Papers of the Month
By Megan Avakian
Genetic mutation increases mesothelioma risk
NIEHS grantees found that individuals with mutations of the BLM gene are more susceptible to developing tumors called mesothelioma, especially after exposure to asbestos, pointing to a gene-environment interaction. Individuals who inherit two mutated copies of the BLM gene have Bloom syndrome, a disease associated with increased cancer risk. This study showed that individuals with a heterozygous BLM mutation — they only have one copy of the mutated gene — also have increased cancer risk.
The researchers sequenced the DNA of 155 mesothelioma patients, looking for heterozygous BLM mutations. Seven of the 155 patients carried such mutations, a significantly higher incidence than the expected frequency of 1 in 900 in the general population.
Using mice and human cells, the researchers determined that heterozygous BLM mutations lead to genomic instability following asbestos exposure. Additionally, in human cells with BLM mutations, asbestos exposure reduced cell death and altered inflammatory responses. The researchers exposed heterozygous BLM and wild-type mice to asbestos. Compared to the wild-type, BLM mutant mice had higher levels of inflammation markers, a hallmark of asbestos-induced cancer, and a higher incidence of mesothelioma.
Taken together, these results suggest that the probability of carrying heterozygous BLM mutations is significantly higher among mesothelioma patients than in the general population. In addition, BLM mutation carriers are at higher risk of developing mesothelioma — a risk that increases upon asbestos exposure. BLM mutation carriers may benefit from exposure prevention measures and screening for early detection, said the authors.
Citation: Bononi A, Goto K, Ak G, Yoshikawa Y, Emi M, Pastorino S, Carparelli L, Ferro A, Nasu M, Kim JH, Suarez JS, Xu R, Tanji M, Takinishi Y, Minaai M, Novelli F, Pagano I, Gaudino G, Pass HI, Groden J, Grzymski JJ, Metintas M, Akarsu M, Morrow B, Hassan R, Yang H, Carbone M. 2020. Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma. Proc Natl Acad Sci U S A 117(52):33466–33473.
Inhaled paraquat enters brain of mice, induces sex-specific effects
An NIEHS-funded study in mice revealed that when inhaled, the pesticide paraquat can enter the brain. The researchers also found that, in male mice only, paraquat exposure impaired sense of smell, an early sign of Parkinson’s and other neurodegenerative diseases. Inhalation represents a realistic route of pesticide exposure for farmers but is often overlooked in basic animal research and risk assessments, according to the authors.
The researchers exposed adult male and female mice to paraquat aerosols in a whole-body inhalation chamber for four weeks. They measured paraquat concentrations in various brain regions, the lungs, and kidneys. Using an olfactory discrimination assay, they assessed how exposure affected the sense of smell.
Paraquat was detected in four regions of the brain as well the lungs and kidney. Levels in the olfactory bulb were substantially higher than in any other brain region, consistent with inhalation exposure through the olfactory system. Paraquat levels in all tissues returned to control values within four weeks of the end of exposure. Exposed male mice had a persistent impaired sense of smell compared to controls. Exposure did not affect sense of smell in female mice. According to the authors, results highlight the importance of considering route of exposure to determine safety estimates for neurotoxic pesticides.
Citation: Anderson T, Merrill AK, Eckard ML, Marvin E, Conrad K, Welle K, Oberdorster G, Sobolewski M, Cory-Slechta DA. 2020. Paraquat inhalation, a translationally relevant route of exposure: disposition to the brain and male-specific olfactory impairment in mice. Toxicol Sci; doi:10.1093/toxsci/kfaa183 [Online 29 Dec 2020]. (Story)
Edible sorbents protect against PFAS toxicity
Edible nutrient-amended sorbents can reduce bioavailability and toxicity of per- and polyfluoroalkyl substances (PFAS) ingested via contaminated water and food, found NIEHS grantees. Clay-based sorbents bind toxins in the stomach and intestine, thereby reducing exposure. Here, the researchers tested whether adding the common nutrients carnitine and choline to a clay-based sorbent would enhance PFAS adsorption.
The researchers performed adsorption tests for common PFAS chemicals under conditions simulating the human stomach. For two of the four PFAS — PFOA, PFOS — and a mixture of those two, both nutrient-amended sorbents enhanced binding capacity, compared with the parent sorbent without nutrients. To test whether the chemicals would remain bound to the sorbents throughout the digestion process, they added PFAS-loaded sorbents to a simulated intestine environment. Only small amount of bound PFAS dissociated from the nutrient-amended sorbents, suggesting the chemicals would remain stable and tightly bind PFAS in the human intestine.
To test the safety and efficacy of the sorbents, the researchers exposed a freshwater organism called a hydra to PFOA, PFOS, and the sorbents. They assessed hydra structural defects to determine PFAS toxicity. Compared to the parent sorbent, both nutrient-amended sorbents significantly protected hydra from PFOA and PFOS toxicity. Additionally, a mixture of the nutrient-amended sorbents provided more protection than either sorbent alone and delivered the highest protection against a PFAS mixture. According to the authors, results show that including these nutrient-amended sorbents in the diet can reduce exposure and related toxicity from PFAS-contaminated food and water.
Citation: Wang M, Orr AA, Jakubowski JM, Bird KE, Casey CM, Hearon SE, Tamamis P, Phillips TD. 2021. Enhanced adsorption of per- and polyfluoroalkyl substances (PFAS) by edible, nutrient-amended montmorillonite clays. Water Res 188:116534.
E-cigarette use reduces viral immune response
E-cigarette users have a suppressed immune response to infection by the influenza virus, according to a new NIEHS-funded study. Results have important public health implications, especially during influenza season and other respiratory-virus pandemics, like COVID-19.
The study included 49 adults aged 18 to 40 years separated into three groups: nonsmokers, smokers, and e-cigarette users. Participants were inoculated with a weakened influenza virus, which allowed the researchers to safely examine immune response to influenza infection. Before and after inoculation, the researchers collected samples of the nasal lining, which is the first line of defense against respiratory infection. They further examined antibody production, gene expression, and markers of immune response and viral load.
Viral load did not differ among the three groups. Post-inoculation, antibodies increased as expected in nonsmokers but not e-cigarette users or smokers. Compared to nonsmokers, levels of important immune proteins following inoculation were reduced in e-cigarette users, but not smokers. E-cigarette users and smokers had decreased expression of immune-related genes compared to nonsmokers, with greater gene expression changes in e-cigarette users than smokers. Sex was a significant modifier of inoculation-induced gene expression, suggesting that immune-related genes are differentially modified in male and female e-cigarette users. However, the sample size did not allow for further sex-stratified analysis.
According to the authors, results indicated that e-cigarette use suppresses immune response to respiratory viral infections and that e-cigarette use and cigarette smoking affected host immune response in different ways.
Citation: Rebuli ME, Glista-Baker E, Hoffman JR, Duffney PF, Robinette C, Speen AM, Pawlak EA, Dhingra R, Noah TL, Jaspers I. 2021. Electronic-cigarette use alters nasal mucosal immune response to live-attenuated influenza virus. A clinical trial. Am J Respir Cell Mol Biol 64(1):126–137.