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The Silent Spring of Obesogens: Translational Mechanisms of Obesity Caused by DDT Exposure Across Lifetimes
Michele A. La Merrill, PhD MPH
Associate Professor of Department of Environmental Toxicology
Adult and prenatal exposures to the pesticide DDT and its metabolite DDE have been associated with risk of obesity in subsequent generations of people, mice and rats in numerous studies. Our research indicates that these obesogenic effects are caused by impaired metabolism. We have observed that prenatal exposure to DDT or DDE impairs body heat production in mice from their first week of life to 9 months of age. Indeed, metabolic reductions in thermogenesis, the production of body heat, are associated not just with DDT and DDE exposures, but also with numerous pharmaceuticals and genes that are known to cause obesity. Epigenome studies in both mice and humans with DDT and DDE exposures have revealed extensive changes in DNA methylation enriching the thermogenesis pathway, including changes in DNA methylation of upstream signaling and substrate regulation pathways. Defects in the thermogenic function but not the structure of mouse brown adipose tissue and cultured brown adipocytes have observed. Additionally, prenatal DDT reduces the innervation of mouse brown adipose tissue, and the upstream synaptic connectivity is reduced by either DDT or DDE exposure prenatally. This body of research evidence indicates that both DDT and DDE act as obesogens by targeting both brown adipose and the sympathetic nervous system to impair thermogenesis.
ENVIRONMENTAL INFLUENCES ON CARDIOMETABOLIC HEALTH ACROSS THE LIFECOURSE
Shohreh F. Farzan, PhD
Asst Professor of Environmental Health, Dept of Population and Public Health Sciences
Keck School of Medicine, University of Southern California
A growing body of evidence supports a role for environmental contaminants, such as air pollutants and toxic metals, in the development and progression of cardiometabolic disease in adults. However, relatively little is known about the influence of these exposures on cardiovascular and metabolic disease risk during vulnerable lifestages, such as childhood, adolescence and pregnancy. For example, pregnancy may act as a window of susceptibility to environmental exposures, but relatively few studies have explored the effects of environmental contaminants on maternal prenatal and postpartum health. Among children, in utero and early life exposures may impact subclinical markers of cardiovascular dysfunction, with potential implications for cardiovascular health trajectories. As such, these lifestages may represent critical periods for intervention, as exposures during these times may exacerbate the risk of long-term cardiometabolic health effects. In this seminar, Dr. Farzan will discuss emerging research in this area, with examples from her work investigating the role of prenatal environmental exposures and psychosocial stressors on maternal perinatal cardiometabolic health, as well as the role of metals and air pollutants on subclinical indicators of cardiovascular disease risk from childhood to young adulthood.
Environmental Epitranscriptomics: Dynamic Rna Modifications And Environmental Health Sciences
Fred Tyson, PhD
Program Director in the Genes, Environment and Health Branch of the Division of Extramural Research and Training(DERT)
Fred Tyson is a Program Director in the Genes, Environment and Health Branch of the Division of Extramural Research and Training (DERT) at the National Institute of Environmental Sciences. He received his PhD in cell biology and developmental genetics from Rutgers University. Postdoctoral training in molecular genetics was obtained at Sloan-Kettering followed by additional training in molecular oncology at Duke. Tyson served as a Senior Staff Fellow at NIEHS in the Laboratory of Molecular Toxicology and as a Senior Scientist at the Saccamanno Cancer Research Institute in Grand Junction, CO. As an NIEHS program officer, Tyson has developed a research portfolio that employs multi-disciplinary approaches to address environmental health science issues. He has supported diverse research programs in environmental justice, health disparities, genomics, epigenomics, epitranscriptomics and marine toxicology. His current portfolio responsibilities include oversight of grants and programs addressing lung cancer, electronic nicotine delivery systems, oceans and human health as well as programs that address how environmental exposures may perturb epigenomic and epitranscriptomic processes. He has worked with trans-NIH programs as well as leading components of Common Fund supported initiatives as well as working across agencies such as the NSF, FDA, CDC and NOAA to advance environmental health science research priorities.
Application Of Single Cell Transcriptomics To Mechanistic Toxicology
Peer Karmaus, Phd
National Institute of Environmental Health Sciences
Toxicology testing has traditionally relied on rudimentary single endpoint outcomes. With the advent of single cell technologies, the biological unit of the cell can be interrogated at the mechanistic level. With recent advances in single cell transcriptomics, an unprecedented level of detail is now revealed on a per cell basis. These technologies now allow the assessment of population heterogeneity and the effect of chemical perturbation on cellular heterogeneity. Here Dr. Karmaus will discuss an example of applying single cell transcriptomics for evaluating the attenuation of T cell activation by atrazine.
