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1.  The contributions of Maternal Sensitivity and Maternal Depressive Symptoms to Epigenetic Processes and Neuroendocrine Functioning 
Child development  2016;87(1):73-85.
This study tested whether maternal responsiveness may buffer the child to the effects of maternal depressive symptoms on DNA methylation of NR3C1, 11β-HSD2, and neuroendocrine functioning. DNA was derived from buccal epithelial cells and pre-stress cortisol was obtained from the saliva of 128 infants. Mothers with depressive symptoms who were more responsive and who engaged in more appropriate touch during face-to-face play had infants with less DNA methylation of NR3C1 and 11β-HSD2 compared to mothers with depressive symptoms who were also insensitive. The combination of exposure to maternal depressive symptoms and maternal sensitivity was related to the highest pre-stress cortisol levels whereas exposure to maternal depressive symptoms and maternal insensitivity was related to the lowest pre-stress cortisol levels.
doi:10.1111/cdev.12483
PMCID: PMC4733872  PMID: 26822444
2.  Epigenetic Regulation of Placental NR3C1: Mechanism Underlying Prenatal Programming of Infant Neurobehavior by Maternal Smoking? 
Child development  2016;87(1):49-60.
Epigenetic regulation of the placental glucocorticoid receptor gene (NR3C1) was investigated as a mechanism underlying links between maternal smoking during pregnancy (MSDP) and infant neurobehavior in 45 mother-infant pairs (49% MSDP-exposed; 52% minorities; ages 18-35). The NICU Network Neurobehavioral Scale was administered 7 times over the first postnatal month; methylation of placental NR3C1 was assessed via bisulfite pyrosequencing. Increased placental NR3C1 methylation was associated with increased infant attention and self-regulation, and decreased lethargy and need for examiner soothing over the first postnatal month. A causal steps approach revealed that NR3C1 methylation and MSDP were independently associated with lethargic behavior. Although preliminary, results highlight the importance of epigenetic mechanisms in elucidating pathways to neurobehavioral alterations from MSDP.
doi:10.1111/cdev.12482
PMCID: PMC4808519  PMID: 26822442
3.  Global motion perception is independent from contrast sensitivity for coherent motion direction discrimination and visual acuity in 4.5-year-old children 
Vision research  2015;115(0 0):83-91.
Global motion processing depends on a network of brain regions that includes extrastriate area V5 in the dorsal visual stream. For this reason, psychophysical measures of global motion perception have been used to provide a behavioural measure of dorsal stream function. This approach assumes that global motion is relatively independent of visual functions that arise earlier in the visual processing hierarchy such as contrast sensitivity and visual acuity. We tested this assumption by assessing the relationships between global motion perception, contrast sensitivity for coherent motion direction discrimination (henceforth referred to as contrast sensitivity) and habitual visual acuity in a large group of 4.5-year-old children (n = 117). The children were born at risk of abnormal neurodevelopment because of prenatal drug exposure or risk factors for neonatal hypoglycaemia. Motion coherence thresholds, a measure of global motion perception, were assessed using random dot kinematograms. The contrast of the stimuli was fixed at 100% and coherence was varied. Contrast sensitivity was measured using the same stimuli by fixing motion coherence at 100% and varying dot contrast. Stereoacuity was also measured. Motion coherence thresholds were not correlated with contrast sensitivity or visual acuity. However, lower (better) motion coherence thresholds were correlated with finer stereoacuity (rho=0.38, p=0.004). Contrast sensitivity and visual acuity were also correlated (rho= −0.26, p=0.004) with each other. These results indicate that global motion perception for high contrast stimuli is independent of contrast sensitivity and visual acuity and can be used to assess motion integration mechanisms in children.
doi:10.1016/j.visres.2015.08.007
PMCID: PMC4587337  PMID: 26318529
Visual development; extrastriate visual cortex; preschool vision assessment; at risk infant
4.  Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment 
Epigenomics  2015;7(5):767-779.
Aim
To determine associations between methylation of NR3C1, HSD11B2, FKBP5 and ADCYAP1R1 and newborn neurobehavioral outcomes.
Methods
In 537 newborns, placental methylation was quantified using bisulfite pyrosequencing. Profiles of neurobehavior were derived via the Neonatal Intensive Care Unit Network Neurobehavioral Scales. Using exploratory factor analysis, the relationships between methylation factor scores and neurobehavioral profiles were examined.
Results
Increased scores of the factor characterized by NR3C1 methylation were associated with membership in a reactive, poorly regulated profile (odds ratio: 1.47; 95% CI: 1.00–2.18), while increased scores of the factor characterized by HSD11B2 methylation reduced this risk.
