Libin Xu and Julia Cui will investigate the effect of antimicrobials on the human microbiome.
Four new projects will receive $40 K in pilot funding for environmental health research spanning a wide range of disciplines.
Each year the pilot projects program of the University of Washington Interdisciplinary Center for Exposures, Diseases, Genomics & Environment (EDGE) grants $40 K to projects that employ a novel approach to questions of high relevance for environmental health. Specifically, these projects advance the priorities of the EDGE Center and the National Institute of Environmental Health Sciences (NIEHS), by, for example, developing markers that help measure environmental exposures, early biological response, and/or genetic susceptibility.
An additional priority for NIEHS is to “improve and expand community-linked research.” In support of this priority, EDGE awards an additional $10 K to projects that include community engagement among their primary aims. Along with additional funding comes staff support from the EDGE community engagement core.
Four pilot projects have been funded for 2022. A summary of each can be found below.
Metagenomic approach to decipher mechanisms of cadmium neurotoxicity
Julia Cui, Sean Gibbons, James Gawel, and Zhengui Xia
Most Americans are exposed to the heavy metal cadmium (Cd) through their food. Cadmium is a neurotoxicant that has been associated with higher rates of mortality from Alzheimer’s Disease (AD) in U.S. adults. Another risk factor for the development of Alzheimer’s is the apoliproprotein E4 (ApoE4) allele—the strongest known genetic risk factor in humans. Changes in the gut microbiome have been noted independently in cases of cadmium exposure and AD. Julia Cui, Sean Gibbons, James Gawel, and Zhengui Xia will use a transdisciplinary approach to test the hypothesis that Cd exposure and the ApoE4 allele disrupt the gut microbiome and change the susceptibility of the host to Cd neurotoxicity. To test their hypothesis, they will first characterize changes in the microbiome in mice with and without the ApoE4 under Cd-exposed and control conditions. Then they’ll transplant the fecal microbiome to germ-free mice and test for the development of AD-like symptoms. Finally, they’ll measure Cd levels in blood samples from randomly selected aging and AD patients to investigate the interactions of Cd levels, ApoE allele type, and microbe interactions on AD. Their results could potentially lead to the development of a probiotic therapy to reduce the risk of developing AD in susceptible populations.
Single-Cell Characterization of the Testes-Immune Axis for Improved Hazard Assessment of Chemical Mixtures
Elaine Faustman and Edward Kelly
Predictive toxicology is an approach that seeks to develop and apply in vitro models—cell cultures that mimic organs—in order to test the health effects of potentially toxic substances. By using cells instead of animal models, scientists can reduce the number of animals required for research. One limitation in predictive toxicology is the inadequate availability of in vitro models for many critical organ systems--such as the developing testis. A useful model of testis requires key development stages to be benchmarked for direct comparison to in vivo (living) systems. Without this, it’s difficult to extrapolate to human health hazards. In their pilot study, Elaine Faustman and Edward Kelly and their graduate student Brad Hansen characterized biological responses through transcriptomics (measuring gene expression) in a novel culture system. They have developed a 3D testis cell model designed to function like a developing testis and a novel 2-well culture device that has allowed the testis to interact with other cell cultures, such as immune cells. This system has now been established to benchmark key developmental stages and characterize the impacts of phthalates on testis (phthalates are used in many consumer products and have been under investigation as reproductive hazards). Their results have important implications for testing the reproductive effects of a wide array of potentially toxic compounds, and, in particular, agents for which mechanistic data is lacking.
Elucidating the effects of increased usage of quaternary ammonium compound disinfectants on human microbiome during COVID-19
Libin Xu and Julia Cui
Quaternary ammonium compounds (QACs) are widely-used antimicrobials used in disinfectants like Clorox and Lysol, other medical and consumer products, and in the food processing industry. Because of their wide usage, humans face high levels of exposure. Recent work by Libin Xu and Julia Cui found QACs in over 80% of random human blood samples. The ongoing COVID-19 pandemic has only increased the use of disinfectants. One study reported a 77% increase in median QAC levels in human blood during the pandemic as compared to before. Xu and Cui have found that a major route of QAC excretion in mice is through the intestine, making it very likely that QACs impact the gut microbiome. They also found that oral exposure to QACs in mice significantly reduced the microbiome diversity. Now Xu and Cui will explore the relationships between QACs and the microbiome in humans to test the hypothesis that increased exposure to QACs during the pandemic would alter the gut microbiome diversity and functions. They will use human fecal samples already collected as part of a separate study to test their predictions. Results will have important clinical significance.
Studying individual variability in inflammatory gene expression response to wildfire exposures using a self-administered blood sampling device
Ashleigh Theberge
Exposure to wildfire smoke and the inhalation of smoke particles causes an inflammatory response that may contribute to the development of diseases like asthma, chronic obstructive pulmonary disease, and heart disease. However, the mechanisms behind this inflammatory response are not well understood, largely because it is hard to get people into clinics for blood draws during unpredictable wildfire events. To address this challenge, Ashleigh Theberge and her team have developed a kit that allows people to collect their own blood, combine it with a stabilizer, and mail it back to the lab. They call the kit homeRNA. In 2021, Theberge and her team used homeRNA to collect and stabilize over 500 blood samples from study participants in the Methow Valley—a region that experienced record wildfires in 2021—and other parts of the western U.S. that did not experience wildfire smoke. The current project will build on this work by performing statistical analysis of the gene expression in samples from 10 people from the Methow Valley and 10 people not exposed to wildfire smoke. It will also engage the Methow Valley community by presenting data from the project and receiving community feedback on future study design. Results of the project will help validate the homeRNA technology as a tool to be used in future disaster research response and to promote equity and accessibility in biomedical research.