Environmental Factor – November 2022: Extramural Papers of the Month

Exploring relationships between meals safety, diet, and the intestine microbiome

A examine funded by NIEHS sheds gentle on associations between folks’s entry to nutritious meals and their intestine microbiome, or the gathering of micro organism inhabiting the digestive system.

Previous analysis analyzing hyperlinks between food regimen and the intestine microbiome centered on meals parts, reminiscent of fiber and fats, or prescribed diets, just like the plant-based Mediterranean food regimen. Few research have investigated how social elements reminiscent of meals insecurity — lack of entry to wholesome meals — form relationships between a person’s general diet and their intestine microbiome.

The researchers mined knowledge on 643 individuals who had participated within the Survey of the Health of Wisconsin — an ongoing examine that collects a spread of well being knowledge from volunteers — and the Wisconsin Microbiome Study.

They gauged contributors’ meals safety and nutrient consumption utilizing the My Nutrition Index, a measure of the dietary worth of an individual’s every day food regimen based mostly on private traits, reminiscent of  physique measurement. The larger the rating, the more healthy the food regimen. Next, the researchers analyzed the microbial composition of every participant’s intestine utilizing genetic sequencing knowledge obtained from stool samples.

To decide connections among the many intestine microbiome, diet, and meals safety ranges, the crew used a statistical modeling method referred to as quantile sum regression. Results confirmed that amongst individuals who have been meals insecure, the next diet rating was related to a wider vary of micro organism, together with Actinomyces, Desulfovibrio, and Lactobacillus.

The findings could point out that diet is extra vital in shaping the intestine microbiome of food-insecure people. In addition, the intestine microbiome could play a task in exacerbating persistent disparities in numerous well being outcomes, in keeping with the authors.

Citation: Bixby M, Gennings C, Malecki KMC, Sethi AK, Safdar N, Peppard PE, Eggers S. 2022. Individual diet is related to altered intestine microbiome composition for adults with meals insecurity. Nutrients 14(16):3407.

Classifying genetic variants to raised perceive most cancers danger, remedy

Researchers funded by NIEHS developed a framework for classifying variants, or DNA adjustments, within the gene RAD51C, which codes for a protein concerned in DNA restore and tumor suppression. Because sure RAD51C variants have been implicated in breast and ovarian cancers, the findings might inform genetic counseling on illness danger and remedy for most cancers sufferers.

The researchers first mined a number of gene databases to pick out 56 RAD51C variants for evaluation. Next, they utilized three generally used algorithms to foretell how every variant would have an effect on RAD51C protein operate. The instruments instructed that almost two-thirds of the variants studied would have a harmful impact on DNA restore.

To take a look at the accuracy of the algorithms, the crew launched 20 of the variants into human mammary cells to see how they affected DNA restore. Only 10 RAD51C variants correlated with poor restore, suggesting that the prediction instruments are restricted, in keeping with the authors.

The researchers additionally investigated how structural adjustments in proteins produced by the 56 RAD51C variants affected their operate in yeast cells. More than half of the variants have been faulty at forming protein complexes vital to DNA restore.

After combining their mobile knowledge, the crew created a structural diagram exhibiting that most of the dangerous RAD51C variants occurred within the Walker A motif, a genetic area that’s extremely conserved, or related, throughout numerous organisms. Further investigation confirmed that most cancers sufferers with sure variants within the Walker A motif responded effectively to remedy. 

According to the authors, the examine might inform assessments of comparable DNA restore genes concerned in susceptibility to environmental stressors.

Citation: Prakash R, Rawal Y, Sullivan MR, Grundy MK, Bret H, Mihalevic MJ, Rein HL, Baird JM, Darrah K, Zhang F, Wang R, Traina TA, Radke MR, Kaufmann SH, Swisher EM, Guérois R, Modesti M, Sung P, Jasin M, Bernstein KA. 2022. Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C recognized by complete evaluation of most cancers variants. Proc Natl Acad Sci U S A 119(38):e2202727119.

