Papers of the Month
By Sara Amolegbe
Analysis method for mixture exposures may amplify bias
NIEHS grantees found that certain approaches for analyzing mixtures of chemicals can, in some cases, amplify bias from unknown variables. This may be a concern when developing statistical approaches to identify the critical exposures from among the many that may contribute to health effects. Identifying these effects is a key goal of epidemiological analysis of complex chemical mixtures, which represent the multitude of chemicals that people are exposed to in everyday life.
The authors used directed acyclic graphs, a method used in epidemiology to display assumptions about causal relationships between variables in a specific context. When they assessed links between exposures and human health, certain exposures were often highly correlated. Unknown or unmeasured variables might also affect the estimates of health effects from mixtures. The study showed how including correlated exposures in a typical regression model could increase the effect, or bias, of unknown or unmeasured variables.
According to the authors, researchers must consider steps to minimize possible co-exposure amplification bias when designing and analyzing epidemiological studies of mixtures. They added that these studies would greatly benefit from interdisciplinary research. Options to remedy this issue include identification and control of the unknown variables, or other analytical approaches. The authors also discussed the importance of exposure assessment studies to understand the strength and basis for correlations between exposures, as well as physiological and toxicological information to improve interpretation of results. This may be particularly important when examining biological markers of exposure.
Citation: Weisskopf MG, Seals RM, Webster TF. 2018. Bias amplification in epidemiologic analysis of exposure to mixtures. Environ Health Perspect 126(4):047003.
Closing coal, oil plants linked to fewer preterm births
Shutting down coal- and oil-fired power plants lowered the rate of preterm births in neighboring communities, according to new research by NIEHS grantees. The researchers examined preterm births before and after eight power plants in California closed between 2001 and 2011.
The researchers compared preterm birth rates one year after the closure of each power plant with the rates during a year-long period before plant closure. Dividing the region surrounding each power plant into rings that represented 0-5 kilometers (km), 5-10 km, and 10-20 km from the plant, they examined state birth records to determine the rate of preterm births in each ring. Those living in the third ring, which was 10-20 km from the plant, were used as a control population.
The rate of preterm births for residents living in the closest ring dropped from 7.0 percent during the year before the plant closed to 5.1 percent in the year after shutdown. Rates for non-Hispanic African-American and Asian women in the closest ring dropped even more — from 14.4 to 11.3 percent. Those living 5-10 km away from the power plant showed less improvement.
The researchers also considered effects of wind on preterm birth rates. Although downwind areas seemed to show greater improvements, the differences were not statistically significant. They replicated their analyses around eight power plants that had not closed and found no differences in preterm births over the same period, which supported the results of their main analyses.
Citation: Casey JA, Karasek D, Ogburn EL, Goin DE, Dang K, Braveman PA, Morello-Frosch R. 2018. Coal and oil power plant retirements in California associated with reduced preterm birth among populations nearby. Am J Epidemiol; doi:10.1093/aje/kwy110 [Online 16 May 2018].
Enzyme plays key role in Parkinson’s disease
New research by NIEHS grantees and colleagues suggested an enzyme in the brain plays a key role in Parkinson’s disease (PD). Scientists demonstrated that inhibiting the enzyme soluble epoxide hydrolase (sEH) in mice helped curb the inflammation associated with the development and progression of PD.
The researchers exposed mice to methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP), a neurotoxicant that leads to symptoms of PD in animals. They found two approaches that protected against MPTP-induced neurotoxicity in the mouse brain — adding a potent sEH inhibitor, and genetically modifying mice to not produce sEH.
When the researchers examined expression of sEH, they found that it was higher in a specific part of the brain of MPTP-treated mice. Looking in humans, they reported that the enzyme was highly expressed in neurons from the stem cells of a PD patient and from the brains of patients with a disease called dementia of Lewy bodies. This form of dementia, like PD, involves deposits of a protein called alpha-synuclein in multiple regions of the brain.
According to the authors, the research suggested that sEH inhibitors could be potentially useful to reduce or prevent the progression of PD and other related diseases.
Citation: Ren Q, Ma M, Yang J, Nonaka R, Yamaguchi A, Ishikawa KI, Kobayashi K, Murayama S, Hwang SH, Saiki S, Akamatsu W, Hattori N, Hammock BD, Hashimoto K. 2018. Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson's disease. Proc Natl Acad Sci U S A 115(25):E5815–E5823.
Pollutants and genes combine to worsen rheumatoid arthritis
NIEHS grantees have identified how a specific genetic variant may interact with environmental pollutants, such as dioxin, to increase the risk of developing rheumatoid arthritis (RA).
The shared epitope (SE), a five-amino acid sequence coded by a specific variant of the gene human leukocyte antigen (HLA), is the single largest genetic risk factor for RA. Based on cell studies, the researchers showed that the SE signaling pathway interacts with another pathway in the body — the aryl-hydrocarbon receptor (AhR) pathway — which leads to enhanced creation of osteoclast cells, which break down bone tissue.
To investigate this relationship in mice, the researchers exposed them to dioxin, which can bind to AhR and initiate a greater signaling response. Common sources of dioxins, which are byproducts of combustion, include cigarette smoke and vehicle exhaust. In dioxin-exposed mice with the HLA gene variant, the researchers saw an increase in arthritis severity and in hyperactivity of osteoclasts, which led to excessive bone destruction.
According to the authors, this study identified a previously unrecognized mechanism to explain the interaction between SE and some environmental pollutants in the development and progression of RA.
Citation: Fu J, Nogueira SV, Drongelen VV, Coit P, Ling S, Rosloniec EF, Sawalha AH, Holoshitz J. 2018. Shared epitope-aryl hydrocarbon receptor crosstalk underlies the mechanism of gene-environment interaction in autoimmune arthritis. Proc Natl Acad Sci U S A 115(18):4755–4760.