2016 Progress Report: Neurodevelopment and Improving Children's Health following EtS exposure (NICHES)

EPA Grant Number: R835437
Center: The Center for Study of Neurodevelopment and Improving Children's Health
Center Director: Murphy, Susan K.
Title: Neurodevelopment and Improving Children's Health following EtS exposure (NICHES)
Investigators: Murphy, Susan K.
Institution: Duke University
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: June 1, 2013 through May 31, 2018 (Extended to May 31, 2019)
Project Period Covered by this Report: June 1, 2016 through May 31,2017
Project Amount: $3,907,780
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2012) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

Project 1 is examining the relationship between smoke exposure during early life and neurobehavioral outcomes in children followed from prior to birth through up to age 7 years, with a particular focus on attention deficit / hyperactivity disorder (ADHD).  This project is also examining the relationship between smoke exposure, ADHD and DNA methylation.

Project 2 is determining how exposure during early development to tobacco smoke extract and to nicotine influences growth and neurobehavioral outcomes in rats and neural differentiation and neurotransmitter phenotypes in vitro. This project is also working to define the most sensitive developmental window(s) of vulnerability to tobacco smoke and nicotine exposure and will determine if dietary interventions can ameliorate the effects of these exposures.

Project 3 is investigating how in utero tobacco smoke and nicotine exposure in rats influences DNA methylation in the brain and blood, and how the methylation profiles in the brain relate to gene expression.  These findings are being applied to study of cord blood from our human cohort to determine if methylation patterns can be used to stratify risk of ADHD prior to onset of symptoms. ADHD-associated genes will also be examined in the in vitro models of neurodifferentiation and neurotransmission to determine associations with these phenotypes.

Progress Summary:

Project 1

Aim 1: To characterize the extent and developmental timing of ETS exposure effects on cognitive and neurobehavioral outcomes in young children.

This aim will be addressed once we have recruited sufficient participants for analysis.

Aim 2: To determine the relation between DNA methylation and cognitive and neurobehavioral outcomes in young children.

This aim also relies on a larger number of individuals to be recruited into the study. MEG3 methylation data is being generated in Project 3 for a subset of the potential participants. 

During our fourth year for this study, the study team decided to open recruitment to all eligible participants above the age of 6. Adjusting the age requirement resulted in 1195 potentially eligible participants in our cohort that met our inclusion criteria. As of 10 March 2017, we have enrolled 282 participants: 61.3% African American, 31.6% Caucasian, 5.3% multi-racial, 1.4% Asian, and 0.4% American Indian/Alaskan Native. The mean age at enrollment is 4.8 years (SD=1.68; range 3-11). Sixty-nine participants have refused or moved out of our catchment area. The number who currently remain eligible are 769 women and their 5-11 year old children. We are actively reaching out to these participants through mail, recruitment events, or meeting them in clinics in order to enroll them for NICHES.

We have completed neurodevelopmental assessments of 280 children and their mothers at the time point 1 visit, and 63 mother-child dyads have completed the 2-year follow-up visit. For both mothers and their children, this includes assessments of executive functioning using the NIH toolbox and an IQ test. Among these children, we have collected saliva from nearly all the participants (269 individual saliva samples at time point 1 and 60 saliva samples at time point 2), which will provide a method for assessing cotinine. Blood samples continue to be challenging to collect from young children; thus, we started to offer the option of collecting blood via capillary tubes in addition to venipuncture. Overall, we have collected blood from 57 participants (41 via venipuncture and 16 via capillary) at time point 1, and we have collected blood from 22 participants (1 via venipuncture and 21 via capillary) at time point 2. All samples are being stored and will be used to assay cotinine and for DNA methylation. Stored prenatal maternal blood was a recently assayed for cotinine and umbilical cord samples are being assayed for DNA methylation in selected differentially methylated regions of interest. Loci chosen are being informed through putative pathways, recent findings in the literature, and findings from Projects 2 and 3.

