Prenatal antidepressant exposure associated with CYP2E1 DNA methylation change in neonates

Some but not all neonates are affected by prenatal exposure to serotonin reuptake inhibitor antidepressants (SRI) and maternal mood disturbances. Distinguishing the impact of these 2 exposures is challenging and raises critical questions about whether pharmacological, genetic, or epigenetic factors can explain the spectrum of reported outcomes. Using unbiased DNA methylation array measurements followed by a detailed candidate gene approach, we examined whether prenatal SRI exposure was associated with neonatal DNA methylation changes and whether such changes were associated with differences in birth outcomes. Prenatal SRI exposure was first associated with increased DNA methylation status primarily at CYP2E1(βNon-exposed = 0.06, βSRI-exposed = 0.30, FDR = 0); however, this finding could not be distinguished from the potential impact of prenatal maternal depressed mood. Then, using pyrosequencing of CYP2E1 regulatory regions in an expanded cohort, higher DNA methylation status—both the mean across 16 CpG sites (P < 0.01) and at each specific CpG site (P < 0.05)—was associated with exposure to lower 3rd trimester maternal depressed mood symptoms only in the SRI-exposed neonates, indicating a maternal mood x SRI exposure interaction. In addition, higher DNA methylation levels at CpG2 (P = 0.04), CpG9 (P = 0.04) and CpG10 (P = 0.02), in the interrogated CYP2E1 region, were associated with increased birth weight independently of prenatal maternal mood, SRI drug exposure, or gestational age at birth. Prenatal SRI antidepressant exposure and maternal depressed mood were associated with altered neonatal CYP2E1 DNA methylation status, which, in turn, appeared to be associated with birth weight.

[1]  S. Murphy,et al.  Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight , 2012, Cancer Causes & Control.

[2]  S. Davis,et al.  Effect of fasting and obesity in humans on the 6‐hydroxylation of chlorzoxazone: A putative probe of CYP2E1 activity , 1994, Clinical pharmacology and therapeutics.

[3]  Eldon Emberly,et al.  Factors underlying variable DNA methylation in a human community cohort , 2012, Proceedings of the National Academy of Sciences.

[4]  Isaac S. Kohane,et al.  Prenatal antidepressant exposure is associated with risk for attention deficit-hyperactivity disorder but not autism spectrum disorder in a large health system , 2014, Molecular Psychiatry.

[5]  D. Popa,et al.  Lasting Syndrome of Depression Produced by Reduction in Serotonin Uptake during Postnatal Development: Evidence from Sleep, Stress, and Behavior , 2008, The Journal of Neuroscience.

[6]  A. Gilbert,et al.  Investigating Outcomes Following the Use of Selective Serotonin Reuptake Inhibitors for Treating Depression in Pregnancy , 2011, Drug safety.

[7]  Hui Xie,et al.  Altered Cytochrome P450 Expression in Mice during Pregnancy , 2011, Drug Metabolism and Disposition.

[8]  Carmen J. Marsit,et al.  miR-16 and miR-21 Expression in the Placenta Is Associated with Fetal Growth , 2011, PloS one.

[9]  M. Merzenich,et al.  Perinatal antidepressant exposure alters cortical network function in rodents , 2011, Proceedings of the National Academy of Sciences.

[10]  K. Conneely,et al.  DNA methylation in neonates born to women receiving psychiatric care , 2012, Epigenetics.

[11]  Emma Y. Wu,et al.  A Role for Repressive Histone Methylation in Cocaine-Induced Vulnerability to Stress , 2011, Neuron.

[12]  Teri E. Klein,et al.  Incorporation of Pharmacogenomics into Routine Clinical Practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process , 2014, Current drug metabolism.

[13]  A. Gilbert,et al.  Neonatal Outcomes After Late-Gestation Exposure to Selective Serotonin Reuptake Inhibitors , 2012, Journal of clinical psychopharmacology.

[14]  E. Moreira,et al.  Behavioral Evaluation of Male and Female Mice Pups Exposed to Fluoxetine during Pregnancy and Lactation , 2007, Pharmacology.

[15]  T. Oberlander,et al.  Prenatal Exposure to Maternal Depressed Mood and the MTHFR C677T Variant Affect SLC6A4 Methylation in Infants at Birth , 2010, PloS one.

[16]  R. Desnick,et al.  Multi-ethnic Cytochrome-P450 Copy Number Profiling: Novel Pharmacogenetic Alleles and Mechanism of Copy Number Variation Formation , 2012, The Pharmacogenomics Journal.

[17]  T. Bale,et al.  Sex-Specific Programming of Offspring Emotionality after Stress Early in Pregnancy , 2008, The Journal of Neuroscience.

[18]  Michael Papsdorf,et al.  Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses , 2008, Epigenetics.

[19]  T. Oberlander,et al.  Neurodevelopmental outcomes following prenatal exposure to serotonin reuptake inhibitor antidepressants: a "social teratogen" or moderator of developmental risk? , 2012, Birth defects research. Part A, Clinical and molecular teratology.