Peer Karmaus is a Staff Scientist at the National Institute for Environmental Health Sciences and an Adjunct Assistant Professor at Michigan State University. His research focuses on how metabolism in innate and adaptive immune cells dictate cell fate and function.
Identification Of Sars-cov-2 Host Factors Using Genome Wide Crispr Screens
Chris Vulpe MD, PhD
Professor, Center for Environmental and Human Toxicology
University of Florida
The COVID-19 pandemic has resulted in 153 million infections and 3.2 million deaths as of May 2021. While effective vaccines are being administered globally, there is still a great need for antiviral therapies as potentially antigenically distinct SARS-CoV-2 variants continue to emerge across the globe. Viruses require host factors at every step in their life cycle, representing a rich pool of candidate targets for antiviral drug design. To identify host factors that promote SARS-CoV-2 infection with potential for broad-spectrum activity across the coronavirus family, we carried out a collaborative effort with Dr. Michel Norris and Dr. Stephanie Karst to perform genome-scale CRISPR knockout screens in two cell lines (Vero E6 and HEK293T ectopically expressing ACE2) with SARS-CoV-2 and the common cold-causing human coronavirus OC43. We identified multiple genes and functional pathways that have been previously reported to promote human coronavirus replication as well as novel genes and pathways. Of note, host factors involved in cell cycle regulation were enriched in our screens as were several key components of the programmed mRNA decay pathway. We identified novel candidate antiviral compounds targeting a number of factors revealed by our screens. Our studies substantiate and expand the growing body of literature focused on understanding key human coronavirus-host cell interactions and exploit that knowledge for rational antiviral drug development.
Interrogating Microglia As A Critical Mediator Of Pfos-induced Neurotoxicity
Manning Assistant Professor of Pathology and Laboratory Medicine
Per- and Polyfluoroalkyl Substances (PFAS) are a class of global toxicants that are resistant to environmental degradation. Exposure to perfluorooctane sulfonate (PFOS), a prevalent PFAS congener, dampens adaptive immune responses in children. However, it is not known whether PFOS exposure affects the development and function of microglia, the resident innate immune cells in the brain. Using a single cell image analysis pipeline, we found that PFOS exposure produced a rounded, activated microglia morphology in developing zebrafish. PFOS-exposed embryos exhibited a heightened microglial response to brain injury. The exacerbated responses were not due to changes in inflammatory cytokine signaling or an increase in cell death; therefore, we examined other factors in the microenvironment that may modulate microglial development and behavior. Using the photoconvertible calcium indicator CaMPARI, we observed increased neural activity following PFOS exposure. The observed increase may reflect aberrant connectivity associated with the failure of microglia to refine neural networks. Alternatively, the increase in neuronal firing may drive the observed activated microglial phenotypes and alter microglial response to injury. Using optogenetics, we were able to induce a ramified, less activated state in microglia and rescue the exacerbated microglial response to brain injury. We are currently conducting experiments to determine if neural silencing is sufficient to rescue the altered microglial morphology in PFOS-exposed embryos and the microglial response to brain injury.
New Technologies To Measure Environmental Exposures And Influences On Human Health
College of Public Health and Human Sciences
Oregon State University
Identifying and preventing environmental causes of disease requires estimating long-term personal exposures. Most environmental exposures do not have valid biomarkers and studies therefore rely on external exposure assessment methods. Approaches are split broadly into methods for modeling exposures for large populations versus measuring exposures for small populations. New technologies and resulting big data offer tremendous opportunity for unifying these approaches and improving long-term personal exposure prediction at scales needed for population-based research. In this presentation I will provide examples from ongoing research projects, such as: (1) leveraging existing individual time-activity data from Google Location History to estimate long-term environment exposures; (2) integrating image-based deep learning models to assess environmental exposures; and (3) applying new air pollution sensors to large epidemiological studies. I will make the case that a multi-disciplinary approach is needed to combine these types of technologies to improve personal exposure measures, enhance epidemiological research, and identify new prevention opportunities.
Uncertain times call for uncertain measures: Challenges in Modern Dose Response Analysis
Graduate Research Fellow
PI: Kim Anderson
Identifying mechanisms for toxicant-induced epigenetic change: towards “bench to community” translation of environmental epigenetics
Caren Weinhouse, PhD, MPH
Oregon Institute of Occupational Health Sciences
Oregon Health & Science University
How Should We Approach Forming Representative Mixtures?
Graduate Research Fellow
Oregon State University