Our current battery of neurodevelopmental tests for the participants include the NIH Toolbox with 8 tasks, the Differential Abilities Scale (DAS) with 4-6 subtests, Wechsler Abbreviated Scale of Intelligence –II (WASI) with 4 subtests, parent self-report measures that include: the Conner’s Adult ADHD Rating Scales (CAARS), Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scale (SWAN), Strengths and Difficulties Questionnaire (SDQ), Behavior rating Inventory of Executive Function (BRIEF), Behavior Assessment System for Children (BASC) and Parent Stress Index (PSI). During this report period we have completed the full battery of tests on the 273 mother and child dyads who completed study visits at time point 1 (280 mother-child dyads have completed all the neurodevelopmental assessments, and 274 mothers have completed all the parent self-report measures). All 63 mother-child dyads who have completed their follow-up (i.e. time point 2) visit have completed the full battery of tests. Cotinine assays have been performed on maternal blood samples (n=853) from the larger NEST cohort. We are preparing methods to do similar assays for the post-natal saliva samples collected from the children and will run those in the coming months. Based on cotinine levels, 135 women (15.83%) had levels indicating passive smoke exposure and 184 women (21.57%) had cotinine levels indicative of active smoking. The remaining 534 women (62.6%) had no significant smoke exposure. Findings from these data are being presented and national/international conferences and follow-up papers are in preparation.

Significance:  This study will add data on the effects of second hand smoke exposure on child cognitive development and identify potential epigenetic signatures mediating these associations.

Project 2

Aim 1. Determine the behavioral phenotypes resulting from developmental nicotine and environmental tobacco smoke (ETS ) exposure.

Aim 2. Determine the deficits in specific neural circuits that cause the behavioral anomalies:  In Vivo Neurochemistry (Slotkin and Seidler)

Aim 3. Determine cellular and molecular mechanisms for nicotine/tobacco extract-induced developmental neurotoxicity

We documented the impact of tobacco smoke extract on neurobehavioral function in a sensitive period analysis. The greatest persisting behavioral and neurochemical effects were seen with exposure during late gestation; however, effects were even seen with exposure that ended prior to mating. In vitro studies identified critical mechanisms of action of tobacco smoke extract. Current studies are assessing interactive effects of principal “bad actors,” nicotine and benzo-a-pyrene, on neurobehavioral function.

Significance: The rat studies show the cause-and-effect relationship between developmental exposure to the complex mixture of tobacco smoke and two principal neurotoxic components, nicotine and BaP, with regard to locomotor hyperactivity as well as cognitive impairment in the novel object recognition test with the tobacco smoke extract causing a more substantial effect than nicotine alone. Analysis of the critical windows of exposure showed that late gestational exposure to the tobacco smoke extract caused the most substantial neurochemical and neurobehavioral effects but that persistent impairments were seen after early gestational and even pre-mating exposure. The in vivo and neurochemical studies demonstrated the that the same tobacco smoke extract exposure disrupted dopaminergic, serotonergic and cholinergic neurotransmitter systems with greater effects of the tobacco constituent mixture compared with nicotine alone. In addition to nicotine, a critical bad actor in the tobacco smoke extract was the polyaromatic hydrocarbon benzo-a-pyrene (BaP). Developmental exposure of rats to a low dose (0.03 mg/kg/day throughout gestation) of BaP caused a significant reversal of a normal sex difference in locomotor activity in which female rats are normally more active than male rats. Prenatal BaP exposure causes a hyperactivity in males but not females, eliminating the normal sex difference in locomotor behavior. Sex-selective effects are also seen with nicotine and BaP exposures in emotional and cognitive tests. Low dose developmental exposure can cause long-lasting diminution of these normal sex differences. BaP also caused a significant impairment in the percent hit performance on the attentional test in male but not female offspring. The in vitro studies showed cellular disruptions of proliferation and differentiation again with the tobacco constituent mixture causing more pervasive effects than the same concentration of nicotine alone. The human neural stem cells are more sensitive to both nicotine and tobacco smoke extract than the rat PC12 cells and provide an opportunity to establish direct concordance between human clinical samples (Project 1) and in vitro exposure phenotypes (Project 2).

Project 3

Aim 1: Identify ETS-related methylation targets.