[20]  T. Cresteil,et al.  Developmental expression of CYP2E1 in the human liver. Hypermethylation control of gene expression during the neonatal period. , 1996, European journal of biochemistry.

[21]  C. Perret,et al.  Fetal and maternal CYP2E1 genotypes and the risk of nonsyndromic oral clefts , 2007, American journal of medical genetics. Part A.

[22]  G. de Sousa,et al.  Tissue-specific expression and methylation of the human CYP2E1 gene. , 1994, Biochemical pharmacology.

[23]  R. Hen,et al.  Early-Life Blockade of the 5-HT Transporter Alters Emotional Behavior in Adult Mice , 2004, Science.

[24]  F. Champagne,et al.  Epigenetic Effects of Prenatal Stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and Fetal Brain , 2012, PloS one.

[25]  U. Wüllner,et al.  Genome-scale methylation analysis of Parkinson's disease patients' brains reveals DNA hypomethylation and increased mRNA expression of cytochrome P450 2E1 , 2012, neurogenetics.

[26]  M Farlow,et al.  A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group. , 1992, JAMA.

[27]  J. Seckl,et al.  Differential regulation of variant glucocorticoid receptor mRNAs in the rat hippocampus by the antidepressant fluoxetine. , 2004, Brain research. Molecular brain research.

[28]  C. De las Cuevas,et al.  Safety of selective serotonin reuptake inhibitors in pregnancy , 2007 .

[29]  L. Bertilsson,et al.  Severe adverse effects in a newborn with two defective CYP2D6 alleles after exposure to paroxetine during late pregnancy. , 2004, Therapeutic drug monitoring.

[30]  Kamil Kuca,et al.  Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease. , 2008, Current drug metabolism.

[31]  Takao K Hensch,et al.  Prenatal exposure to antidepressants and depressed maternal mood alter trajectory of infant speech perception , 2012, Proceedings of the National Academy of Sciences.

[32]  C. Lieber,et al.  Induction of cytochrome P450IIE1 in the obese overfed rat. , 1991, Molecular pharmacology.

[33]  H. Malm,et al.  Risks associated with in utero and lactation exposure to selective serotonin reuptake inhibitors (SSRIs). , 2010, Reproductive toxicology.

[34]  I. Hertz-Picciotto,et al.  Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay , 2014, Pediatrics.

[35]  A. P. Shaik,et al.  Meta-analysis study of glutathione-S-transferases (GSTM1, GSTP1, and GSTT1) gene polymorphisms and risk of acute myeloid leukemia , 2009, Leukemia & lymphoma.

[36]  F. A. Schroeder,et al.  Setdb1 Histone Methyltransferase Regulates Mood-Related Behaviors and Expression of the NMDA Receptor Subunit NR2B , 2010, The Journal of Neuroscience.

[37]  F. A. Schroeder,et al.  Antidepressant-Like Effects of the Histone Deacetylase Inhibitor, Sodium Butyrate, in the Mouse , 2007, Biological Psychiatry.

[38]  M. Forman,et al.  The effects of depression and use of antidepressive medicines during pregnancy on the methylation status of the IGF2 imprinted control regions in the offspring , 2011, Clinical Epigenetics.

[39]  Anthony P. Fejes,et al.  DNA methylation, genotype and gene expression: who is driving and who is along for the ride? , 2013, Genome Biology.

[40]  M. Ingelman-Sundberg,et al.  The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model. , 2009, Journal of hepatology.

[41]  C. Connor,et al.  Setdb 1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit , 2017 .

[42]  Yonghua Hu,et al.  Cytochrome P450 gene polymorphisms and risk of low birth weight , 2005, Genetic epidemiology.

[43]  Emma Y. Wu,et al.  Antidepressant Actions of Histone Deacetylase Inhibitors , 2009, The Journal of Neuroscience.

[44]  Lang Li,et al.  Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. , 2003, British journal of clinical pharmacology.

[45]  R. Duman,et al.  Chromatin Remodeling: A Novel Mechanism of Psychotropic Drug Action , 2006, Molecular Pharmacology.

[46]  J. Morrison,et al.  Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens , 2010, Nature Neuroscience.

[47]  R. Steer,et al.  Self-reported depression and negative pregnancy outcomes. , 1992, Journal of clinical epidemiology.

[48]  T. Field,et al.  CHRONIC PRENATAL DEPRESSION AND NEONATAL OUTCOME , 2008, The International journal of neuroscience.

[49]  E. Sellers,et al.  Inhibition by fluoxetine of cytochrome P450 2D6 activity , 1993, Clinical pharmacology and therapeutics.

[50]  Defeng Wu,et al.  Role of oxidative stress in alcohol-induced liver injury , 2009, Archives of Toxicology.

