R01ES032638

The Epitranscriptome as a Novel Mechanism of Arsenic-Induced Diabetes - Summary

In the United States, the prevalence of type 2 diabetes mellitus (T2DM) is particularly high among American Indian (AI) communities. Arsenic (As), a pervasive environmental contaminant disproportionately affecting AI communities, may explain this increased risk. Arsenic induces oxidative stress and systemic low-grade inflammation, leading to β-cell dysfunction and insulin resistance in target tissues.

However, the impact of As on T2DM has been disputed due to a lack of coherent mechanism for these findings. Previous studies have focused on epigenomic mechanisms (e.g., DNA methylation, histone modifications), overlooking downstream regulatory mechanisms that can more directly shape phenotypes.

We propose to investigate the RNA modification N6-methyladenosine (m6A), the most prevalent epitranscriptomic modification on messenger RNA, which is directly involved in the cellular stress response. In experimental systems, arsenic induces an m6A response. m6A also modulates key processes underlying T2DM pathogenesis, including immune response and systemic inflammation.

m6A is controlled by a group of proteins called reader, writer, and erasers (RWES), responsible for adding, interpreting, and removing m6A marks. Fat mass and obesity-associated protein (FTO) is one example of an arsenic-sensitive m6A eraser with strong ties to T2DM and glucose homeostasis. Our pilot study in elderly men exposed to low-level arsenic supported these findings.

We propose to test the hypothesis that altered m6A and RWES are plausible mechanisms for As-related T2DM in the Strong Heart Study (SHS). The SHS is an ongoing longitudinal study in AI communities in Arizona, Oklahoma, and North/South Dakota with detailed clinical data for T2DM and metabolic syndrome (METS). The SHS has measured speciated As exposure data covering childhood and adult exposure windows, both independently associated with T2DM in previous research.

Leveraging the cohort design, exposure and phenotypic data, infrastructure, and study team, we propose to conduct epitranscriptomic analysis of mRNA m6A profiles via m6A sequencing and measure mRNA expression of 20 RWES using whole blood from 1100 participants at the upcoming SHS follow-up visit (scheduled for 2022-23).

Our specific aims are to:
1) Determine the association of past and current As exposure with epitranscriptomic profiles of m6A and RWES mRNA expression levels in blood.
2) Determine the association of blood m6A epitranscriptomic profiles with metabolic markers and METS, clinical T2DM prevalence, and T2DM control (glycated hemoglobin, albuminuria).
3) Develop a predictive m6A fingerprint that quantifies the risk of T2DM due to As exposure using machine learning approaches. For aims 1 and 2, we will further use Mendelian randomization to assess causal relationships.

Characterization of m6A profiles in a population of AI adults highly impacted by T2DM will reveal biological features linking a pervasive toxicant such as As to diabetes. In addition to leading to interventions to reduce As exposure in the US and globally, defining the roles of m6A and RWES in T2DM may contribute to new targets for future diabetes therapies.