Conclusion
These results suggest that coordinated regulation of these genes influences neurobehavior and demonstrates the importance of examining these alterations in a harmonized fashion.
doi:10.2217/epi.15.28
PMCID: PMC4772971  PMID: 26343289
ADCYAP1R1; fetal basis of adult disease; FKBP5; glucocorticoids; HSD11B2; neurobehavior; NR3C1; placenta
5.  Developmental and behavioral consequences of prenatal methamphetamine exposure: a review of the Infant Development, Environment, and Lifestyle (IDEAL) Study 
This study reviews the findings from the Infant Development, Environment, and Lifestyle Study (IDEAL), a multisite, longitudinal, prospective study designed to determine maternal outcome and child growth and developmental findings following prenatal methamphetamine exposure from birth up to age 7.5 years. These findings are presented in the context of the home environment and caregiver characteristics to determine how the drug and the environment interact to affect the outcome of these children. No neonatal abstinence syndrome requiring pharmacologic intervention was observed but heavy drug exposure was associated with increased stress responses in the neonatal period. Poorer inhibitory control was also observed in heavy methamphetamine exposed children placing them at high risk for impaired executive function. Independent of methamphetamine exposure, children with more responsive home environments to developmental and emotional needs demonstrated lower risks for internalizing and externalizing behavior.
doi:10.1016/j.ntt.2015.07.006
PMCID: PMC4668928  PMID: 26212684
6.  Transactional relations between caregiving stress, executive functioning, and problem behavior from early childhood to early adolescence 
Development and psychopathology  2016;28(3):743-756.
Developmental psychopathologists face the difficult task of identifying the environmental conditions that may contribute to early childhood behavior problems. Highly stressed caregivers can exacerbate behavior problems, while children with behavior problems may make parenting more difficult and increase caregiver stress. Unknown is: (1) how these transactions originate, (2) whether they persist over time to contribute to the development of problem behavior and (3) what role resilience factors, such as child executive functioning, may play in mitigating the development of problem behavior. In the present study, transactional relations between caregiving stress, executive functioning, and behavior problems were examined in a sample of 1,388 children with prenatal drug exposures at three developmental time points: early childhood (birth-age 5), middle childhood (ages 6 to 9), and early adolescence (ages 10 to 13). Transactional relations differed between caregiving stress and internalizing versus externalizing behavior. Targeting executive functioning in evidence-based interventions for children with prenatal substance exposure who present with internalizing problems and treating caregiving psychopathology, depression, and parenting stress in early childhood may be particularly important for children presenting with internalizing behavior.
doi:10.1017/S0954579416000286
PMCID: PMC4955944  PMID: 27427803
7.  Expression of imprinted genes in placenta is associated with infant neurobehavioral development 
Epigenetics  2015;10(9):834-841.
Genomic imprinting disorders often exhibit delayed neurobehavioral development, suggesting this unique mechanism of epigenetic regulation plays a role in mental and neurological health. While major errors in imprinting have been linked to adverse health outcomes, there has been little research conducted on how moderate variability in imprinted gene expression within a population contributes to differences in neurobehavioral outcomes, particularly at birth. Here, we profiled the expression of 108 known and putative imprinted genes in human placenta samples from 615 infants assessed by the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). Data reduction identified 10 genes (DLX5, DHCR24, VTRNA2-1, PHLDA2, NPAP1, FAM50B, GNAS-AS1, PAX8-AS1, SHANK2, and COPG2IT1) whose expression could distinguish between newborn neurobehavioral profiles derived from the NNNS. Clustering infants based on the expression pattern of these genes identified 2 groups of infants characterized by reduced quality of movement, increased signs of asymmetrical and non-optimal reflexes, and increased odds of demonstrating increased signs of physiologic stress and abstinence. Overall, these results suggest that common variation in placental imprinted gene expression is linked to suboptimal performance on scales of neurological functioning as well as with increased signs of physiologic stress, highlighting the central importance of the control of expression of these genes in the placenta for neurobehavioral development.
doi:10.1080/15592294.2015.1073880
PMCID: PMC4623032  PMID: 26198301
developmental origins of health and disease; Epigenetics; imprinting; neurodevelopment; placenta
8.  A Flexible Analysis Tool for the Quantitative Acoustic Assessment of Infant Cry 
Purpose
In this article, the authors describe and validate the performance of a modern acoustic analyzer specifically designed for infant cry analysis.
Method
Utilizing known algorithms, the authors developed a method to extract acoustic parameters describing infant cries from standard digital audio files. They used a frame rate of 25 ms with a frame advance of 12.5 ms. Cepstral-based acoustic analysis proceeded in 2 phases, computing frame-level data and then organizing and summarizing this information within cry utterances. Using signal detection methods, the authors evaluated the accuracy of the automated system to determine voicing and to detect fundamental frequency (F0) as compared to voiced segments and pitch periods manually coded from spectrogram displays.