We have largely completed this objective. Whole Genome Bisulfite Sequencing data was generated for two brain regions, including the frontal cortex and hippocampus, as well as from the peripheral blood of pooled rat specimens (6 per pool, 2 pools for each exposure). The exposure groups included control (vehicle exposed), 0.2 mg/kg/day nicotine, 2.0 mg/kg/day nicotine and tobacco smoke extract with a nicotine level of 0.2 mg/kg/day. The data have undergone QA/QC and the most differentially methylated CpG sites and regions across the genome have been identified. We are currently working to validate a number of the top hits in the individual brain and blood tissues (by bisulfite pyrosequencing) from the same rats whose tissues were used for the WGBS, and will also determine the stability of any altered methylation over time in an independent set of rat specimens.

We are still at the initial stages of the analysis. Preliminarily, we have found that, among the top 1,000 hits comparing the tissues from the tobacco smoke extract exposed offspring to vehicle exposed controls, there are at least 35 genes associated with CpG sites whose methylation is altered by exposure across both brain regions and in the peripheral blood, at least 75 genes for peripheral blood and frontal cortex, and at least 88 for peripheral blood and hippocampus. This is important because we are seeking areas of differential methylation that show this effect in either brain tissue and blood so that it may be possible to detect such changes in cord blood from our human cohort. For many genes, there are multiple CpG sites showing differential methylation that are all among the top 1,000 hits. We are conducting bioinformatics analysis to determine if there are particular gene ontology terms or molecular pathways that are enriched among this group of genes.

Analysis of other comparisons will also be performed, including for example, comparisons of the nicotine exposed animals versus controls at the two dosages used, and comparisons of the nicotine exposed to the TSE exposed animals. The initial data analysis included CpG sites that are located within 10kb upstream of the promoter of an annotated gene. We also have gene lists that expand this distance to 100kb upstream, and up to 500kb upstream or downstream. In addition, our statistician performed these comparisons in two ways – the first by specific CpG sites, which is the data just described, and the second using an approach to identify regions that are showing differential methylation by exposure.

Aim 2: Identify ETS-altered methylation-expression relationships in frontal cortex.

The cohorts of rats to be used for this aim have been generated (breeding, exposure, behavioral measures, tissue collection) as part of Project 2. We have prepared the RNA (concurrent with the DNA used for WGBS), assessed QA/QC metrics and pooled equal amounts of RNA from each of the rats comprising a group from frontal cortex as well as from the hippocampus of the rats. RNA-Seq data have been generated and are being analyzed independent of, and together with, the WGBS data.

Aim 3: Determine if DNA methylation varies with ETS dose in humans.

Cotinine levels have been generated for ~800 mothers of children who are participating in or are potential participants in NICHES Project 1. Cotinine levels vary widely, and there are few pregnant women who have no measurable cotinine in their blood. Targeted methylation analysis of promoter regions, designed prior to WGBS data returned has been analyzed.

Significance: Identified DNA methylation changes in blood, cortex and hippocampus are currently being prioritized for analysis, and extrapolation to the human cohort.  Identification of genes or CpG loci whose methylation status changes with exposure in all three tissues would be indicative of a very early embryonic exposure causing the change, while methylation changes in any one tissue but not the others would be indicative of a later development exposure inducing the change.  For extrapolation of the results from rats to humans, for which we have cord blood for analysis, we will be restricted to changes that have occurred in at least one region of the brain and in peripheral blood.  Such findings would support the use of rodent models for study of the effects of exposures leading to epigenetic modifications of genes involved in neurodevelopmental or neurobehavioral processes in humans.

Future Activities:

Project 1

To achieve the goals and aims of this project will require maintaining our active recruitment and retention efforts. We are targeting at least 3-4 visits a week in order to enroll about 300 participants during the study timeline.

Recruitment: To maintain our recruitment we will continue to do the following. Enhance communication efforts to increase awareness of the NICHES study among NEST cohort participants, the cohort from whom we are recruiting. This is being done through electronic and print-based media. For example, we have designed an easy-to-read brochure that includes a description of the NICHES study. This information is being integrated more seamlessly into the NEST communications materials. We have included this information about the NICHES study on the NEST website, NEST quarterly newsletters, and NEST greeting cards (mother’s day, birthday, etc). In the NEST study, it was common to hold pizza parties where several participants were invited to complete the surveys. We have adopted this strategy for the NICHES study, since it is familiar to many NEST participants. Specifically, we organize pizza and holiday parties approximately every three months where eligible participants are invited. During this meeting, we present the NICHES study and if interested participants are scheduled to come for a NICHES study visit. We will continue to recruit eligible participants when they come for their child’s well –child appointments. Meeting the families in person to recruit them while they complete NEST follow-up packets has helped us with recruitment.

