Project Grant R03ES035480

MITIGATING DEVELOPMENTAL NEUROTOXICITY THROUGH MATERNAL AND OFFSPRING EXERCISE - PROJECT SUMMARY/ABSTRACT BENZO[A]PYRENE (BAP) IS A KNOWN CARCINOGEN AND RANKED 8TH ON THE U.S. GOVERNMENT'S PRIORITY POLLUTANTS LIST WHILE THE ENTIRE CLASS OF COMPOUNDS (POLYCYCLIC AROMATIC HYDROCARBONS OR PAHS) RANKS 9TH. HUMAN EXPOSURES ARE WIDESPREAD FROM TRAFFIC-RELATED AIR POLLUTION, WILDFIRES, CIGARETTE SMOKE, AND GRILLED FOODS AND NEARLY IMPOSSIBLE TO AVOID. RECENT HUMAN STUDIES FOUND STRONG CORRELATIONS BETWEEN PRENATAL PAH EXPOSURE AND PERSISTENT COGNITIVE AND BEHAVIORAL DEFICITS IN EXPOSED CHILDREN. WE RECENTLY REPORTED RESULTS FROM A MOUSE STUDY DEMONSTRATING THAT GENETIC DIFFERENCES IN THE ARYL HYDROCARBON RECEPTOR (AHR) AND CYP1A2 INCREASE RISK FOLLOWING DEVELOPMENTAL EXPOSURE TO BAP. AHRBCYP1A2(-/-) MICE WITH THE HIGH-AFFINITY AHR AND AHRDCYP1A2(-/-) MICE WITH THE POOR-AFFINITY RECEPTOR BOTH HAD IMPAIRED PERFORMANCE IN THE MORRIS WATER MAZE TEST OF SPATIAL LEARNING AND MEMORY. HIGH-AFFINITY AHR KNOCKOUTS ALSO HAD MOTOR DEFICITS IN ROTAROD, AND POOR-AFFINITY KNOCKOUTS EXHIBITED HIGHER LEVELS OF ANXIETY-LIKE BEHAVIOR. THE BENEFITS OF REGULAR EXERCISE ON BRAIN HEALTH ARE WELL ESTABLISHED, BUT CONSIDERABLY LESS IS KNOWN ABOUT THE EFFECTS OF EXERCISE DURING PREGNANCY ON THE HEALTH OF THE MOTHER AND BRAIN FUNCTION IN HER OFFSPRING. THE NEUROLOGICAL BENEFITS OF EXERCISE INCLUDE INCREASED LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND BENEFICIAL MODIFICATIONS OF NEUROSIGNALING BY SEROTONIN, DOPAMINE AND NORADRENALINE. THE MECHANISM OF ACTION FOR AEROBIC EXERCISE BENEFITS ON HIPPOCAMPAL DEPENDENT LEARNING AND MEMORY WERE DIRECTLY TIED TO BDNF SIGNALING. BOTH MATERNAL AND OFFSPRING EXERCISE HAVE BEEN SUCCESSFUL IN REVERSING SPATIAL LEARNING AND MEMORY DEFICITS INDUCED BY PRENATAL STRESS. EXERCISE DURING EARLY LIFE HAS ADDITIONAL BENEFITS ON IMPROVING MOOD AND REDUCING LEVELS OF STRESS HORMONES WHEREAS ANXIETY-LIKE BEHAVIOR IS INCREASED IN MICE WITH A KNOCKDOWN OF THE BDNF RECEPTOR TRKB. WE CONDUCTED PILOT STUDIES IN C57BL/6J MICE AND FOUND THAT BOTH MATERNAL AND OFFSPRING VOLUNTARY WHEEL RUNNING INCREASED CIRCULATING BDNF LEVELS. OUR PROPOSED STUDIES WILL USE AEROBIC EXERCISE TO INCREASE BDNF LEVELS IN OFFSPRING EXPOSED TO BAP DURING EARLY BRAIN DEVELOPMENT WITH THE GOAL OF RESCUING THE NEUROLOGICAL DEFICITS OBSERVED IN OUR PREVIOUS STUDIES. FIRST, WE WILL COMPARE THE RELATIVE EFFECTIVENESS OF FOUR DIFFERENT EXERCISE TREATMENTS AND ENSURE THEY DO NOT CAUSE HARM TO THE DAM OR PUPS. NEXT, WE WILL USE THE EXERCISE REGIMEN DETERMINED TO BE SAFE AND MOST EFFECTIVE IN AN ATTEMPT TO RESCUE LEARNING AND MEMORY AND MOTOR DEFICITS AND TO REDUCE ANXIETY-LIKE BEHAVIOR IN OUR MOST SUSCEPTIBLE MOUSE LINES.THE TRANSLATIONAL VALUE OF THESE STUDIES IS HIGH, BECAUSE WE SEEK TO IDENTIFY THE MINIMUM LEVEL OF EXERCISE NECESSARY TO PRODUCE BENEFICIAL EFFECTS. THIS GREATLY INCREASES THE FEASIBILITY OF COMPLIANCE IN THE HUMAN POPULATION.