Papers of the Month
By Julie Leibach
Exploring relationships between food security, nutrition, and the gut microbiome
A study funded by NIEHS sheds light on associations between people’s access to nutritious food and their gut microbiome, or the collection of bacteria inhabiting the digestive system.
Previous research examining links between diet and the gut microbiome focused on food components, such as fiber and fat, or prescribed diets, like the plant-based Mediterranean diet. Few studies have investigated how social factors such as food insecurity — lack of access to healthy food — shape relationships between an individual’s overall nutrition and their gut microbiome.
The researchers mined data on 643 people who had participated in the Survey of the Health of Wisconsin — an ongoing study that collects a range of health data from volunteers — and the Wisconsin Microbiome Study.
They gauged participants’ food security and nutrient intake using the My Nutrition Index, a measure of the nutritional value of a person’s daily diet based on personal characteristics, such as body size. The higher the score, the healthier the diet. Next, the researchers analyzed the microbial composition of each participant’s gut using genetic sequencing data obtained from stool samples.
To determine connections among the gut microbiome, nutrition, and food security levels, the team used a statistical modeling technique called quantile sum regression. Results showed that among people who were food insecure, a higher nutrition score was associated with a wider range of bacteria, including Actinomyces, Desulfovibrio, and Lactobacillus.
The findings may indicate that nutrition is more important in shaping the gut microbiome of food-insecure individuals. In addition, the gut microbiome may play a role in exacerbating persistent disparities in various health outcomes, according to the authors.
Citation: Bixby M, Gennings C, Malecki KMC, Sethi AK, Safdar N, Peppard PE, Eggers S. 2022. Individual nutrition is associated with altered gut microbiome composition for adults with food insecurity. Nutrients 14(16):3407.
Classifying genetic variants to better understand cancer risk, treatment
Researchers funded by NIEHS developed a framework for classifying variants, or DNA changes, in the gene RAD51C, which codes for a protein involved in DNA repair and tumor suppression. Because certain RAD51C variants have been implicated in breast and ovarian cancers, the findings could inform genetic counseling on disease risk and treatment for cancer patients.
The researchers first mined several gene databases to select 56 RAD51C variants for analysis. Next, they applied three commonly used algorithms to predict how each variant would affect RAD51C protein function. The tools suggested that nearly two-thirds of the variants studied would have a damaging effect on DNA repair.
To test the accuracy of the algorithms, the team introduced 20 of the variants into human mammary cells to see how they affected DNA repair. Only 10 RAD51C variants correlated with deficient repair, suggesting that the prediction tools are limited, according to the authors.
The researchers also investigated how structural changes in proteins produced by the 56 RAD51C variants affected their function in yeast cells. More than half of the variants were defective at forming protein complexes critical to DNA repair.
After combining their cellular data, the team created a structural diagram showing that many of the harmful RAD51C variants occurred in the Walker A motif, a genetic region that is highly conserved, or similar, across various organisms. Further investigation showed that cancer patients with certain variants in the Walker A motif responded well to treatment.
According to the authors, the study could inform assessments of similar DNA repair genes involved 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 identified by comprehensive analysis of cancer variants. Proc Natl Acad Sci U S A 119(38):e2202727119.
Children born near fracking sites have higher leukemia risk
Children born near unconventional oil and gas development sites have a greater risk of developing acute lymphoblastic leukemia (ALL), the most common form of childhood leukemia, according to an NIEHS-funded study.
Causes of ALL, which affects the blood and bone marrow, likely stem from genetic susceptibility and environmental exposures, according to the authors. Unconventional oil and gas development, or fracking, involves chemicals that have been linked to cancer, including heavy metals, radioactive material, volatile organic compounds, and polycyclic aromatic hydrocarbons.
Using the Pennsylvania Cancer Registry, the researchers gathered data on 405 children ages 2-7 years diagnosed with ALL and 2,080 cancer-free kids of the same ages. Next, the team measured the distance of birth homes to fracking wells, noting the location of wells that could potentially contaminate drinking water.
To investigate associations between ALL and fracking, the team used two exposure windows: a primary window, measured from 3 months before birth to 1 year before ALL diagnosis, and a perinatal window that measured preconception to birth.
Statistical analysis showed that children born within 2 kilometers of at least one fracking well during the primary exposure window were nearly twice as likely to develop ALL compared with control children. Odds increased to nearly three-fold during the perinatal window. Models that considered exposure through drinking water showed similar results.
The study adds to a small but growing body of research that suggests that proximity to fracking negatively affects health. According to the authors, the results could inform policies that establish minimum allowable distances, or setbacks, between private residences and well activity.
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 gas development exposure and risk of childhood acute lymphoblastic leukemia: a case-control study in Pennsylvania, 2009-2017. Environ Health Perspect 130(8):87001.
Unraveling how DDT exposure contributes to Alzheimer’s disease risk
NIEHS-funded researchers revealed a mechanism linking DDT pesticide exposure to Alzheimer’s disease. The findings could inform approaches to identifying people at risk for the disease, and for tailoring treatment options.
In those with Alzheimer’s disease, protein pieces called amyloid beta accumulate in the brain. However, what causes the disease in people older than 65 years ― known as late-onset Alzheimer’s — remains unclear.
Lately, researchers have been investigating the role of environmental factors. The team previously showed that people whose blood contained higher levels of a certain DDT metabolite, or breakdown product, had an increased risk of developing Alzheimer’s disease.
Building on that work, the researchers conducted cell and animal studies to explore whether DDT contributed to amyloid beta aggregation. Specifically, they treated fruit flies, human-derived cells, and mice with levels of DDT within the range that Americans encountered in the 1960s and 1970s. Then they applied an array of laboratory techniques — such as western immunoblotting and a multiplex assay — to assess amyloid processing and buildup.
Across their studies, the team found that DDT enhanced amyloid beta production. Specifically, DDT exposure increased the amount of messenger RNA — a molecule that carries instructions for making proteins — associated with APP, a gene that encodes the protein that cleaves into amyloid beta.
The researchers also learned that they could stop amyloid beta production by treating cells with tetrodotoxin, a compound that blocks sodium channels, which are structures that help brain cells communicate.
Taken together, the team’s earlier work and the present study provide evidence that DDT exposure affects the amyloid pathway, according to 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 levels and amyloid beta pathology: mechanistic links to Alzheimer's disease risk. Environ Health Perspect 130(8):87005.
(Julie Leibach is a senior science writer at MDB Inc., a contractor for the NIEHS Superfund Research Program.)