in the development of diabetes. This novel link between pulmonary oxidative stress and vascular insulin resistance may explain how exposure to air pollution increases the risk of developing both cardiovascular and metabolic diseases.
The researchers studied mice fed a normal or a high-fat diet, exposing them to either air concentrated with PM2.5 or filtered air. They then measured insulin sensitivity and inflammation. Upon exposure to PM2.5, mice developed vascular insulin resistance, which is associated with development of diet-induced obesity and diabetes, even in the absence of a high-fat diet. They also found that reducing oxidative stress in the lungs, either with antioxidant treatment or by overexpressing an enzyme responsible for creating antioxidants, prevented the PM2.5-induced vascular insulin resistance and inflammation.
The findings provide a new template for understanding how PM2.5 exposure might affect both cardiovascular processes and metabolic changes by inducing vascular insulin resistance. According to the authors, these results also suggested that conditions associated with decreased antioxidant capacity in the lung, such as asthma, smoking, advanced age, and influenza, could increase susceptibility to the cardiovascular effects of air pollution.
Haberzettl P, O'Toole TE, Bhatnagar A, Conklin DJ. 2016. Exposure to fine particulate air pollution causes vascular insulin resistance by inducing pulmonary oxidative stress. Environ Health Perspect 124(12):1830−1839.