Results
The system detected F0 with 88% to 95% accuracy, depending on tolerances set at 10 to 20 Hz. Receiver operating characteristic analyses demonstrated very high accuracy at detecting voicing characteristics in the cry samples.
Conclusions
This article describes an automated infant cry analyzer with high accuracy to detect important acoustic features of cry. A unique and important aspect of this work is the rigorous testing of the system’s accuracy as compared to ground-truth manual coding. The resulting system has implications for basic and applied research on infant cry development.
doi:10.1044/1092-4388(2013/11-0298)
PMCID: PMC4956095  PMID: 23785178
cry; acoustics; analysis; infants; developmental disorders
9.  Early caregiving stress exposure moderates the relation between respiratory sinus arrhythmia reactivity at 1 month and biobehavioral outcomes at age 3 
Psychophysiology  2016;53(1):83-96.
There is a growing scientific interest in the psychophysiological functioning of children living in low-socioeconomic status (SES) contexts, though this research is complicated by knowledge that physiology–behavior relations often operate differently in these environments among adults. Importantly, such research is made more difficult because SES may be a proxy for a wide range of risk factors including poor caregiving and exposure to parental substance use. We used factor analysis to organize risk-exposure data collected from 827 children—many of whom were raised in low-SES contexts and exposed to substances prenatally—into dissociable components including economic stress, caregiving stress (e.g., stress the caregiver may experience, including parental psychopathology), and postnatal substance exposure. These factors, along with respiratory sinus arrhythmia (RSA) reactivity at age 1 month, were used to predict behavior dysregulation and resting RSA at age 3 years. A significant RSA Reactivity × Caregiving Stress interaction indicated that infants who exhibited high RSA reactivity at 1 month experienced the greatest behavior dysregulation at 3 years, but only when they were exposed to high levels of caregiving stress. Among African Americans, the highest resting RSA at 3 years was found in infants with less RSA reactivity, but only if they also experienced less caregiving stress. Our work is consistent with biological sensitivity to context, adaptive calibration, and allostatic load models, and highlights the importance of studying Physiology × Environment interactions in low-SES contexts for predicting behavior and resting RSA.
doi:10.1111/psyp.12569
PMCID: PMC4944757  PMID: 26681620
Individual differences; Infants/children; Heart rate
10.  Introduction to the Special Section on Epigenetics 
Child development  2016;87(1):29-37.
Epigenetics provides the opportunity to revolutionize our understanding of the role of genetics and the environment in explaining human behavior, although the use of epigenetics to study human behavior is just beginning. In this introduction, the authors present the basics of epigenetics in a way that is designed to make this exciting field accessible to a wide readership. The authors describe the history of human behavioral epigenetic research in the context of other disciplines and graphically illustrate the burgeoning of research in the application of epigenetic methods and principles to the study of human behavior. The role of epigenetics in normal embryonic development and the influence of biological and environmental factors altering behavior through epigenetic mechanisms and developmental programming are discussed. Some basic approaches to the study of epigenetics are reviewed. The authors conclude with a discussion of challenges and opportunities, including intervention, as the field of human behavioral epigenetics continue to grow.
doi:10.1111/cdev.12489
PMCID: PMC4943839  PMID: 26822440
11.  Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapy in utero 
Epigenetics  2015;10(8):708-716.
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.
doi:10.1080/15592294.2015.1060389
PMCID: PMC4622750  PMID: 26067216
anti-retroviral; atazanavir; developmental origins; DNA methylation; HIV; newborn; pediatrics; pharmaceuticals; prenatal; repetitive elements
12.  Examining the joint contribution of placental NR3C1 and HSD11B2 methylation for infant neurobehavior 
Psychoneuroendocrinology  2014;52:32-42.
