Cannabis use is associated with potentially heritable widespread changes in autism candidate gene <i>DLGAP2</i> DNA methylation in sperm.
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2020-01
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Abstract
Parental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.
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Schrott, Rose, Kelly Acharya, Nilda Itchon-Ramos, Andrew B Hawkey, Erica Pippen, John T Mitchell, Scott H Kollins, Edward D Levin, et al. (2020). Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm. Epigenetics, 15(1-2). pp. 161–173. 10.1080/15592294.2019.1656158 Retrieved from https://hdl.handle.net/10161/28271.
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Scholars@Duke
Kelly S Acharya
John T Mitchell
Scott Haden Kollins
Scott H. Kollins, PhD received his undergraduate degree in psychology from Duke and his Master’s and Doctorate degrees in Clinical Psychology from Auburn University. After completing his clinical internship at the University of Mississippi Medical Center, where he served as Chief Intern, he joined the faculty of the Department of Psychology at Western Michigan University for three years, before joining the Duke faculty in 2000. Dr. Kollins has published more than 125 scientific papers in peer-reviewed journals. Over the past 10 years, his research has been supported by 6 different federal agencies, including NICHD, NIDA, NIMH, NIEHS, NINDS, and EPA, and he currently holds a mid-career K24 award from NIDA. He has also served as PI on more than 40 industry-funded clinical trials and is a consultant to a number of pharmaceutical companies in the area of ADHD clinical psychopharmacology. He has served as a standing member of the Child Psychopathology and Developmental Disabilities study section and also served as an ad-hoc reviewer for 10 additional NIH study sections and 7 international granting agencies. He is an Associate Editor for the Journal of Attention Disorders and has reviewed for more than 50 different peer-reviewed journals. He is an elected member of the College on Problems of Drug Dependence and the American College of Neuropsychopharmacology. Dr. Kollins is a licensed clinical psychologist and maintains a practice through the ADHD Program’s outpatient clinic. His research interests are in the areas of psychopharmacology and the intersection of ADHD and substance abuse, particularly cigarette smoking.
Edward Daniel Levin
Dr. Levin is Chief of the Neurobehavioral Research Lab in the Psychiatry Department of Duke University Medical Center. His primary academic appointment is as Professor in the Department of Psychiatry and Behavioral Sciences. He also has secondary appointments in the Department Pharmacology and Cancer Biology, the Department of Psychological and Brain Sciences and the Nicholas School of the Environment at Duke. His primary research effort is to understand basic neural interactions underlying cognitive function and addiction and to apply this knowledge to better understand cognitive dysfunction and addiction disorders and to develop novel therapeutic treatments.
The three main research components of his laboratory are focused on the themes of the basic neurobiology of cognition and addiction, neurobehavioral toxicology and the development of novel therapeutic treatments for cognitive dysfunction and substance abuse. Currently, our principal research focus concerns nicotine. We have documented the basic effects of nicotine on learning memory and attention as well as nicotine self-administration. We are continuing with more mechanistic studies in rat models using selective lesions, local infusions and neurotransmitter interaction studies. We have found that nicotine improves memory performance not only in normal rats, but also in rats with lesions of hippocampal and basal forebrain connections. We are concentrating on alpha7 and alpha4beta2 nicotinic receptor subtypes in the hippocampus, amygdala , thalamus and frontal cortex and how they interact with dopamine D1 and D2 and glutamate NMDA systems with regard to memory and addiction. I am also conducting studies on human cognitive behavior. We have current studies to assess nicotine effects on attention, memory and mental processing speed in schizophrenia, Alzheimer's Disease and Attention Deficit Hyperactivity Disorder. In the area of neurobehavioral toxicology, I have continuing projects to characterize the adverse effects of prenatal and adolescent nicotine exposure. Our primary project in neurobehavioral toxicology focuses on the cognitive deficits caused by the marine toxins. The basic and applied aims of our research complement each other nicely. The findings concerning neural mechanisms underlying cognitive function help direct the behavioral toxicology and therapeutic development studies, while the applied studies provide important functional information concerning the importance of the basic mechanisms under investigation.
Susan Kay Murphy
Dr. Murphy is a tenured Associate Professor in the Department of Obstetrics and Gynecology and serves as Chief of the Division of Reproductive Sciences. As a molecular biologist with training in human epigenetics, her research interests are largely centered around the role of epigenetic modifications in health and disease.
Dr. Murphy has ongoing projects on gynecologic malignancies, including approaches to eradicate ovarian cancer cells that survive chemotherapy and later give rise to recurrent disease. Dr. Murphy is actively involved in many collaborative projects relating to the Developmental Origins of Health and Disease (DOHaD).
Her lab is currently working on preconception environmental exposures in males, particularly on the impact of cannabis on the sperm epigenome and the potential heritability of these effects. They are also studying the epigenetic and health effects of in utero exposures, with primary focus on children from the Newborn Epigenetics STudy (NEST), a pregnancy cohort she co-founded who were recruited from central North Carolina between 2005 and 2011. Dr. Murphy and her colleagues continue to follow NEST children to determine relationships between prenatal exposures and later health outcomes.
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