FK506 binding protein 5 (FKBP5) alters stress response system functioning, and childhood maltreatment is associated with methylation of the FKBP5 gene. Yet it is unknown if maltreatment contributes to change in FKBP5 methylation over time. The current study draws upon a sample of 231 preschoolers, including 123 with child welfare documentation of moderate to severe maltreatment in the past 6 months, to understand if maltreatment contributes to change in FKBP5 methylation over a 6-month period. Review of child protection records and semistructured interviews in the home were used to assess maltreatment and exposure to other contextual stressors, as well as service utilization. Methylation of FKBP5 at two CpG sites in intron 7 was measured from saliva DNA at the time of initial study enrollment, and 6 months following enrollment. Child maltreatment was associated with change in FKBP5 methylation over time, but only when children were exposed to high levels of other contextual stressors. Service utilization was associated with increases in methylation over time, but only among children with the FKPB5 rs1360780 protective CC genotype. Methylation of FKBP5 is sensitive to stress exposure and may be a mechanism linking early adversity to long-term health and developmental outcomes.

Epigenetics processes may play a vital role in the biological embedding of early environmental adversity and the development of psychopathology. Accumulating evidence suggests that maltreatment is linked to methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), which is a key regulator of the hypothalamus–pituitary–adrenal axis. However, prior work has been exclusively cross-sectional, greatly constraining our understanding of stress-related epigenetic processes over time. In the current study, we examined the effect of maltreatment and other adversity on change in NR3C1 methylation among at-risk preschoolers to begin to characterize within-child epigenetic changes during this sensitive developmental period. Participants were 260 preschoolers (3–5 years old, 53.8% female), including 51.5% with moderate to severe maltreatment in the past 6 months. Child protection records, semistructured interviews, and parent reports were used to assess child stress exposure. Methylation of exons 1D and 1F of NR3C1 via saliva DNA were measured at two time points approximately 6 months apart. Results indicate that maltreated children evidence higher baseline levels of NR3C1 methylation, significant decreases in methylation over time, and then at follow-up, lower levels of methylation, relative to nonmaltreated preschoolers. Findings from the current study highlight the complex nature of stress-related epigenetic processes during early development.

Serotonin signaling pathways play a key role in brain development, stress reactivity, and mental health. Epigenetic alterations in the serotonin system may underlie the effect of early life stress on psychopathology. The current study examined methylation of the serotonin receptor 2A (HTR2A) gene in a sample of 228 children including 119 with child welfare documentation of moderate to severe maltreatment within the last 6 months. Child protection records, semistructured interviews in the home, and parent reports were used to assess child stress exposure, psychiatric symptoms, and behavior. The HTR2A genotype and methylation of HTR2A were measured at two CpG sites (–1420 and –1224) from saliva DNA. HTR2A genotype was associated with HTR2A methylation at both CpG sites. HTR2A genotype also moderated associations of contextual stress exposure and HTR2A methylation at site –1420. Contextual stress was positively associated with –1420 methylation among A homozygotes, but negatively associated with –1420 methylation among G homozygotes. Posttraumatic stress disorder and major depressive disorder symptoms were negatively associated with methylation at –1420, but positively associated with methylation at –1224. Results support the view that the serotonin system is sensitive to stress exposure and psychopathology, and HTR2A methylation may be a mechanism by which early adversity is biologically encoded.

A growing body of evidence suggests that alterations of the stress response system may be a mechanism by which childhood maltreatment alters risk for psychopathology. FK506 binding protein 51 (FKBP5) binds to the glucocorticoid receptor and alters its ability to respond to stress signaling. The aim of the present study was to examine methylation of the FKBP5 gene (FKBP5), and the role of an FKBP5 genetic variant, in relation to childhood maltreatment in a sample of impoverished preschool-aged children. One hundred seventy-four families participated in this study, including 69 with child welfare documentation of moderate to severe maltreatment in the past 6 months. The children, who ranged in age from 3 to 5 years, were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors; and a composite variable assessed the number exposures to these adversities. Methylation of two sites in intron 7 of FKBP5 was measured via sodium bisulfite pyrosequencing. Maltreated children had significantly lower levels of methylation at both CpG sites (p < .05). Lifetime contextual stress exposure showed a trend for lower levels of methylation at one of the sites, and a trend for an interaction with the FKBP5 polymorphism. A composite adversity variable was associated with lower levels of methylation at one of the sites as well (p < .05). FKBP5 alters glucocorticoid receptor responsiveness, and FKBP5 gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.