Infant neurobehavior, a potential sentinel of future mental and behavioral morbidity characterized in part by reflex symmetry, excitability and habituation to stimuli, is influenced by aspects of the intrauterine environment partially through epigenetic alterations of genes involved in the stress response. DNA methylation of two related cortisol response genes, the glucocorticoid receptor (NR3C1), a nuclear receptor to which cortisol binds, and 11-beta hydroxysteroid dehydrogenase (HSD11B2), the enzyme responsible for conversion of cortisol into inactive cortisone, independently associate with infant neurobehavior. Although these factors are part of a common cortisol regulation pathway, the combined effect of DNA methylation of these factors on infant neurobehavior has not been characterized. Therefore, we conducted an examination of the joint contribution of NR3C1 and HSD11B2 DNA methylation on infant neurobehavior. Among 372 healthy term newborns, we tested the interaction between placental NR3C1 and HSD11B2 DNA methylation in association with neurobehavior as assessed with the validated NICU Network Neurobehavioral Scales. Controlling for confounders, interactions between DNA methylation of these genes were detected for distinct domains of neurobehavior (habituation, excitability, asymmetrical reflexes). Moreover, different patterns of DNA methylation across the cortisol regulation pathway associated with different neurobehavioral phenotypes. Those with low NR3C1 methylation but high HSD11B2 methylation had lower excitability scores; those with high NR3C1 methylation but low HSD11B2 methylation had more asymmetrical reflexes; those with high DNA methylation across the entire pathway had higher habituation scores. These results suggest that epigenetic alterations across the cortisol regulation pathway may contribute to different neurobehavioral phenotypes, likely though varying degrees of glucocorticoid exposure during gestation. While the postnatal environment may continue to affect neurobehavioral risk, this study provides novel insights into the molecular basis for fetal origins of mental conditions.
doi:10.1016/j.psyneuen.2014.11.004
PMCID: PMC4350656  PMID: 25459891
NR3C1; HSD11B2; DNA methylation; epigenetic; placenta; infant; neurobehavior; developmental origins of health and disease
13.  Methylation of the Glucocorticoid Receptor (NR3C1) in Placenta Is Associated with Infant Cry Acoustics 
Epigenetic mechanisms regulating expression of the glucocorticoid receptor gene (NR3C1) promoter may influence behavioral and biological aspects of stress response in human infants. Acoustic features of infant crying are an indicator of neurobehavioral and neurological status not yet investigated in relation to epigenetic mechanisms. We examined NR3C1 methylation in placental tissue from a series of 120 healthy newborn infants in relation to a detailed set of acoustic features extracted from newborn infant cries. We identified significant associations of NR3C1 methylation with energy variation in infants' cries as well as with the presence of very high fundamental frequency in cry utterances. The presence of high fundamental frequency in cry (above 1 kHz) has been linked to poor vocal tract control, poor regulation of stress response, and may be an indicator or poor neurobehavioral integrity. Thus, these results add to evidence linking epigenetic alteration of the NR3C1 gene in the placenta to neurodevelopmental features in infants.
doi:10.3389/fnbeh.2016.00100
PMCID: PMC4889592  PMID: 27313516
infancy; human; placenta; epigenetic; neurodevelopment; cry; acoustics
14.  Prenatal Stress, Fearfulness, and the Epigenome: Exploratory Analysis of Sex Differences in DNA Methylation of the Glucocorticoid Receptor Gene 
Exposure to stress in utero is a risk factor for the development of problem behavior in the offspring, though precise pathways are unknown. We examined whether DNA methylation of the glucocorticoid receptor gene, NR3C1, was associated with experiences of stress by an expectant mother and fearfulness in her infant. Mothers reported on prenatal stress and infant temperament when infants were 5 months old (n = 68). Buccal cells for methylation analysis were collected from each infant. Prenatal stress was not related to infant fearfulness or NR3C1 methylation in the sample as a whole. Exploratory sex-specific analysis revealed a trend-level association between prenatal stress and increased methylation of NR3C1 exon 1F for female, but not male, infants. In addition, increased methylation was significantly associated with greater fearfulness for females. Results suggest an experience-dependent pathway to fearfulness for female infants via epigenetic modification of the glucocorticoid receptor gene. Future studies should examine prenatal stress in a comprehensive fashion while considering sex differences in epigenetic processes underlying infant temperament.
doi:10.3389/fnbeh.2016.00147
PMCID: PMC4940423  PMID: 27462209
DNA methylation; fearfulness; prenatal stress; sex differences; glucocorticoid receptor gene; temperament
15.  Prenatal exposure to recreational drugs affects global motion perception in preschool children 
Scientific Reports  2015;5:16921.
Prenatal exposure to recreational drugs impairs motor and cognitive development; however it is currently unknown whether visual brain areas are affected. To address this question, we investigated the effect of prenatal drug exposure on global motion perception, a behavioural measure of processing within the dorsal extrastriate visual cortex that is thought to be particularly vulnerable to abnormal neurodevelopment. Global motion perception was measured in one hundred and forty-five 4.5-year-old children who had been exposed to different combinations of methamphetamine, alcohol, nicotine and marijuana prior to birth and 25 unexposed children. Self-reported drug use by the mothers was verified by meconium analysis. We found that global motion perception was impaired by prenatal exposure to alcohol and improved significantly by exposure to marijuana. Exposure to both drugs prenatally had no effect. Other visual functions such as habitual visual acuity and stereoacuity were not affected by drug exposure. Prenatal exposure to methamphetamine did not influence visual function. Our results demonstrate that prenatal drug exposure can influence a behavioural measure of visual development, but that the effects are dependent on the specific drugs used during pregnancy.
doi:10.1038/srep16921
PMCID: PMC4652269  PMID: 26581958
16.  Cortisol Reactivity to Social Stress as a Mediator of Early Adversity on Risk and Adaptive Outcomes 
Child development  2014;85(6):2279-2298.
