Project Grant R43DA054030

IDENTIFICATION OF EPIGENETIC BIOMARKERS ASSOCIATED WITH PRENATAL EXPOSURE TO SUBSTANCES OF ABUSE - PROJECT SUMMARY PRENATAL SUBSTANCE USE REMAINS A SIGNIFICANT PUBLIC HEALTH CONCERN, WITH DEFINED CONSEQUENCES ESTABLISHED IN THE NEONATAL PERIOD AND ADDITIONAL HEALTH CONSEQUENCES IDENTIFIED AT BIRTH AND THROUGH ADOLESCENCE. TOBACCO AND ALCOHOL REMAIN THE MOST FREQUENTLY USED SUBSTANCES DURING PREGNANCY, FOLLOWED BY MARIJUANA, METHAMPHETAMINE, OPIATES AND COCAINE. ESTIMATES FROM THE NATIONAL SURVEY ON DRUG USE AND HEALTH SUGGEST THAT OVER FIVE PERCENT OF PREGNANT WOMEN USE ONE OR MORE ILLICIT SUBSTANCES. PRENATAL EXPOSURE TO SUBSTANCES OF ABUSE CAN NOT ONLY CAUSE NEONATAL ABSTINENCE SYNDROME (NAS) AND OTHER COMPLICATIONS AT BIRTH, BUT CAN ALSO LEAD TO A NUMBER OF NEUROBEHAVIORAL AND COGNITIVE DEVELOPMENTAL DISABILITIES IN ADOLESCENCE. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, PROVIDE A MECHANISTIC LINK BETWEEN PRENATAL EXPOSURE AND HEALTH CONSEQUENCES FOLLOWING THE PRENATAL PERIOD. ALTERATIONS TO THE EPIGENOME DURING PRENATAL DEVELOPMENT, DUE TO ENVIRONMENTAL EXPOSURE TO TOXINS OR DRUGS, CAN INDUCE LASTING EPIGENETIC CHANGES THAT CAN INDUCE PHYSIOLOGICAL CHANGES TO THE FETUS. WHILE MULTIPLE STUDIES HAVE ALREADY ESTABLISHED UNIQUE METHYLATION SIGNATURES RELATED TO PRENATAL EXPOSURE TO TOBACCO AND ALCOHOL, THERE ARE NO REPORTED HUMAN EPIGENETIC STUDIES ON THE IMPACT OF PRENATAL EXPOSURE TO ILLICIT DRUGS ON THE FETAL EPIGENOME AND HOW THESE PERTURBATIONS IMPACT SUBSEQUENT DEVELOPMENTAL CONSEQUENCES. RESEARCH TO UNDERSTAND THE EPIGENETIC PREDISPOSITION RESULTING FROM DRUG EXPOSURES AND IDENTIFICATION OF BIOMARKERS SPECIFIC TO EACH SUBSTANCE IS NECESSARY TO IDENTIFY AFFECTED NEONATES AND TAILOR EFFECTIVE TREATMENT INTERVENTIONS. THIS PHASE I PROPOSAL WILL BE THE FIRST STUDY TO EVALUATE WHOLE EPIGENOME METHYLATION SIGNATURES FROM NEWBORNS WITH KNOWN EXPOSURE TO SUBSTANCES OF ABUSE IN UTERO, IDENTIFY SPECIFIC METHYLATION SITES THAT ARE SIGNIFICANTLY DIFFERENTIATED FROM NON-EXPOSED CONTROLS, AND EXAMINE THE CORRELATION WITH BIRTH OUTCOMES IN NEWBORNS INCLUDING SEVERITY OF NAS. THE DIFFERENTIAL PATTERNS OF DNA METHYLATION IDENTIFIED WILL BE EXAMINED IN A PHASE II STUDY TO EXAMINE THE CORRELATION BETWEEN FETAL EXPOSURE TO ILLICIT DRUGS, METHYLATION PATTERNS IN EXPOSED NEWBORNS VERSUS HEALTHY CONTROLS, NAS SEVERITY, AND DEVELOPMENTAL OUTCOMES AS THE INFANTS MATURE. OUR LONG-TERM GOAL IS TO EXAMINE A CORRELATION BETWEEN IDENTIFIED EPIGENETIC CHANGES AND AN INCREASED RISK OF THE DEVELOPMENTAL DISABILITIES ASSOCIATED WITH PRENATAL EXPOSURE TO ILLICIT DRUGS. ESTABLISHMENT OF AN EPIGENETIC BIOMARKER OF FETAL EXPOSURE TO ILLICIT DRUGS USING NEONATAL BLOOD SPOTS WOULD BE MORE BENEFICIAL THAN CURRENT SCREENING METHODS IN ITS ABILITY TO PREDICT FETAL DAMAGE AT A VERY EARLY TIME POINT ALLOWING FOR PROMPT DIAGNOSIS AND EARLY INTERVENTION.