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Parental methamphetamine exposure affects offspring’s behavior and DNA methylation

Parental methamphetamine exposure affects offspring’s behavior and DNA methylation. Juan I. Young John P. Hussman Institute for Human Genomics Dr. John T. Macdonald Foundation Department of Human Genetics *SCOR *NIH/NIMH No conflict of interest to declare.

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Parental methamphetamine exposure affects offspring’s behavior and DNA methylation

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  1. Parental methamphetamine exposure affects offspring’s behavior and DNA methylation Juan I. Young John P. Hussman Institute for Human Genomics Dr. John T. Macdonald Foundation Department of Human Genetics *SCOR *NIH/NIMH No conflict of interest to declare

  2. Heritable transmission of environmentally induced phenotypes: multigenerational inheritance • Studies suggest the transmission of behavioral traits acquired by one generation to subsequent generations through epigenetic processes Exposure to a drug of abuse (methamphetamine) Phenotype A Phenotype B Multigenerational persistence Phenotype B

  3. Environmetal intervention: Exposure to metamphetamine • Methamphetamine is a major drug of abuse in many parts of the world. Current use of METH surpasses the use of cocaine and opiates. • Methamphetamine addiction is associated with psychotic behavior and long term cognitive impairment. • Surveys of past-month illicit drug use among females aged 15-44 showed that 6-7% of these women were pregnant, and continued to use drugs during all three trimesters of pregnancy; 2,000-3,000 abused Methamphetamine.

  4. Environmetal intervention: Exposure to metamphetamine • A major concern is the prospect that parental methamphetamine abuse and in utero exposure may have debilitating effects on generations that are either indirectly exposed, or even unexposed to the drug. • Exposure: simulated the human pattern of parental METH exposure. • Male and female mice (F0) were exposed to an intermittent escalating regiment of METH or saline from adolescence through adulthood and during pregnancy.

  5. F1 phenotype: motivational effects of cocaine • Long lasting effect of methamphetamine on CPP (sexually dismorphic) • Male pups insensitive to maternal influence • Female pups sensitive to maternal effects In utero: S S S S M M M M Fostering dam: S M S M S M S M Molecular Psychiatry , (18 February 2014)

  6. F1 phenotype: associativelearning and memory • Long lasting effect of methamphetamine on fear conditioining • Sensitive to maternal effects : Fostering of METH pups by saline dams restored dampened freezing of METH pups In utero: S S S S M M M M Fostering dam: S M S M S M S M Molecular Psychiatry , (18 February 2014)

  7. F1 phenotype: activity and anxiety In utero: S M S M Fostering dam: S M M S • Long lasting effect of methamphetamine-induced maternal effect • Maternal care of METH dams had a significant sex-dependent effect on anxiety-like behavior of saline offspring In utero: S S S S M M M M Fostering dam: S M S M S M S M Molecular Psychiatry , (18 February 2014)

  8. F1 summary (Behavior) • Prenatal METH exposure produces long-lasting changes in the offspring’s behavioral phenotypes. • Effects are phenotype dependent: • CPP: Sexual dimorphism • Maternal influence on the phenotype (independent of dam treatment) also sexually dimorphic • Fear conditioning: Maternal influence on the phenotype dependent on dam treatment (“salinerescue”) • Open field: Maternally influenced phenotye (dependent on dam treatment (“METH induced”) • Light/dark box:Maternally influenced phenotye (dependent on dam treatment (“METH induced”) and sexually dimorphic

  9. Mechanism by which prenatal exposures affect long term phenotypes • One possible mechanism involves alterations of DNA methylation marks in the genome. • compared the DNA methylome of the hippocampus of the F1 SpSd, MpMd, SpMd and MpSd mice by MeDIP-microarray NimbleGen microarray: covers 15,936 UCSC annotated CpG islands and all RefSeq gene promoter regions

  10. F1 epigenotype: DNA methylation in hippocampus • The group that exhibited the highest number of identified peaks was MpMd, suggesting that the combination of in utero exposure to METH and METH-induced maternal care mostly promotes DNA methylation. • A comparison of MpMd vs. SpSd samples identified 1822 methylation peaks aligning to gene promoter regions as differentially methylated regions (DMR). The majority of these DMR showed hypermethylation in MpMd, as compared to SpSd.

  11. F1 epigenotype: DNA methylation in hippocampus • Validation: 75% of selected DMR showed methylation differences by bisulfite sequencing concordant with the array data . • More variability in methylation levels in samples from maternally METH exposed mice than in SpSd samples, suggesting that the response of hippocampal cells to maternal METH exposure is heterogeneous. Molecular Psychiatry , (18 February 2014)

  12. SpSdvsMpSd DMR: effect of paternal METH on pup under the care of a saline dam SpMdvsMpMd DMR: effect of paternal METH on pup under the care of a METH dam SpSdvsSpMd DMR: effect of METH on maternal care (on saline embryos) MpMdvsMpSd DMR: effect of METH on maternal care on METH embryos 429 847 1216 243 1360 317 489 769 SpSdvsMpMd DMR: combination of effect of paternal METH on embryo and effect of METH on maternal care SpSdvsMpMd DMR: combination of effect of paternal METH on embryo and effect of METH on maternal care 1240 552 1240 552 SpMd vs MpMd MpMd vs MpSd EMR: No effect of paternal METH on pup DMR: effect of paternal METH on pup EMR: No effect of METH on maternal care DMR: effect of METH on maternal care : 129 49 : 111 47 : 70 33 : 62 35 Paternal METH effects on the F1 pup’s methylome independent of maternal care influences. Paternal METH effects on the F1 pup’s methylome mediated by altered maternal care. Numbers in black: hypermethylated DMR; numbers in red: hypomethylated DMR; EMR: equally methylated region.

  13. F1 epigenotype: DNA methylation in hippocampus Prenatal METH exposure induce changes in several genes shown to be modulated by: direct exposure to drugs of abuse,and maternal effects.

  14. METH-induced methylation, which should produce gene silencing, occurs in promoters that have a histone modification signature of active transcription. Top 10 enriched histone terms for the hypermethylated DMR

  15. METH-induced demethylation was observed in promoters associated with an epigenetic signature of transcriptional silencing. Top 10 enriched histone terms for the demethylated DMR.

  16. F1 summary • Prenatal METH exposure produces long-lasting changes in the offspring’s brain epigenome that could contribute to the initiation and maintenance of the observed behavioral phenotypes. • Our experiments indicate a significant influence of maternal effects on the epigenotype and behavioral phenotype of the F1 progeny. • Parental METH exposure has important consequences on the hippocampal transcriptional landscape of the progeny; promoters that are usually active become methylated while inactive promoters are demethylated.

  17. Aknowledgements YossefItzhak Ian Ergui Michael kaplan Vladimir Camarena

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