Children chronically exposed to stress early in life are at increased risk for maladaptive outcomes, though the physiological mechanisms driving these effects are unknown. Cortisol reactivity was tested as a mediator of the relation between prenatal substance exposure and/or early adversity on adaptive and maladaptive outcomes. Data were drawn from a prospective longitudinal study of prenatal substance exposure (N = 860). Cortisol reactivity was assessed at age 11. Among African-Americans, prenatal substance exposure exerted an indirect effect through early adversity and cortisol reactivity to predict externalizing behavior, delinquency, and a positive student-teacher relationship at age 11. Decreased cortisol reactivity was related to maladaptive outcomes, and increased cortisol reactivity predicted better executive functioning and a more positive student-teacher relationship.
doi:10.1111/cdev.12316
PMCID: PMC4236260  PMID: 25376131
Prenatal Substance Exposure; Early Adversity; cortisol; problem behavior; delinquency
17.  Cross-national comparison of prenatal methamphetamine exposure on infant and early child physical growth: A natural experiment 
The current study seeks to compare the effects of prenatal methamphetamine exposure (PME) on infant and child physical growth between the United States (US) and New Zealand (NZ). This cross-national comparison provides a unique opportunity to examine the potential impact of services provided to drug using mothers on child health.
Methods
The longitudinal Infant Development, Environment and Lifestyle (IDEAL) study of PME from birth to 36 months was conducted in the US and NZ. The US cohort included 204 children with PME and 212 non-PME matched comparisons (NPME); the NZ cohort included 108 children with PME and 115 NPME matched comparisons. Latent growth curve models were used to examine effects of PME, country of origin, and the country × PME interaction on growth in length/height and weight.
Results
In regard to length/height, PME and country of origin were associated with initial length and growth over time. There was also a significant interaction effect, such that children with PME in the US were shorter at birth than children with PME in NZ after controlling for other prenatal exposures, infant set, socioeconomic status, and maternal height. In regard to weight, there was only an effect of country of origin.
Conclusions
Effects of PME on infant and child growth were shown to differ across countries, with exposed children in NZ faring better than exposed children in the US. Implications for prevention programs and public policy are discussed.
doi:10.1007/s11121-013-0431-5
PMCID: PMC3947752  PMID: 23943149
prenatal methamphetamine exposure; length/height; weight; cross-national research
18.  Maternal smoking during pregnancy and infant stress response: Test of a prenatal programming hypothesis 
Psychoneuroendocrinology  2014;48:29-40.
Background
Maternal smoking during pregnancy (MSDP) is associated with early and long-term neurobehavioral deficits; however mechanisms remain unknown. We tested the hypothesis that MSDP programs the hypothalamic pituitary adrenocortical (HPA) axis of the offspring leading to adverse outcomes. In an intensive, prospective study, we investigated associations between MSDP and infant cortisol stress response and explored whether alterations in cortisol response were mediated by epigenetic modulation of the placental glucocorticoid receptor gene (NR3C1).
Methods
Participants were 100 healthy mother-infant pairs (53% MSDP-exposed; 42% female) from a low income, racially/ethnically diverse sample (55% minorities). MSDP was assessed by timeline followback interview verified by saliva and meconium cotinine. Infant cortisol responses to a neurobehavioral exam were assessed 7 times over the first postnatal month. Methylation of placental NR3C1 promoter exon 1F was assessed using bisulfite pyrosequencing in a subsample (n=45).
Results
MSDP-exposed infants showed significantly and persistently attenuated basal and reactive cortisol levels over the first postnatal month vs. unexposed infants. Exploratory analyses revealed that MSDP was associated with altered methylation of the placental NR3C1 promoter; degree of methylation of the placental NR3C1 was associated with infant basal and reactive cortisol over the first postnatal month and mediated effects of MSDP on infant basal cortisol.