This was a prospective longitudinal multisite study of the effects of prenatal cocaine and/or opiate exposure on temperament in 4-month-olds of the Maternal Lifestyle Study (N = 958: 366 cocaine exposed, 37 opiate exposed, 33 exposed to both drugs, 522 matched comparison). The study evaluated positivity and negativity during The Behavior Assessment of Infant Temperament (Garcia Coll et al., 1988). Parents rated temperament (Infant Behavior Questionnaire; Rothbart, 1981). Cocaine-exposed infants showed less positivity overall, mainly during activity and threshold items, more negativity during sociability items, and less negativity during irritability and threshold items. Latent profile analysis indicated individual temperament patterns were best described by three groups: low/moderate overall reactivity, high social negative reactivity, and high nonsocial negative reactivity. Infants with heavy cocaine exposure were more likely in high social negative reactivity profile, were less negative during threshold items, and required longer soothing intervention. Cocaine- and opiate-exposed infants scored lower on Infant Behavior Questionnaire smiling and laughter and duration of orienting scales. Opiate-exposed infants were rated as less respondent to soothing. By including a multitask measure of temperament we were able to show context-specific behavioral dysregulation in prenatally cocaine-exposed infants. The findings indicate flatter temperament may be specific to nonsocial contexts, whereas social interactions may be more distressing for cocaine-exposed infants.

Exposure to early life adversity is linked to impaired affective, cognitive, and behavioral functioning and increases risk for various psychiatric and medical conditions. Stress-induced increases in pro-inflammatory cytokines may be a biological mechanism of these effects. Few studies have examined cytokine levels in children experiencing early life adversity, and very little research has investigated cytokines or other markers of inflammation in saliva. In the present study, we examined salivary interleukin (IL)-1β and C-reactive protein (CRP) levels in relation to stress exposure in 40 children aged 3 to 5 years who were enrolled in a larger study of early life adversity. Childhood maltreatment status was assessed via review of child welfare records. Contextual stress exposure, traumatic life event history, and symptoms of psychopathology were assessed via caregiver interviews at a home visit. In a subsequent visit, salivary IL-1β and CRP were obtained before and after participation in four emotion-eliciting tasks. The number of past-month contextual stressors, lifetime contextual stressors, and traumatic life events each demonstrated a significant main effect on IL-1β. Baseline IL-1β was positively associated with each of the significant main-effect adversities. Postchallenge IL-1β displayed positive associations with each adversity variable, but these were not significant. CRP was not significantly associated with any of the adversity variables. Given the evidence suggesting the involvement of IL-1β in the neuropathology of psychiatric conditions, these results may have important implications for developmental outcomes.

Epigenetic modifications to the genome are a key mechanism involved in the biological encoding of experience. Animal studies and a growing body of literature in humans have shown that early adversity is linked to methylation of the gene for the glucocorticoid receptor (GR), which is a key regulator of the hypothalamic–pituitary–adrenal axis as well as a broad range of physiological systems including metabolic and immune function. One hundred eighty-four families participated, including n = 74 with child welfare documentation of moderate-severe maltreatment in the past 6 months. Children ranged in age from 3 to 5 years, and were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors, and a composite variable assessed the number exposures to these adversities. Methylation of regions 1D, 1F, and 1H of the GR gene was measured via sodium bisulfite pyrosequencing. The composite measure of adversity was positively correlated with methylation at exons 1D and 1F in the promoter of the GR gene. Individual stress measures were significantly associated with a several CpG sites in these regions. GR gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.