The Trustees Of Columbia University In The City Of New York

TO FOSTER UNDERSTANDING OF HUMAN HEALTH EFFECTS OF EXPOSURE TO ENVIRONMENTAL AGENTS IN THE HOPE THAT THESE STUDIES WILL LEAD TO: THE IDENTIFICATION OF AGENTS THAT POSE A HAZARD AND THREAT OF DISEASE, DISORDERS AND DEFECTS IN HUMANS, THE DEVELOPMENT OF EFFECTIVE PUBLIC HEALTH OR DISEASE PREVENTION STRATEGIES, THE OVERALL IMPROVEMENT OF HUMAN HEALTH EFFECTS DUE TO ENVIRONMENTAL AGENTS, THE DEVELOPMENT OF PRODUCTS AND TECHNOLOGIES DESIGNED TO BETTER STUDY OR AMELIORATE THE EFFECTS OF ENVIRONMENTAL AGENTS, AND THE SUCCESSFUL TRAINING OF RESEARCH SCIENTISTS IN ALL AREAS OF ENVIRONMENTAL HEALTH RESEARCH. SUPPORTED GRANT PROGRAMS FOCUS ON THE FOLLOWING AREAS: (1) UNDERSTANDING BIOLOGICAL RESPONSES TO ENVIRONMENTAL AGENTS BY DETERMINING HOW CHEMICAL AND PHYSICAL AGENTS CAUSE PATHOLOGICAL CHANGES IN MOLECULES, CELLS, TISSUES, AND ORGANS, AND BECOME MANIFESTED AS RESPIRATORY DISEASE, NEUROLOGICAL, BEHAVIORAL AND DEVELOPMENTAL ABNORMALITIES, CANCER, AND OTHER DISORDERS, (2) DETERMINING THE MECHANISMS OF TOXICITY OF UBIQUITOUS AGENTS LIKE METALS, NATURAL AND SYNTHETIC CHEMICALS, PESTICIDES, AND MATERIALS SUCH AS NANOPARTICLES, AND NATURAL TOXIC SUBSTANCES, AND THEIR EFFECTS OF ON VARIOUS HUMAN ORGAN SYSTEMS, ON METABOLISM, ON THE ENDOCRINE AND IMMUNE SYSTEMS, AND ON OTHER BIOLOGICAL FUNCTIONS, (3) DEVELOPING AND INTEGRATING SCIENTIFIC KNOWLEDGE ABOUT POTENTIALLY TOXIC AND HAZARDOUS CHEMICALS BY CONCENTRATING ON TOXICOLOGICAL RESEARCH, TESTING, TEST DEVELOPMENT, VALIDATION AND RISK ESTIMATION, (4) IDENTIFYING INTERACTIONS BETWEEN ENVIRONMENTAL STRESSORS AND GENETIC SUSCEPTIBILITY AND UNDERSTANDING BIOLOGIC MECHANISMS UNDERLYING THESE INTERACTIONS, INCLUDING THE STUDY OF ENVIRONMENTAL INFLUENCES ON EPIGENOMICS AND TRANSCRIPTIONAL REGULATION, (5) CONDUCTING ENVIRONMENTAL PUBLIC HEALTH RESEARCH, INCLUDING IN AREAS OF ENVIRONMENTAL JUSTICE AND HEALTH DISPARITIES, THAT REQUIRES COMMUNITIES AS ACTIVE PARTICIPANTS IN ALL STAGES OF RESEARCH, DISSEMINATION, AND EVALUATION TO ADVANCE BOTH THE SCIENCE AND THE DEVELOPMENT OF PRACTICAL MATERIALS FOR USE IN COMMUNITIES, WITH A FOCUS ON TRANSLATING RESEARCH FINDINGS INTO TOOLS, MATERIALS, AND RESOURCES THAT CAN BE USED TO PREVENT, REDUCE, OR ELIMINATE ADVERSE HEALTH OUTCOMES CAUSED BY ENVIRONMENTAL EXPOSURES, (6) EXPANDING AND IMPROVING THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (7) EXPANDING AND IMPROVING THE STTR PROGRAM TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (8) PROVIDING SUPPORT FOR BROADLY BASED MULTI-DISCIPLINARY RESEARCH AND TRAINING PROGRAMS IN ENVIRONMENTAL HEALTH .THESE PROGRAMS INCLUDE THE ENVIRONMENTAL HEALTH SCIENCES CORE CENTERS , WHICH SERVE AS NATIONAL FOCAL POINTS AND RESOURCES FOR RESEARCH AND MANPOWER DEVELOPMENT. THROUGH THESE PROGRAMS, NIEHS EXPECTS TO ACHIEVE THE LONG-RANGE GOAL OF DEVELOPING NEW CLINICAL AND PUBLIC HEALTH APPLICATIONS TO IMPROVE DISEASE PREVENTION, DIAGNOSIS, AND THERAPY. ADDITIONAL CENTERS PROGRAMS DEVELOPED IN RECENT YEARS, INCLUDE THE CENTERS FOR OCEANS AND HUMAN HEALTH (CO-FUNDED WITH NSF), CHILDREN'S ENVIRONMENTAL HEALTH CENTERS (CO-FUNDED WITH US EPA) AND THE AUTISM CENTERS OF EXCELLENCE (CO-FUNDED WITH OTHER NIH INSTITUTES), AND THE HUMAN HEALTH EXPOSURE ANALYSIS RESOURCE (HHEAR) PROGRAM, (9) SUPPORTING RESEARCH TRAINING PROGRAMS WHICH SERVE TO INCREASE THE POOL OF TRAINED RESEARCH MANPOWER WITH NEEDED EXPERTISE IN THE ENVIRONMENTAL HEALTH SCIENCES THROUGH SUPPORT OF INDIVIDUAL AND INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS), (10) THE OUTSTANDING NEW ENVIRONMENTAL SCIENTIST PROGRAM WHICH PROVIDES FIRST TIME RESEARCH GRANT FUNDING TO OUTSTANDING JUNIOR SCIENTISTS IN THE FORMATIVE STAGES OF THEIR CAREER WHO ARE PROPOSING TO MAKE A LONG TERM COMMITMENT TO ENVIRONMENTAL HEALTH SCIENCES RESEARCH AND TO ADDRESS THE ADVERSE EFFECTS ON ENVIRONMENTAL EXPOSURES ON HUMAN BIOLOGY, HUMAN PATHOPHYSIOLOGY AND HUMAN DISEASE.

93.113 - Environmental Health

National Institute of Environmental Health Sciences (NIEHS) [HHS - NIH]

New York, New York 100323727 United States

Single Zip Code

Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) (PA-20-272)

Amendment Since initial award the total obligations have increased 464% from $684,582 to $3,858,238.