[51]  M. Smidt,et al.  Modulation of Serotonin Transporter Function during Fetal Development Causes Dilated Heart Cardiomyopathy and Lifelong Behavioral Abnormalities , 2008, PloS one.

[52]  Even chromatin gets the blues , 2006, Nature Neuroscience.

[53]  Z. Dong,et al.  Mechanism of induction of cytochrome P-450ac (P-450j) in chemically induced and spontaneously diabetic rats. , 1988, Archives of biochemistry and biophysics.

[54]  M. Ingelman-Sundberg,et al.  Structural and functional characterization of the 5'-flanking region of the rat and human cytochrome P450 2E1 genes: identification of a polymorphic repeat in the human gene. , 1999, Biochemical and biophysical research communications.

[55]  Satish Iyengar,et al.  A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. , 2010, Archives of general psychiatry.

[56]  Lucie Blais,et al.  First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. , 2007, Birth defects research. Part B, Developmental and reproductive toxicology.

[57]  P. Cau,et al.  Hypomethylation and hypoexpression of human CYP2E1 gene in lung tumors. , 1994, Biochemical and biophysical research communications.

[58]  J. Launay,et al.  MiR-16 Targets the Serotonin Transporter: A New Facet for Adaptive Responses to Antidepressants , 2010, Science.

[59]  C. Mulligan,et al.  Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight , 2012, Epigenetics.

[60]  T. Oberlander,et al.  Fetal Serotonin Reuptake Inhibitor Antidepressant Exposure: Maternal and Fetal Factors , 2012, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[61]  T. Field,et al.  Prenatal depression restricts fetal growth. , 2009, Early human development.

[62]  Richard Mayeux,et al.  Clinical practice. Early Alzheimer's disease. , 2010, The New England journal of medicine.

[63]  Takayoshi Suzuki,et al.  Epigenetic Status of Gdnf in the Ventral Striatum Determines Susceptibility and Adaptation to Daily Stressful Events , 2011, Neuron.

[64]  T. Field,et al.  Prenatal depression effects on the fetus and newborn: a review. , 2006, Infant behavior & development.

[65]  K. Doi,et al.  Effects of pregnancy on CYPs protein expression in rat liver. , 2005, Experimental and molecular pathology.

[66]  J. Zwiller,et al.  Fluoxetine and Cocaine Induce the Epigenetic Factors MeCP2 and MBD1 in Adult Rat Brain , 2006, Molecular Pharmacology.

[67]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[68]  V. Glover,et al.  Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? , 2007, Journal of child psychology and psychiatry, and allied disciplines.

[69]  M. Hamilton.  A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.

[70]  A. Boobis,et al.  Expression of CYP2E1 during human fetal development: methylation of the CYP2E1 gene in human fetal and adult liver samples. , 1992, Biochemical pharmacology.

[71]  F. Gonzalez,et al.  Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. , 2005, Mutation research.

[72]  B. H. Miller,et al.  Evaluating genetic markers and neurobiochemical analytes for fluoxetine response using a panel of mouse inbred strains , 2011, Psychopharmacology.

[73]  Y. Saijo,et al.  Adverse birth outcomes associated with maternal smoking and polymorphisms in the N-Nitrosamine-metabolizing enzyme genes NQO1 and CYP2E1. , 2007, American journal of epidemiology.

[74]  E. Nestler,et al.  Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action , 2006, Nature Neuroscience.

[75]  Claudia H. Kawas,et al.  Early Alzheimer's Disease , 2003 .

[76]  P. Svenningsson,et al.  Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression. , 2012, The international journal of neuropsychopharmacology.

[77]  R. Weksberg,et al.  WNT2 promoter methylation in human placenta is associated with low birthweight percentile in the neonate , 2011, Epigenetics.

[78]  C. Hertzman,et al.  Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population-based health data. , 2008, Birth defects research. Part B, Developmental and reproductive toxicology.

[79]  Alexandra M. Binder,et al.  Genome-wide DNA methylation in neonates exposed to maternal depression, anxiety, or SSRI medication during pregnancy , 2014, Epigenetics.

[80]  O. Maksymchuk,et al.  The impact of psychogenic stressors on oxidative stress markers and patterns of CYP2E1 expression in mice liver. , 2012, Pathophysiology : the official journal of the International Society for Pathophysiology.

[81]  Jeffrey T Leek,et al.  The optimal discovery procedure for large-scale significance testing, with applications to comparative microarray experiments. , 2007, Biostatistics.

[82]  M. Weissman,et al.  Children of depressed mothers 1 year after the initiation of maternal treatment: findings from the STAR*D-Child Study. , 2008, The American journal of psychiatry.

[83]  H. Eom,et al.  Glutathione-S-transferase genotypes influence the risk of chemotherapy-related toxicities and prognosis in Korean patients with diffuse large B-cell lymphoma. , 2010, Cancer genetics and cytogenetics.

[84]  C. Marsit,et al.  Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta , 2011, Epigenetics.