Retention. In addition to the standard methods for retention (frequent quarterly communication via newsletters, semi-annual greetings cards and a static websites) we have developed a unique cohort management platform that allows research staff to maintain contact with birth cohort participants, recruit them for participation in our ongoing follow-up studies, and allow for the delivery of SMS text, Interactive Voice Response, and mobile-based surveys. The platform has launched and we are beginning to recruit eligible NICHES participants to enroll in the system when they participate in other NEST studies.

Project 2

  • Finish neurobehavioral assessment for all cohorts in the windows study of attention, learning, spatial working and reference memory, non-spatial memory, anxiety, fear and anxiety for male and female rats exposed throughout early development to TSE at a dose modeling environmental tobacco smoke exposure, and the equivalent dose of nicotine (0.2 mg/kg/day) without the other constituents of TSE in comparison with vehicle control and a positive comparison group of higher dose of nicotine (2 mg/kg/day) modeling the nicotine exposure from primary smoking.
  • Determine the most sensitive neurobehavioral effects. In the third major study test rescue and therapeutic treatments.
  • Test the efficacy of antioxidant and methyl donor rescue of TSE exposure induced neurobehavioral effects.
  • Assess pharmacotherapies (methylphenidate, amphetamine and atomoxetine) to attenuate the neurobehavioral dysfunction caused by TSE and nicotine exposure during development.
  • Perform brain regional dissections in an age range from birth through weaning, adolescence and adulthood of male and female rats exposed in discrete developmental windows, to TSE at a dose modeling environmental tobacco smoke exposure (0.2 mg/kg/day) in comparison with vehicle control.
  • Perform brain region specific neurochemical analyses characterizing monoaminergic and cholinergic neurotransmitter systems of in vivo tissues from TSE administration.
  • Elucidate mechanisms underlying the TSE effects on phenotypic fate (neurons, astroglia, oligodendrocytes) in rat neural stem cells.
  • Prepare TSE exposed samples from in vivo and in vitro studies for epigenetics evaluations.
  • The mechanistic qPCR survey will identify key genes in hNSCs that will be assayed for nicotine/TSE-induced DNA methylation changes in vitro and concordant changes explored in human clinical samples from Project 1/3 and in banked fetal tissues. A novel gender-specific
  • hNSC in vitro model will be developed through selections from male WA01 and female WA09 hESCs. hESC exposure phenotypes also will be determined. A 3D model of hNSCs (brainoids) will be developed to test how architecture affects genomic and epigenetic response.
  • In parallel, the new hNSC models will be evaluated using quantitative phase microscopy to identify label-free optical signatures to score living cells in real time as they differentiate.

Project 3

  • For Aim 1, continue data analysis to identify targets of methylation changes due to prenatal exposure to nicotine or tobacco smoke extract and continue the process of validation in the individual rats and extend these results to analysis of the human cohort.
  • For Aim 2, the same rat tissues from Aim 1 were used for pooled RNA transcriptome profiling to identify gene expression changes that occur in frontal cortex and hippocampus as a result of prenatal exposure to nicotine or tobacco smoke extract. Expression changes will be validated in the individual rats. These data will also be integrated with the whole genome bisulfite sequencing data from Aim 1 to identify top candidate genes (i.e., those showing a methylation change from prenatal exposure to nicotine or tobacco smoke extract and concordance in methylation change between brain and blood and that also show a correlation between methylation and expression in control versus exposed animals) for analysis in our human cohort in Aim 3.
  • For Aim 3, we will continue to examine candidate targets of methylation in exposed humans and rats and relate this to level of exposure. This will shift to examination of candidates identified from results obtained by Aims 1 and 2 once the data analysis is completed. We plan to generate the genotyping data as well as the lead exposure data for the children in the coming year.
  • We will continue to bank and track biological specimens as they are collected from Projects 1 and 2.