Conclusions
Results provide initial support for our hypothesis that MSDP programs offspring HPA (dys) regulation. Epigenetic regulation of placental GR may serve as a novel underlying mechanism. Results may have implications for delineating pathways to adverse outcomes from MSDP.
doi:10.1016/j.psyneuen.2014.05.017
PMCID: PMC4136384  PMID: 24999830
Smoking; tobacco; pregnancy; infant; cortisol; stress; epigenetic; fetal; programming; methylation; glucocorticoid receptor (GR); placenta; NR3C1
19.  Epigenetic Variation in the Mu-opioid Receptor Gene in Infants with Neonatal Abstinence Syndrome 
The Journal of pediatrics  2014;165(3):472-478.
Objective
Neonatal abstinence syndrome (NAS) from in utero opioid exposure is highly variable with genetic factors appearing to play an important role. Epigenetic changes in cytosine:guanine (CpG) dinucleotide methylation can occur after drug exposure and may help to explain NAS variability. We correlated DNA methylation levels in the mu-opioid receptor (OPRM1) promoter in opioid-exposed infants and correlate them with NAS outcomes.
Study design
DNA samples from cord blood or saliva were analyzed for 86 infants being treated for NAS according to institutional protocol. Methylation levels at 16 OPRM1 CpG sites were determined and correlated with NAS outcome measures, including need for treatment, treatment with >2 medications, and length of hospital stay. We adjusted for co-variates and multiple genetic testing.
Results
Sixty-five percent of infants required treatment for NAS, and 24% required ≥2 medications. Hypermethylation of the OPRM1 promoter was measured at the −10 CpG in treated versus non-treated infants [adjusted difference δ=3.2% (95% CI 0.3–6.0%), p=0.03; NS after multiple testing correction]. There was hypermethylation at the −14 [δ=4.9% (95% CI 1.8–8.1%), p=0.003], −10 [δ=5.0% (95% CI 2.3–7.7%), p=0.0005)], and +84 [δ=3.5% (95% CI 0.6 – 6.4), p=0.02] CpG sites in infants requiring ≥2 medications which remained significant for −14 and −10 after multiple testing correction.
Conclusions
Increased methylation within the OPRM1 promoter is associated with worse NAS outcomes, consistent with gene silencing.
doi:10.1016/j.jpeds.2014.05.040
PMCID: PMC4145036  PMID: 24996986
DNA methylation; NAS; opioids; genetics; OPRM1
20.  Risk for Neurobehavioral Disinhibition in Prenatal Methamphetamine-Exposed Young Children with Positive Hair Toxicology Results 
Therapeutic drug monitoring  2014;36(4):535-543.
Background
The objective was to evaluate effects of prenatal methamphetamine exposure (PME) and postnatal drug exposures identified by child hair analysis on neurobehavioral disinhibition at 6.5 years of age.
Methods
Mother-infant pairs were enrolled in the Infant Development, Environment, and Lifestyle (IDEAL) Study in Los Angeles, Honolulu, Tulsa and Des Moines. PME was determined by maternal self-report and/or positive meconium results. At the 6.5-year follow-up visit, hair was collected and analyzed for methamphetamine, tobacco, cocaine, and cannabinoid markers. Child behavioral and executive function test scores were aggregated to evaluate child neurobehavioral disinhibition. Hierarchical linear regression models assessed the impact of PME, postnatal substances, and combined PME with postnatal drug exposures on the child’s neurobehavioral disinhibition aggregate score. Past year caregiver substance use was compared to child hair results.
Results
A total of 264 children were evaluated. Significantly more PME children (n=133) had hair positive for methamphetamine/amphetamine (27.1% versus 8.4%) and nicotine/cotinine (38.3% versus 25.2%) than children without PME (n=131). Overall, no significant differences in analyte hair concentrations were noted between groups. Significant differences in behavioral and executive function were observed between children with and without PME. No independent effects of postnatal methamphetamine or tobacco exposure, identified by positive hair test, were noted and no additional neurobehavioral disinhibition was observed in PME children with postnatal drug exposures, as compared to PME children without postnatal exposure.
Conclusions
Child hair testing offered a non-invasive means to evaluate postnatal environmental drug exposure, although no effects from postnatal drug exposure alone were seen. PME, alone and in combination with postnatal drug exposures, was associated with behavioral and executive function deficits at 6.5 years.
doi:10.1097/FTD.0000000000000049
PMCID: PMC4101149  PMID: 24518561
methamphetamine; hair; children; prenatal drug exposure; toxicology
21.  Physiological Correlates of Neurobehavioral Disinhibition that Relate to Drug Use and Risky Sexual Behavior in Adolescents with Prenatal Substance Exposure 
Developmental neuroscience  2014;36(0):306-315.