Evidence now implicates inflammatory proteins in the neurobiology of internalizing disorders. Genetic factors may influence individual responses to maltreatment; however, little work has examined inflammatory genetic variants in adults and none in children. The present study examined the role of an interleukin 1B gene (IL1B) variant in preschoolers exposed to maltreatment and other forms of adversity in internalizing symptom development. One hundred ninety-eight families were enrolled, with one child (age 3–5 years) from each family. Adversity measures included child protective service documentation of moderate–severe maltreatment in the last 6 months and interview-assessed contextual stressors. Internalizing symptoms were measured using the Child Behavior Checklist and the Diagnostic Infant and Preschool Assessment. Maltreated children had higher major depressive disorder (MDD) and posttraumatic stress disorder symptoms and marginally higher internalizing symptoms on the Child Behavior Checklist. Controlling for age, sex, and race, IL1B genotype was associated with MDD symptoms (p = .002). Contextual stressors were significantly associated with MDD and posttraumatic stress disorder and marginally with internalizing symptoms. The IL1B genotype interacted with contextual stress such that children homozygous for the minor allele had more MDD symptoms (p = .045). These results suggest that genetic variants of IL1B may modulate the development of internalizing symptoms in the face of childhood adversity.

The factors contributing to the mental health of a sample of 18-year-olds were analyzed in a hierarchical multiple regression analysis. The contribution of proximal variables such as parenting behavior, intermediate variables such as other family factors, and the more distal variables such as social class and minority status were all highly significant. Child variables were also found to make significant contributions to understanding mental health. When the sample was divided into three subsamples, white advantaged, white disadvantaged, and African American (almost entirely disadvantaged), the mental health of the African American sample was higher than that of the white disadvantaged sample. The regression coefficients fit to the whole sample underestimated the mental health of the African Americans and overestimated the health of the white disadvantaged. The parenting of the African American sample was less approving and more critical and more controlling than that of the other two samples. To investigate the correlates of resilience, pairs of subjects were contrasted who had the same mental health but differed in whether they exceeded or were less than the mental health predicted for them. None of the variables in the study differentiated significantly between the two groups.

Studies have investigated the potential effects of prenatal cocaine exposure (CE) on children's development. However, few studies have examined predictors of resilient outcomes in this population. We examined vagal tone (VT) as a resilience factor in prenatal CE. Utilizing data from the Maternal Lifestyle Study, a cumulative risk index was derived for children with and without prenatal CE. Presence of CE and other prenatal drugs was summed with postnatal risks in infancy to yield a 15-item risk index. Preschool cognitive outcomes, problem behaviors, and adaptive behaviors were measured. VT was assessed during an infant exam at 1 month and toy exploration at 36 months. We included children with complete physiologic data (217 CE, 333 non-CE). Children were classified as having consistently high, consistently low, or fluctuating VT at 1 and 36 months. Children were also classified as high versus low risk. High-risk children had lower IQ scores, more problem behaviors, and lower ratings of adaptive behaviors than low-risk children. A significant risk by VT–stability interaction indicated that for high-risk children, those with stable low VT had higher ratings of adaptive behaviors at 36 months. This is consistent with theory linking reduced VT during tasks to adaptive regulation and indicates that such regulatory functioning may serve as a protective factor in prenatal CE.

We explored attachment in a family context by applying family systems principles to the investigation of multiple attachment relationships within families. This study focused on maternal adult attachment with respect to family of origin experiences (assessed using the Adult Attachment Interview [AAI]) as well as maternal marital attachment (assessed using the Marital Attachment Interview [MAI]). We examined associations between maternal adult attachment (or marital attachment) and three levels of family functioning including individual maternal depression symptoms, dyadic marital satisfaction (reported by mothers), and family unit functioning. We also examined associations between combined attachment security (consistent secure, AAI secure/MAI insecure, AAI insecure/MAI secure, and consistent insecure) and family outcomes. Finally, we assessed the extent to which attachment representations operate differently in the context of family stress, namely maternal depression. We found that attachment security with respect to particular relationships was differentially associated with different levels of family functioning. Examination of the security of combined adult and marital attachment further supported the multilevel organization of the family system.