IMPACT OF HEAT STRESS ON DRUG METABOLIZING ENZYME EXPRESSION AND FUNCTION - PROJECT SUMMARY/ABSTRACT EXCESSIVE HEAT (WET BULB GLOBE TEMPERATURE [WBGT] EXCEEDING 32oC TERMED "HEAT STRESS") REQUIRES HEAT DISSIPATION TO MAINTAIN NORMAL BODY TEMPERATURE (37oC). WHEN HEAT STRESS EXCEEDS HEAT DISSIPATION, THE CONCURRENT RISE IN INTERNAL BODY TEMPERATURES ABOVE 38oC (TERMED "HEAT STRAIN") OR OVER 40oC (TERMED "HEAT STROKE"), RESULTS IN MORE DEATHS THAN ALL OTHER CLIMATE DISASTERS COMBINED. WITHIN THE UNITED STATES, MANY AREAS REGULARLY EXPERIENCE TEMPERATURES THAT SURPASS 40oC ANNUALLY, AND MANY WORKING CONDITIONS LEAD TO A HIGH NUMBER OF INDIVIDUALS WITH LITTLE OR NO ACCESS TO CLIMATE-CONTROL THROUGHOUT THE DAY. ADDITIONALLY, MANY WORKERS WHO LABOR IN EXCESSIVE HEAT FOR LONG PERIODS ARE CONCURRENTLY EXPOSED TO OCCUPATIONAL AND ENVIRONMENTAL CHEMICALS. TOXICITY FROM THESE COMPOUNDS IS LARGELY DETERMINED BY THE ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION PROCESSES THAT DETERMINE THE FATE OF CHEMICALS WITHIN THE BODY, WHERE METABOLISM AND TRANSPORT DETERMINE EXPOSURE AND TOXICITY. INTERINDIVIDUAL VARIABILITY THAT REDUCES METABOLISM AND ELIMINATION OF THESE CHEMICALS RESULTS IN INCREASED SUSCEPTIBILITY. GENETIC VARIABILITY IS OFTEN SEEN AS THE MECHANISTIC CAUSE OF SUSCEPTIBILITY, BUT GENETICS IS NOT THE ONLY FACTOR IN ADME FUNCTION. TRANSIENT PHENOTYPIC CONVERSION (PHENOCONVERSION) DUE TO TEMPORARY ENVIRONMENTAL CHANGES SUCH AS HEAT STRAIN IS OFTEN OVERLOOKED BUT CAN RESULT IN ALTERATIONS IN DRUG METABOLIZING ENZYME FUNCTION LEADING TO THE INABILITY TO PROPERLY ELIMINATE TOXICANTS. WHEREAS GENETIC VARIABILITY IDENTIFIES INDIVIDUALS WHO ARE INHERENTLY SUSCEPTIBLE TO TOXICITY, PHENOCONVERSION IDENTIFIES CONDITIONS IN WHICH ANY INDIVIDUAL CAN BE AT GREATER RISK OF TOXICITY. THE INVESTIGATIVE TEAM HAS DEMONSTRATED NUMEROUS TOXICOLOGIC EXAMPLES OF PHENOCONVERSION IN BOTH ANIMAL MODELS AND HUMAN PARTICIPANTS WITH METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS (MASH), INCLUDING PESTICIDES, ENVIRONMENTAL CONTAMINANTS, CHEMOTHERAPEUTICS, AND OVER-THE-COUNTER DRUGS. PRELIMINARY DATA SUGGESTS THAT HEAT STRAIN LEADS TO PROFOUND ALTERATIONS IN DRUG METABOLIZING ENZYME EXPRESSION WITH THE POTENTIAL TO INCREASE TOXICITY. EXPOSURES TO CHEMICALS CONSIDERED SAFE IN HEALTHY INDIVIDUALS UNDER CONTROLLED CONDITIONS MAY HAVE SIGNIFICANTLY DIFFERENT OUTCOMES IN THOSE SAME INDIVIDUALS FOLLOWING HEAT-INDUCED PHENOCONVERSION. THUS, PHENOCONVERSION MAY PROVIDE A MECHANISTIC BASIS FOR INCREASED EXPOSURE AND TOXICITY IN WORKERS AND INDIVIDUALS EXPOSED TO EXCESSIVE HEAT. THE CENTRAL HYPOTHESIS IS THAT EXCESSIVE HEAT ALTERS THE EXPRESSION AND FUNCTION OF MAJOR DMES AND TRANSPORTERS, THEREBY INCREASING THE RISK OF TOXICITIES IN WORKERS OR INDIVIDUALS EXPERIENCING HEAT STRAIN. I WILL TEST THE HYPOTHESIS WITH THE FOLLOWING AIMS. AIM 1: IDENTIFY THE EFFECTS OF ACUTE AND CYCLICAL HEAT STRAIN ON THE EXPRESSION AND FUNCTION OF GENES IMPORTANT FOR DETOXIFICATION THROUGH DISPOSITION IN MICE. AIM 2: ANALYZE THE EFFECTS OF HEAT STRAIN ON THE TOXICOKINETICS AND TOXICITY OF ENVIRONMENTAL AND OCCUPATIONAL CHEMICALS IN MICE.