Physiological correlates of behavioral and emotional problems, substance use onset and initiation of risky sexual behavior have not been studied in adolescents with prenatal drug exposure. We studied the concordance between baseline respiratory sinus arrhythmia (RSA) at age 3 and baseline Cortisol levels at age 11. We hypothesized that children who showed concordance between RSA and Cortisol would have lower neurobehavioral disinhibition scores which would in turn predict age of substance use onset and first sexual intercourse. The sample included 860 children aged 16 years participating in the Maternal Lifestyle Study, a multisite longitudinal study of children with prenatal exposure to cocaine and other substances. Structural equation modeling was used to test pathways between prenatal substance exposure, early adversity, baseline RSA, baseline Cortisol, neurobehavioral disinhibition, drug use, and sexual behavior outcomes. Concordance was studied by examining separate male and female models in which there were statistically significant interactions between baseline RSA and Cortisol. Prenatal substance exposure was operationalized as the number of substances to which the child was exposed. An adversity score was computed based on caregiver postnatal substance use, depression and psychological distress, number of caregiver changes, socioeconomic and poverty status, quality of the home environment, and child history of protective service involvement, abuse and neglect. RSA and Cortisol were measured during a baseline period prior to the beginning of a task. Neurobehavioral disinhibition, based on composite scores of behavioral dysregulation and executive dysfunction, substance use and sexual behavior were derived from questionnaires and cognitive tests administered to the child. Findings were sex specific. In females, those with discordance between RSA and Cortisol (high RSA and low Cortisol or low RSA and high Cortisol) had the most executive dysfunction which, in turn, predicted earlier initiation of alcohol by age 16. Among boys, there also existed a significant baseline RSA by baseline Cortisol interaction. Boys with low baseline RSA and high baseline Cortisol had the highest levels of behavioral dysregulation. This increase in behavioral dysregulation was in turn related to initiation of alcohol use by age 16 and lower age of first sexual intercourse. We found sex-specific pathways to the initiation of alcohol use and risky sexual behavior through the combined activity of parasympathetic and neuroendocrine functioning. The study of multiple physiological systems may suggest new pathways to the study of age of onset of substance use and engagement in risky sexual behavior in adolescents.
doi:10.1159/000365004
PMCID: PMC4476628  PMID: 25033835
Cortisol; Heart rate variability; Adversity; Sex differences; Teenage substance use onset; Behavioral problems; Executive function
22.  Structural Brain Imaging in Children and Adolescents Following Prenatal Cocaine Exposure 
Developmental neuroscience  2014;36(0):316-328.
Brain morphometry of 21 children, who were followed from birth and underwent structural brain magnetic resonance imaging (MRI) at 8–10 years, were studied. This cohort included 11 children with prenatal cocaine exposure (CE) and 10 non-cocaine exposed children (NCE). We compared the CE versus NCE groups using FreeSurfer to automatically segment and quantify the volume of individual brain structures. In addition, we created a pediatric atlas specifically for this population and demonstrate the enhanced accuracy of this approach. We found an overall trend towards smaller brain volumes among CE children. The volume differences were significant for cortical gray matter, thalamus and putamen. Here, reductions in thalamic and putaminal volumes showed a robust inverse-correlation with exposure levels, thus highlighting effects on dopamine rich brain regions that form key components of brain circuitry known to play important roles in behavior and attention. Interestingly, head circumferences (HCs) at birth as well as at the time of imaging showed a tendency for smaller size among CE children. HCs at the time of imaging correlated well with the cortical volumes, for all subjects. In contrast, HCs at birth were predictive of the cortical volume only for the CE group.
A subgroup of these subjects (6 CE and 4 NCE) was also scanned at 13–15 years old. In subjects who were scanned twice, we found that the trend for smaller structures continues into 13–15 years of age. We found that the differences in structural volumes between CE and NCE groups are largely diminished when the HCs are matched by study design or controlled for. Participants in this study were drawn from a unique longitudinal cohort, and while the small sample size precludes strong conclusions, the results point to reductions in HCs and in specific brain structures that persist through teenage years in children who were exposed to cocaine in utero.
doi:10.1159/000362685
PMCID: PMC4125447  PMID: 24994509
structural brain imaging; prenatal cocaine exposure; Developing brain; Magnetic resonance imaging; Prenatal cocaine
23.  Placental DNA Methylation Related to Both Infant Toenail Mercury and Adverse Neurobehavioral Outcomes 
Environmental Health Perspectives  2015;123(7):723-729.
Background
Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. Because Hg can interfere with placental functioning and cross the placenta to target the fetal brain, prenatal Hg exposure can inhibit fetal growth and development directly and indirectly.
Objectives
We examined potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes.
Methods
The methylation status of > 485,000 CpG loci was interrogated in 192 placental samples using Illumina’s Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU Network Neurobehavioral Scales (NNNS) in an independent subset of 151 infants.