Children born close to fracking websites have larger leukemia danger

Children born close to unconventional oil and fuel growth websites have a larger danger of creating acute lymphoblastic leukemia (ALL), the commonest type of childhood leukemia, in keeping with an NIEHS-funded examine.

Causes of ALL, which impacts the blood and bone marrow, probably stem from genetic susceptibility and environmental exposures, in keeping with the authors. Unconventional oil and fuel growth, or fracking, includes chemical substances which were linked to most cancers, together with heavy metals, radioactive materials, unstable natural compounds, and polycyclic fragrant hydrocarbons.

Using the Pennsylvania Cancer Registry, the researchers gathered knowledge on 405 youngsters ages 2-7 years identified with ALL and a pair of,080 cancer-free children of the identical ages. Next, the crew measured the gap of delivery houses to fracking wells, noting the placement of wells that might probably contaminate ingesting water.

To examine associations between ALL and fracking, the crew used two publicity home windows: a major window, measured from 3 months earlier than delivery to 1 yr earlier than ALL prognosis, and a perinatal window that measured preconception to delivery.

Statistical evaluation confirmed that youngsters born inside 2 kilometers of not less than one fracking effectively throughout the major publicity window have been practically twice as more likely to develop ALL in contrast with management youngsters. Odds elevated to almost three-fold throughout the perinatal window. Models that thought of publicity by way of ingesting water confirmed related outcomes.

The examine provides to a small however rising physique of analysis that means that proximity to fracking negatively impacts well being. According to the authors, the outcomes might inform insurance policies that set up minimal allowable distances, or setbacks, between non-public residences and effectively exercise.

Citation: Clark CJ, Johnson NP, Soriano M Jr, Warren JL, Sorrentino KM, Kadan-Lottick NS, Saiers JE, Ma X, Deziel NC. 2022. Unconventional oil and fuel growth publicity and danger of childhood acute lymphoblastic leukemia: a case-control examine in Pennsylvania, 2009-2017. Environ Health Perspect 130(8):87001.

Unraveling how DDT publicity contributes to Alzheimer’s illness danger

NIEHS-funded researchers revealed a mechanism linking DDT pesticide publicity to Alzheimer’s illness. The findings might inform approaches to figuring out folks in danger for the illness, and for tailoring remedy choices.

In these with Alzheimer’s illness, protein items referred to as amyloid beta accumulate within the mind. However, what causes the illness in folks older than 65 years ― often called late-onset Alzheimer’s — stays unclear.

Lately, researchers have been investigating the function of environmental elements. The crew beforehand confirmed that individuals whose blood contained larger ranges of a sure DDT metabolite, or breakdown product, had an elevated danger of creating Alzheimer’s illness.

Building on that work, the researchers performed cell and animal research to discover whether or not DDT contributed to amyloid beta aggregation. Specifically, they handled fruit flies, human-derived cells, and mice with ranges of DDT throughout the vary that Americans encountered within the Sixties and Nineteen Seventies. Then they utilized an array of laboratory methods — reminiscent of western immunoblotting and a multiplex assay — to evaluate amyloid processing and buildup.

Across their research, the crew discovered that DDT enhanced amyloid beta manufacturing. Specifically, DDT publicity elevated the quantity of messenger RNA — a molecule that carries directions for making proteins — related to APP, a gene that encodes the protein that cleaves into amyloid beta.

The researchers additionally realized that they may cease amyloid beta manufacturing by treating cells with tetrodotoxin, a compound that blocks sodium channels, that are buildings that assist mind cells talk.

Taken collectively, the crew’s earlier work and the current examine present proof that DDT publicity impacts the amyloid pathway, in keeping with the authors.

Citation: Eid A, Mhatre-Winters I, Sammoura FM, Edler MK, von Stein R, Hossain MM, Han Y, Lisci M, Carney K, Konsolaki M, Hart RP, Bennett JW, Richardson JR. 2022. Effects of DDT on amyloid precursor protein ranges and amyloid beta pathology: mechanistic hyperlinks to Alzheimer’s illness danger. Environ Health Perspect 130(8):87005.