title: Long-term parental methamphetamine exposure of mice influences behavior and hippocampal DNA methylation of the offspring.
abstract: The high rate of methamphetamine (METH) abuse among young adults and women of childbearing age makes it imperative to determine the long-term effects of METH exposure on the offspring. We hypothesized that parental METH exposure modulates offspring behavior by disrupting epigenetic programming of gene expression in the brain. To simulate the human pattern of drug use, male and female C57Bl/6J mice were exposed to escalating doses of METH or saline from adolescence through adulthood; following mating, females continue to receive drug or saline through gestational day 17. F1 METH male offspring showed enhanced response to cocaine-conditioned reward and hyperlocomotion. Both F1 METH male and female offspring had reduced response to conditioned fear. Cross-fostering experiments have shown that certain behavioral phenotypes were modulated by maternal care of either METH or saline dams. Analysis of offspring hippocampal DNA methylation showed differentially methylated regions as a result of both METH in utero exposure and maternal care. Our results suggest that behavioral phenotypes and epigenotypes of offspring that were exposed to METH in utero are vulnerable to (a) METH exposure during embryonic development, a period when wide epigenetic reprogramming occurs, and (b) postnatal maternal care.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Cellular and Molecular Pharmacology and Neuroscience Division, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Itzhak
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: I
authors.initials: I
authors.lastname: Ergui
authors.affiliation: 1] John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA [2] Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Young
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005239:Fear / Q000187:drug effects / Q000523:psychology; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D008425:Maternal Behavior / Q000187:drug effects; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D018709:Statistics, Nonparametric
chemical_list: D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D008694:Methamphetamine; D003042:Cocaine; D004298:Dopamine