Journal Articles: 48 Displayed | Download in RIS Format

Other center views: All 178 publications 54 publications in selected types All 48 journal articles
Type Citation Sub Project Document Sources
Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children's Environmental Health Studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. R835437 (Final)
R835432 (2016)
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  • Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies:the Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. R835437 (Final)
    R835436 (2017)
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  • Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Hussey Freeland DM, Miller R, Murphy SK. Small-magnitude effect sizes in epigenetic end points are important in children’s environmental health studies: the Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. R835437 (2017)
    R835432 (Final)
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  • Journal Article Small Magnitude Effect Sizes in Epigenetic Endpoints are Important in Children's Environmental Health Studies:The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017; 125(4):511-526. R835437 (2016)
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  • Journal Article Cauley M, Hall BJ, Abreu-Villaca Y, Junaid S, White H, Kiany A, Slotkin TA, Levin ED. Critical developmental periods for effects of low-level tobacco smoke exposure on behavioral performance. Neurotoxicology 2018;68:81-87. R835437 (2017)
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  • Journal Article Fleisch AF, Kloog I, Luttmann-Gibson H, Gold DR, Oken E, Schwartz JD. Air pollution exposure and gestational diabetes mellitus among pregnant women in Massachusetts: a Cohort Study. Environmental Health 2016;15(1):40 (9 pp.). R835437 (Final)
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  • Journal Article Fleisch AF, Kloog I, Luttmann-Gibson H, Gold DR, Oken E, and Schwartz JD. Air Pollution Exposure and Gestational Diabetes Mellitus Among Pregnant Women in Massachusetts:a Cohort Study. Environmental Health 2016; 15:40-48. R835437 (2016)
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  • Journal Article Fuemmeler BF, Wang L, Iversen ES, Maguire R, Murphy SK, Hoyo C. Association between prepregnancy body mass index and gestational weight gain with size, tempo, and velocity of infant growth: analysis of the Newborn Epigenetic Study cohort. Childhood Obesity 2016;12(3):210-218. R835437 (2015)
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  • Journal Article Fuemmeler BF, Lee CT, Soubry A, Iversen ES, Huang Z, Murtha AP, Schildkraut JP, Jirtle RL, Murphy SK, Hoyo C. DNA methylation of regulatory regions of imprinted genes at birth and its relation to infant temperament. Genetics and Epigenetics 2016;8:59-67. R835437 (2017)
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  • Journal Article Gao L, Liu X, Millstein J, Siegmund KD, Dubeau L, Maguire RL, Zhang JJ, Fuemmeler BF, Kollins SH, Hoyo C, Murphy SK, Breton CV. Self-reported prenatal tobacco smoke exposure, AXL gene-body methylation, and childhood asthma phenotypes. Clinical Epigenetics 2018;10(1):98 (11 pp.). R835437 (2017)
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  • Journal Article Hall BJ, Cauley M, Burke D, Kiany A, Slotkin TA, Levin ED. Cognitive and behavioral impairments evoked by low-level exposure to tobacco smoke components: comparison with nicotine alone. Toxicological Sciences 2016;151(2):236-244. R835437 (2015)
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  • Journal Article Hall BJ, Abreu-Villaca Y, Cauley M, Junaid S, White H, Kiany A, Levin ED. The ventral hippocampal muscarinic cholinergic system plays a key role in sexual dimorphisms of spatial working memory in rats. Neuropharmacology 2017;117:106-113. R835437 (2017)
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  • Journal Article King KE, Kane JB, Scarbrough P, Hoyo C, Murphy SK. Neighborhood and family environment of expectant mothers may influence prenatal programming of adult cancer risk: discussion and an illustrative DNA methylation example. Biodemography and Social Biology 2016;62(1):87-104. R835437 (2015)