Results
We identified 339 loci with an average methylation difference > 0.125 between any two toenail Hg tertiles. Variation among these loci was subsequently found to be associated with a high-risk neurodevelopmental profile (omnibus p-value = 0.007) characterized by the NNNS. Ten loci had p < 0.01 for the association between methylation and the high-risk NNNS profile. Six of 10 loci reside in the EMID2 gene and were hypomethylated in the 16 high-risk profile infants’ placentas. Methylation at these loci was moderately correlated (correlation coefficients range, –0.33 to –0.45) with EMID2 expression.
Conclusions
EMID2 hypomethylation may represent a novel mechanism linking in utero Hg exposure and adverse infant neurobehavioral outcomes.
Citation
Maccani JZ, Koestler DC, Lester B, Houseman EA, Armstrong DA, Kelsey KT, Marsit CJ. 2015. Placental DNA methylation related to both infant toenail mercury and adverse neurobehavioral outcomes. Environ Health Perspect 123:723–729; http://dx.doi.org/10.1289/ehp.1408561
doi:10.1289/ehp.1408561
PMCID: PMC4492267  PMID: 25748564
24.  Regional Brain Morphometry and Impulsivity in Adolescents Following Prenatal Exposure to Cocaine and Tobacco 
JAMA pediatrics  2013;167(4):348-354.
Importance
Animal studies have suggested that prenatal cocaine exposure (PCE) deleteriously influences the developing nervous system, in part attributable to its site of action in blocking the function of monoamine reuptake transporters, increasing synaptic levels of serotonin and dopamine.
Objective
To examine the brain morphologic features and associated impulsive behaviors in adolescents following prenatal exposure to cocaine and/or tobacco.
Design
Magnetic resonance imaging data and behavioral measures were collected from adolescents followed up longitudinally in the Maternal Lifestyle Study.
Setting
A hospital-based research center.
Participants
A total of 40 adolescent participants aged 13 to 15 years were recruited, 20 without PCE and 20 with PCE; a subset of each group additionally had tobacco exposure. Participants were selected and matched based on head circumference at birth, gestational age, maternal alcohol use, age, sex, race/ethnicity, IQ, family poverty, and socioeconomic status.
Main Outcome Measures
Subcortical volumetric measures of the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens; cortical thickness measures of the dorsolateral prefrontal cortex and ventral medial prefrontal cortex; and impulsivity assessed by Conners' Continuous Performance Test and the Sensation Seeking Scale for Children.
Results
After controlling for covariates, cortical thickness of the right dorsolateral prefrontal cortex was significantly thinner in adolescents following PCE (P=.03), whereas the pallidum volume was smaller in adolescents following prenatal tobacco exposure (P=.03). Impulsivity was correlated with thalamic volume following either PCE (P=.05) or prenatal tobacco exposure (P=.04).
Conclusions and Relevance
Prenatal cocaine or tobacco exposure can differentially affect structural brain maturation during adolescence and underlie enhanced susceptibility to impulsivity. Additional studies with larger sample sizes are warranted.
doi:10.1001/jamapediatrics.2013.550
PMCID: PMC4467165  PMID: 23400239
25.  Children of Addicted Women 
Journal of addictive diseases  2010;29(2):259-276.
The purpose of this article was to review follow up studies of children with prenatal drug exposure from preschool through adolescence. Specifically, the authors focus on the effects of prenatal exposure to cocaine, methamphetamine, and opiates on behavior and development. The largest number of studies have examined cocaine-exposed children. The authors identified 42 studies that suggest that there are unique effects of prenatal cocaine exposure on 4- to 13-year-old children, particularly in the areas of behavior problems, attention, language, and cognition. In addition, studies make reasonable attempts to control for possible confounding factors. Systematic research on the long-term effects of prenatal methamphetamine exposure is just beginning but seems to be showing similar effects to that of cocaine. The literature on the on the long-term effects of children with prenatal opiate exposure is more substantial than the methamphetamine literature but it is still relatively sparse and surprising in that there is little recent work. Thus, there are no studies on the current concerns with opiates used for prescription mediation. There is a growing literature using neuroimaging techniques to study the effects of prenatal drug exposure that holds promise for understanding brain/behavior relationships. In addition to pharmacological and teratogenic effects, drugs can also be viewed from a prenatal stressor model. The author discuss this “fetal origins” approach that involves fetal programming and the neuroendocrine system and the potential implications for adolescent brain and behavioral development.
doi:10.1080/10550881003684921
PMCID: PMC4451952  PMID: 20407981
Prenatal drug exposure; follow-up; fetal origins

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