ANTIBIOTIC-ATTRIBUTABLE ARSENICOSIS RISK: TOXICITY AND CARCINOGENESIS - ABSTRACT ARSENIC IS A GLOBAL ENVIRONMENTAL TOXIN AND KNOWN HUMAN CARCINOGEN THAT CONTAMINATES THE DRINKING WATER OF OVER 200 MILLION PEOPLE. DESPITE ACCOUNTING FOR HOST FACTORS SUCH AS GENETICS AND DIET, THERE IS SIGNIFICANT INTER- INDIVIDUAL VARIABILITY AMONG SIMILARLY EXPOSED INDIVIDUALS IN THE DEVELOPMENT AND PROGRESSION OF ARSENIC-RELATED DISEASES (ARSENICOSIS), INCLUDING BLADDER CANCER, DIABETES, AND CARDIOVASCULAR DISEASE. EMERGING EVIDENCE IMPLICATES THE GUT MICROBIOME AS A KEY MODULATOR OF ARSENIC TOXICITY. NOTABLY, EVALUATION OF MURINE MODELS OF HUMAN ARSENICOSIS HAS DEMONSTRATED THAT ANTIBIOTIC-INDUCED GUT MICROBIOME DISRUPTION SIGNIFICANTLY INCREASES ARSENIC TOXICITY AND RECAPITULATES INTERINDIVIDUAL SUSCEPTIBILITY SEEN IN HUMANS. THESE FINDINGS ARE CONCERNING BECAUSE EVERY YEAR ~70% OF AMERICANS RECEIVE ANTIBIOTICS THAT COULD TRIGGER OR EXACERBATE THE LONG-TERM HEALTH CONSEQUENCES OF ARSENIC. ANTIBIOTIC USE AND MICROBIOME DIVERSITY ARE NOT PART OF CURRENT RISK ASSESSMENTS OF ARSENIC OR OTHER ENVIRONMENTAL TOXICANTS. THIS PROJECT TESTS THE OVERARCHING HYPOTHESIS THAT ANTIBIOTIC-INDUCED DISRUPTION OF THE GUT MICROBIOME INCREASES ARSENIC TOXICITY AND CARCINOGENESIS IN VIVO. IN AIM 1, A HUMANIZED MOUSE MODEL WILL BE USED TO EVALUATE HOW COMMONLY PRESCRIBED ANTIBIOTICS IN THE US INFLUENCE ARSENIC TOXICITY, USING A STANDARDIZED MORBIDITY SCORING SYSTEM, MICROBIOME SEQUENCING, ARSENIC SPECIATION ANALYSIS, AND TISSUE HISTOPATHOLOGY. IN AIM 2, CARCINOGENESIS OF THE BLADDER EPITHELIUM WILL BE COMPARED IN DIFFERENT GROUPS OF MICROBIOME COMPETENT AND ANTIBIOTIC-TREATED MICE USING AN ESTABLISHED CO-EXPOSURE MODEL THAT COMBINES ARSENIC WITH THE BLADDER-SPECIFIC CARCINOGEN, BBN. THESE STUDIES WILL RANK ANTIBIOTICS BY THEIR TOXICITY AND CARCINOGENIC POTENTIAL IN THE CONTEXT OF ARSENIC EXPOSURE AND HELP DEFINE MICROBIOME-TARGETED STRATEGIES TO REDUCE DISEASE RISK. A FELLOWSHIP TRAINING PLAN HAS BEEN DEVELOPED AROUND THIS RESEARCH THAT PROVIDES A COMPREHENSIVE, INTERDISCIPLINARY INSTRUCTION IN TOXICOLOGY, ONCOLOGY, MICROBIOME RESEARCH, AND DATA ANALYSIS UNDER THE MENTORSHIP OF EXPERTS IN THESE FIELDS. TRAINING GOALS WILL BE ACHIEVED IN A HIGHLY COLLABORATIVE AND SUPPORTIVE ENVIRONMENT WITH ACCESS TO STATE-OF-THE-ART FACILITIES FOR GNOTOBIOTICS, PATHOLOGY, AND MICROBIOME ANALYSIS. COMPLETION OF THIS PROJECT WILL ENHANCE THE CANDIDATE'S UNDERSTANDING OF MICROBIOME-TOXIN INTERACTIONS IN PREPARATION FOR A SUCCESSFUL, INDEPENDENT RESEARCH CAREER, AND HOLDS GREAT POTENTIAL TO SIGNIFICANTLY IMPROVE RISK ASSESSMENT FOR ARSENIC AND OTHER ENVIRONMENTAL CARCINOGENS.