Prenatal antiepileptic exposure associates with neonatal DNA methylation differences

Smith, Alicia K.; Conneely, Karen N.; Newport, D. Jeffrey; Kilaru, Varun; Schroeder, James W.; Pennell, Page B.; Knight, Bettina T.; Cubells, Joseph; Stowe, Zachary N.; Brennan, Patricia A.

doi:10.4161/epi.19617

Cited by 46 publications

(36 citation statements)

References 34 publications

(40 reference statements)

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“…44 Only a single prior study has examined the association of a pharmaceutical agent during gestation with global DNA methylation, specifically examining the use of anti-epileptic drugs. 45 Using a measure of DNA methylation based on the average extent of methylation profiled on the Illumina Infinium 27K array platform, the authors identified a reduction in global methylation associated with maternal antiepileptic drug use during gestation; longer durations of exposures led to greater reductions in methylation, and a number of specific genes were targeted for altered methylation associated with antiepileptic exposures. 45 Within the SMARTT study of antiretroviral-exposed subjects, we identified a specific effect of atazanavir compared to other antiretroviral exposure on a reduction in AluYb8 methylation.…”

Section: Discussionmentioning

confidence: 99%

Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapyin utero

et al. 2015

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The use of combination antiretroviral therapy (cART) to prevent HIV mother-to-child transmission during pregnancy and delivery is generally considered safe. However, vigilant assessment of potential risks of these agents remains warranted. Epigenetic changes including DNA methylation are considered potential mechanisms linking the in utero environment with long-term health outcomes. Few studies have examined the epigenetic effects of prenatal exposure to pharmaceutical agents, including antiretroviral therapies, on children. In this study, we examined the methylation status of the LINE-1 and ALU-Yb8 repetitive elements as markers of global DNA methylation alteration in peripheral blood mononuclear cells obtained from newborns participating in the Pediatric HIV/AIDS Cohort Study SMARTT cohort of HIV-exposed, cART-exposed uninfected infants compared to a historical cohort of HIV-exposed, antiretroviral-unexposed infants from the Women and Infants Transmission Study Cohort. In linear regression models controlling for potential confounders, we found the adjusted mean difference of AluYb8 methylation of the cART-exposed compared to the -unexposed was -0.568 (95% CI: -1.023, -0.149) and for LINE-1 methylation was -1.359 (95% CI: -1.860, -0.857). Among those exposed to cART, subjects treated with atazanavir (ATV), compared to those on other treatments, had less AluYb8 methylation (-0.524, 95% CI: -0.025, -1.024). Overall, these results suggest a small but statistically significant reduction in the methylation of these repetitive elements in an HIV-exposed, cART-exposed cohort compared to an HIV-exposed, cART-unexposed historic cohort. The potential long-term implications of these differences are worthy of further examination.

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Section: Discussionmentioning

confidence: 99%

Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapyin utero

et al. 2015

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“…The primary predictor in the current study was SRI DrugWeeks (i.e., number of SRI medications X number of weeks taken, standardized to 40 weeks gestation). DrugWeeks of exposure to other medication classes were tested as potential confounds using the same approach (number of drugs in a given class X number of weeks exposed, standardized to 40 weeks gestation) 29 .…”

Section: Methodsmentioning

confidence: 99%

Preschool Outcomes Following Prenatal Serotonin Reuptake Inhibitor Exposure

Johnson

Smith

Stowe

et al. 2016

J. Clin. Psychiatry

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OBJECTIVE To test the hypothesis that prenatal exposure to serotonin reuptake inhibitors (SRIs) would be associated with language and behavioral outcomes in preschool-aged children, while accounting for confounds such as concomitant exposures and maternal mental illness. METHOD An observational, prospective, longitudinal study of mental illness in pregnancy was conducted at a university-based women’s mental health clinic (April 2010–November 2012). A sample of 178 mother-child dyads participated in a laboratory visit at preschool age (2.5–5.5 years). The majority of women (93%) received psychotropic medication during pregnancy. Psychiatric status (based on DSM-IV), other medication use and substance use were serially assessed and tested as confounds. Primary outcome measures included standardized measures of expressive language and cognitive function, and mother and alternate caregiver ratings of child behavior problems, including a Persavive Developmental Disorders (PDD) subscale. RESULTS Linear regression analyses revealed that, after controlling for relevant covariates, expressive language scores from the Test of Early Language Development-3rd edition were negatively associated with prenatal SRI exposure (β=−0.15, t=−2.41), while the PDD behavioral problems subscales completed by alternate caregivers and mothers were positively associated with prenatal SRI exposure (β=0.17, t=2.01; β=0.16, t=2.00). Cognitive function, measured using the Differential Ability Scales-2nd edition, was not associated with any medication exposures. CONCLUSION The current data suggest a small but significant association between prenatal SRI exposure and preschool outcomes, including expressive language and behavior problems. These data corroborate data from recent, population-based studies; though overall, published findings are mixed. Replication and identification of moderating risk factors are needed to understand potential clinical implications.

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“…This promising area of research has been providing insight into biological mechanisms through which gene expression varies in response to the environment [35]. For example, exposure to antiepileptic medications can promote widespread changes in DNA methylation as well as other epigenetic modifications [36–39]. In addition to medication exposure, preclinical research using animal models and clinical research with human subjects [40–42] supports the hypothesis that exposure to early life stressors may result in DNA methylation changes in the glucocorticoid receptor ( NR3C1 ), a hormone-activated factor that mediates many of the downstream effects of the stress hormone cortisol.…”

Section: Genetic and Epigenetic Biomarkersmentioning

confidence: 99%

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Enaw

Smith

2013

J Neurol Psychol

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Biomarkers are biological measures that are indicative of a specific disorder, its severity or response to treatment. They are widely used in many areas of medicine, but biomarker development for brain-based disorders lags behind. Using examples from the field of psychiatry, this article reviews the concepts of biomarkers, challenges to their development and the recent progress along those lines. In addition to discussing historical biomarker candidates such as cortisol or catecholamine levels, we include progress from recent genetic, epigenetic, proteomic, neuroimaging and EEG studies. Successful identification of biomarkers will advance the field of psychiatry towards the goal of biological tests for diagnosis, symptom management and treatment response.

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Prenatal antiepileptic exposure associates with neonatal DNA methylation differences

Cited by 46 publications

References 34 publications

Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapyin utero

Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapyin utero

Preschool Outcomes Following Prenatal Serotonin Reuptake Inhibitor Exposure

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