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  • Journal Article Lee W-C, Shen L, Catalano PJ, Mickley LJ, and Koutrakis P. Effects of Future Temperature Change on PM2.5 Infiltration in the Greater Boston Area. Atmospheric Environment 2017;150:98-105. R835437 (2016)
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  • Journal Article Lee W-C, Shen L, Catalano PJ, Mickley LJ, Koutrakis P. Effects of future temperature change on PM2.5 infiltration in the Greater Boston area. Atmospheric Environment 2017;150:98-105. R835437 (Final)
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  • Journal Article Levin ED. Learning about cognition risk with the radial-arm maze in the developmental neurotoxicology battery. Neurotoxicology and Teratology 2015;52(Pt A):88-92. R835437 (2014)
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  • Journal Article Murphy SK, Erginer E, Huang Z, Visco Z, Hoyo C. Genotype-epigenotype interaction at the IGF2 DMR. Genes 2015;6(3):777-789. R835437 (2014)
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  • Journal Article Nye MD, Fry RC, Hoyo C, Murphy SK. Investigating epigenetic effects of prenatal exposure to toxic metals in newborns: challenges and benefits. Medical Epigenetics 2014;2(1):53-59. R835437 (2013)
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  • Journal Article Nye MD, Hoyo C, Murphy SK. In vitro lead exposure changes DNA methylation and expression of IGF2 and PEG1/MEST. Toxicology In Vitro 2015;29(3):544-550. R835437 (2014)
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  • Journal Article Nye MD, King KE, Darrah TH, Maguire R, Jima DD, Huang Z, Mendez MA, Fry RC, Jirtle RL, Murphy SK, Hoyo C. Maternal blood lead concentrations, DNA methylation of MEG3 DMR regulating the DLK1/MEG3 imprinted domain and early growth in a multiethnic cohort. Environmental Epigenetics 2016;2(1):1-8. R835437 (2015)
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  • Journal Article Schechter JC, Kollins SH. Prenatal smoke exposure and ADHD: advancing the field. Pediatrics 2017;139(2):e20163481 (2 pp.). R835437 (2017)
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  • Journal Article Schechter JC, Fuemmeler, BF, Hoyo C, Murphy SK, Zhang JJ, Kollins SH. Impact of smoking ban on passive smoke exposure in pregnant non-smokers: using cotinine as a biomarker of exposure. International Journal of Environmental Research and Public Health 2018;15(1):E83 (16 pp.). R835437 (2017)
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  • Journal Article Slotkin TA, Card J, Seidler FJ. Adverse benzo[a]pyrene effects on neurodifferentiation are altered by other neurotoxicant coexposures: interactions with dexamethasone, chlorpyrifos, or nicotine in PC12 cells. Environmental Health Perspectives 2013;121(7):825-831. R835437 (2013)
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  • Journal Article Slotkin TA, Card J, Seidler FJ. Nicotine administration in adolescence reprograms the subsequent response to nicotine treatment and withdrawal in adulthood: sex-selective effects on cerebrocortical serotonergic function. Brain Research Bulletin 2014;102:1-8. R835437 (2014)
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  • Journal Article Slotkin TA, Card J, Stadler A, Levin ED, Seidler FJ. Effects of tobacco smoke on PC12 cell neurodifferentiation are distinct from those of nicotine or benzo[a]pyrene. Neurotoxicology and Teratology 2014;43:19-24. R835437 (2013)
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  • Journal Article Slotkin TA, Skavicus S, Card J, Levin ED, Seidler FJ. Amelioration strategies fail to prevent tobacco smoke effects on neurodifferentiation: nicotinic receptor blockade, antioxidants, methyl donors. Toxicology 2015;333:63-75. R835437 (2014)
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  • Journal Article Slotkin TA, Skavicus S, Card J, Stadler A, Levin ED, Seidler FJ. Developmental neurotoxicity of tobacco smoke directed toward cholinergic and serotonergic systems: more than just nicotine. Toxicological Sciences 2015;147(1):178-189. R835437 (2014)
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  • Journal Article Slotkin TA, Stadler A, Skavicus S, Seidler FJ. Adolescents and adults differ in the immediate and long-term impact of nicotine administration and withdrawal on cardiac norepinephrine. Brain Research Bulletin 2016;122:71-75. R835437 (2015)
