title: Prenatal cocaine exposure impairs cognitive function of progeny via insulin growth factor II epigenetic regulation.
abstract: Studies have showed that prenatal cocaine exposure (PCOC) can impair cognitive function and social behavior of the offspring; however, the mechanism underlying such effect is poorly understood. Insulin-like growth factor II (Igf-II), an imprinted gene, has a critical role in memory consolidation and enhancement. We hypothesized that epigenetic regulation of hippocampal Igf-II may attribute to the cognitive deficits of PCOC offspring. We used Morris water maze and open-field task to test the cognitive function in PCOC offspring. The epigenetic alteration involved in hippocampal Igf-II expression deficit in PCOC offspring was studied by determining Igf-II methylation status, DNA methyltransferases (DNMT) expressions and L-methionine level. Moreover, IGF-II rescue experiments were performed and the downstream signalings were investigated in PCOC offspring. In behavioral tests, we observed impaired spatial learning and memory and increased anxiety in PCOC offspring; moreover, hippocampal IGF-II mRNA and protein expressions were significantly decreased. Hippocampal methylation of cytosine-phospho-guanine (CpG) dinucleotides in differentially methylated region (DMR) 2 of Igf-II was elevated in PCOC offspring, which may be driven by the upregulation of L-methionine and DNA methyltransferase (DNMT) 1. Importantly, intra-hippocampal injection of recombinant IGF-II reactivated the repressed calcium calmodulin kinase II α (CaMKIIα) and reversed cognitive deficits in PCOC offspring. Collectively, our findings suggest that cocaine exposure during pregnancy impairs cognitive function of offspring through epigenetic modification of Igf-II gene. Enhancing IGF-II signaling may represent a novel therapeutical strategy for cocaine-induced cognitive impairment.
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hou
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Shao
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Ruiming
authors.initials: R
authors.lastname: Zhu
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Bu
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gu
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Baolai
authors.initials: B
authors.lastname: Zhang
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Changman
authors.initials: C
authors.lastname: Du
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Dengqi
authors.initials: D
authors.lastname: Fu
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Jueying
authors.initials: J
authors.lastname: Kong
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Hailei
authors.initials: H
authors.lastname: Long
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Deng
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: xbcen@scu.edu.cn.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cen
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000378:metabolism / Q000523:psychology
chemical_list: D007335:Insulin-Like Growth Factor II; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003042:Cocaine
keywords: CaMKIIα; Cognitive function; DNA methylation; DNMTs; IGF-II; Prenatal cocaine exposure; l-Methionine