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  • Journal Article Slotkin TA, Skavicus S, Card J, Levin ED, Seidler FJ. Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes. Toxicology 2016;372:42-51. R835437 (2016)
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  • Journal Article Slotkin TA, Stadler A, Skavicus S, Card J, Ruff J, Levin ED, Seidler FJ. Is there a critical period for the developmental neurotoxicity of low-level tobacco smoke exposure? Toxicological Sciences 2017;155(1):75-84. R835437 (2017)
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  • Journal Article Slotkin, T.A., Stadler, A., Skavicus, S., Card, J., Ruff, J., Levin, E.D., Seidler, F.J. 2016. Is there a critical period for the developmental neurotoxicity of low-level tobacco smoke exposure? Toxicological Sciences. DOW:10.1093. R835437 (2016)
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    Journal Article Smeester L, Yosim AE, Nye MD, Hoyo C, Murphy SK, Fry RC. Imprinted genes and the environment: links to the toxic metals arsenic, cadmium, lead and mercury. Genes 2014;5(2):477-496. R835437 (2014)
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  • Journal Article Soubry A, Hoyo C, Jirtle RL, Murphy SK. A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. BioEssays 2014;36(4):359-371. R835437 (2013)
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  • Journal Article Tindula G, Murphy SK, Grenier C, Huang Z, Huen K, Escudero-Fung M, Bradman A, Eskenazi B, Hoyo C, Holland N. DNA methylation of imprinted genes in Mexican-American newborn children with prenatal phthalate exposure. Epigenomics 2018;10(7):1011-1026. R835437 (2017)
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  • Journal Article Vidal AC, Benjamin Neelon SE, Liu Y, Tuli AM, Fuemmeler BF, Hoyo C, Murtha AP, Huang Z, Schildkraut J, Overcash F, Kurtzberg J, Jirtle RL, Iversen ES, Murphy SK. Maternal stress, preterm birth, and DNA methylation at imprint regulatory sequences in humans. Genetics and Epigenetics 2014;6:37-44. R835437 (2014)
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  • Journal Article Barry CM, Sabhlok A, Saba VC, Majors AD, Schechter JC, Levine EL, Streicher M, Bennett GG, Kollins SH, Fuemmeler BF. An Automated Text-Messaging Platform for Enhanced Retention and Data Collection in a Longitudinal Birth Cohort:Cohort Management Platform Analysis. JMIR Public Health Surveillance 2019 Apr 2;5(2):e11666. doi:10.2196/11666. PubMed PMID:30938689; PubMed Central PMCID:PMC6465978. R835437 (Final)
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  • Journal Article Dozmorov MG, Bilbo SD, Kollins SH, Zucker N, Do EK, Schechter JC, Zhang JJ, Murphy SK, Hoyo C, Fuemmeler BF. Associations between maternal cytokine levels during gestation and measures of child cognitive abilities and executive functioning. Brain Behavior, and Immunity 2018;70:390-397. doi:10.1016/j.bbi.2018.03.029. PubMed PMID:29588230; PubMed Central PMCID:PMC6471612. R835437 (Final)
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  • Journal Article Green AJ, Hoyo C, Mattingly CJ, Luo Y, Tzeng JY, Murphy SK, Buchwalter DB, Planchart A. Cadmium exposure increases the risk of juvenile obesity:a human and zebrafish comparative study. International Journal of Obesity (London) 2018 Jul;42(7):1285-1295. doi:10.1038/s41366-018-0036-y. PubMed PMID:29511319; PubMed Central PMCID:PMC6054604. R835437 (Final)
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  • Journal Article Slotkin TA, Skavicus S, Ko A, Levin ED, Seidler FJ. Corrigendum to "The Developmental Neurotoxicity of Tobacco Smoke Can Be Mimicked by a Combination of Nicotine and Benzo[a]pyrene:Effects on Cholinergic and Serotonergic Systems. Toxicological Sciences 2019 Mar 1;168(1):280. doi:10.1093/toxsci/kfy304. PubMed PMID:30615185. R835437 (Final)
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  • Journal Article Gonzalez-Nahm S, Mendez MA, Benjamin-Neelon SE, Murphy SK, Hogan VK, Rowley DL, Hoyo C. DNA methylation of imprinted genes at birth is associated with child weight status at birth, 1 year, and 3 years.Clinical Epigenetics 2018 Jun 28;10:90. doi:10.1186/s13148-018-0521-0. eCollection 2018. PubMed PMID:29988473; PubMed Central PMCID:PMC6025828. R835437 (Final)
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  • Journal Article Schechter J, Do EK, Zhang JJ, Hoyo C, Murphy SK, Kollins SH, Fuemmeler B. Effect of Prenatal Smoke Exposure on Birth Weight:The Moderating Role of Maternal Depressive Symptoms. Nicotine and Tobacco Research 2018 Dec 24. doi:10.1093/ntr/nty267. [Epub ahead of print] PubMed PMID:30590728. R835437 (Final)
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  • Journal Article Sorrow P, Maguire R, Murphy SK, Belcher SM, Hoyo C. Elevated metabolites of acetaminophen in cord blood of children with obesity. Pediatr Obes. 2019 Jan;14(1). doi:10.1111/ijpo.12465. Epub 2018 Sep 25. PubMed PMID:30253079. R835437 (Final)
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    Journal Article Hawkey A, Junaid S, Yao L, Spiera Z, White H, Cauley M, Levin ED. Gestational exposure to nicotine and/or benzo[a]pyrene causes long-lasting neurobehavioral consequences. Birth Defects Research 2019 Jul 31. doi:10.1002/bdr2.1568. [Epub ahead of print] PubMed PMID:31368242. R835437 (Final)
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  • Journal Article Martin CL, Jima D, Sharp GC, McCullough LE, Park SS, Gowdy KM, Skaar D, Cowley M, Maguire RL, Fuemmeler B, Collier D, Relton CL, Murphy SK, Hoyo C. Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood:an epigenome-wide association study. Epigenetics 2019 Apr;14(4):325-340. doi:10.1080/15592294.2019.1581594. Epub 2019 Mar 26. PubMed PMID:30773972; PubMed Central PMCID:PMC6557549. R835437 (Final)
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  • Journal Article Hawkey AB, White H, Pippen E, Greengrove E, Rezvani AH, Murphy SK, Levin ED. Paternal nicotine exposure in rats produces long-lasting neurobehavioral effects in the offspring. Neurotoxicology and Teratology. 2019 Jul-Aug;74:106808. doi:10.1016/j.ntt.2019.05.001. Epub 2019 May 16. PubMed PMID:31103693; PubMed Central PMCID:PMC6642846. R835437 (Final)
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  • Journal Article House JS, Mendez M, Maguire RL, Gonzalez-Nahm S, Huang Z, Daniels J, Murphy SK, Fuemmeler BF, Wright FA, Hoyo C. Periconceptional Maternal Mediterranean Diet Is Associated With Favorable Offspring Behaviors and Altered CpG Methylation of Imprinted Genes. Frontiers in Cell and Developmental Biology 2018 Sep 7;6:107. doi:10.3389/fcell.2018.00107. eCollection 2018. PubMed PMID:30246009; PubMed Central PMCID:PMC6137242. R835437 (Final)
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  • Journal Article Fuemmeler BF, Zucker N, Sheng Y, Sanchez CE, Maguire R, Murphy SK, Kollins SH, Hoyo C. Pre-Pregnancy Weight and Symptoms of Attention Deficit Hyperactivity Disorder and Executive Functioning Behaviors in Preschool Children. International Journal of Environmental Research and Public Health 2019 Feb;16(4):667-681. doi:10.3390/ijerph16040667. PubMed PMID:30823531; PubMed Central PMCID:PMC6406951. R835437 (Final)
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  • Journal Article Slotkin TA, Skavicus S, Ko A, Levin ED, Seidler FJ. The Developmental Neurotoxicity of Tobacco Smoke Can Be Mimicked by a Combination of Nicotine and Benzo[a]Pyrene:Effects on Cholinergic and Serotonergic Systems. Toxicological Sciences 2019 Jan 1;167(1):293-304. doi:10.1093/toxsci/kfy241. Erratum in:Toxicological Sciences 2019 Mar 1;168(1):280. PubMed PMID:30247698; PubMed Central PMCID:PMC6681680. R835437 (Final)
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  • Supplemental Keywords:

    Secondhand smoke, nicotine, tobacco smoke extract, attention deficit hyperactivity disorder, neurobehavior, cognitive function, neurotransmission, human neural stem cells, pyrosequencing, DNA methylation, epigenetics, Instagram

    Relevant Websites:

    NICHES web site:  NiCHES Children's Environmental Health and Disease Prevention Research Center Exit

    Science Education web site: http://www.rise.duke.edu Exit

    COTC web site: Help Babies Avoid Smoke! Exit

    Progress and Final Reports:

    Original Abstract
  • 2013 Progress Report
  • 2014 Progress Report
  • 2015 Progress Report
  • 2017 Progress Report
  • Final Report