Impact of prenatal tobacco smoking on infant telomere length trajectory and ADHD symptoms at 18 months: a longitudinal cohort study.

BACKGROUND: Prenatal maternal tobacco smoking is a predictor of child attention-deficit/hyperactivity disorder (ADHD) and is associated with offspring telomere length (TL). In this study, we examine the relationship between maternal prenatal smoking, infant TL, and maternal report of early childhood symptoms of ADHD. METHODS: One-hundred and eighty-one mother-infant dyads were followed prospectively for the infant's first 18 months of life. Prenatal smoking was assessed from maternal report and medical records. TL was measured from infant buccal swab DNA obtained across the first 18 months of life. ADHD symptoms were obtained from maternal report on the Child Behavior Check List. Multiple regression models tested the relation between prenatal smoking and both ADHD symptoms and infant TL. Additional analyses tested whether the change in infant TL influenced the relation between prenatal smoking and ADHD symptoms. RESULTS: Sixteen percent of mothers reported prenatal smoking. Infant TL at 4, 12, and 18 months of age were correlated. Consistent with previous cross-sectional studies linking shorter offspring TL to maternal prenatal smoking, maternal prenatal smoking predicted greater telomere shortening from four to 18 months of infant age (ß = - 5.797, 95% CI [-10.207, -1.386]; p = 0.010). Maternal depression was positively associated with both prenatal smoking (odds ratio (OR): 4.614, 95% CI [1.733, 12.282]; p = 0.002) and child ADHD symptoms (ß = 4.713, 95% CI [2.073, 7.354]; p = 0.0006). To prevent confounding, analyses examined the relation between TL, ADHD symptoms, and prenatal smoking only in non-depressed mothers. In non-depressed mothers, infant TL attrition across the first 18 months moderated the relation between smoking and child ADHD. CONCLUSIONS: The findings extend previous studies linking prenatal smoking to shorter infant TL by providing data demonstrating the effect on TL trajectory. The relation between prenatal smoking and early infant ADHD symptoms was moderated by the change in TL. The findings provide novel initial evidence suggesting that TL dynamics are one mechanistic pathway influencing the relation between maternal prenatal smoking and ADHD.

Adverse Childhood Experiences: Implications for Offspring Telomere Length and Psychopathology.

OBJECTIVE: Adverse childhood experiences (ACEs) are associated with mental and physical health risks that, through biological and psychosocial pathways, likely span generations. Within an individual, telomere length (TL), an established marker of cellular stress and aging, is associated with both ACE exposure and psychopathology, providing the basis for an emerging literature suggesting that TL is a biomarker of the health risks linked to early-life adversity both within and across generations. The authors tested the effect of maternal ACEs on both the trajectory of infant TL and infant social-emotional problems at 18 months of age. METHODS: Pregnant women were recruited, and maternal scores on the Adverse Childhood Experience questionnaire were obtained, along with demographic and prenatal stress measures. Postnatal visits with 155 mother-infant dyads occurred when infants were 4, 12, and 18 months of age. At each visit, infant buccal swabs were collected for TL measurement, and mothers completed measures of maternal depression. Mothers also completed the Child Behavior Checklist at the 18-month visit. Mixed-effects modeling was used to test how maternal ACEs influenced infant TL trajectory. Linear regression was used to test the association between maternal ACEs and infant internalizing and externalizing behaviors. Finally, the interaction between telomere attrition from 4 to 18 months and maternal ACEs was examined as a predictor of infant scores on the Child Behavior Checklist. RESULTS: Higher maternal ACEs were associated with shorter infant TL across infancy and higher infant externalizing behavioral problems at 18 months. No associations were found with internalizing behavioral problems. Telomere attrition from 4 to 18 months interacted with maternal ACEs to predict externalizing behaviors. In infants whose mothers reported higher scores on the Adverse Childhood Experience questionnaire, greater telomere attrition predicted higher externalizing problems, even when accounting for maternal postnatal depression and prenatal stress. CONCLUSIONS: These data demonstrate an interactive pathway between maternal early-life adversity and infant TL that predicts emerging behavioral problems in the next generations.

The transgenerational transmission of maternal adverse childhood experiences (ACEs): Insights from placental aging and infant autonomic nervous system reactivity.

OBJECTIVE: To test alterations in placental cellular aging as one pathway by which maternal early adversity influences physiologic development in her offspring. METHODS: Maternal report of her adverse childhood experiences (ACE) was obtained prenatally along with measures of prenatal stress and demographic information. Placentas (N = 67) were collected at birth and telomere length (TL) was measured in four separate fetally-derived placental tissues: amnion, chorion, villus, and umbilical cord. At four months of age, infants completed the still-face paradigm (SFP) during which respiratory sinus arrhythmia (RSA) data were collected; RSA reactivity and RSA recovery was available from 44 and 41 infants respectively. Multi-level mixed effects models examined the impact of maternal ACE score on placental TL. Generalized linear models tested the relation between composite placental TL and infant RSA, as well as the moderation of maternal ACE score and infant RSA by composite placental TL. RESULTS: Higher maternal ACE score significantly predicted shorter placental TL across tissues (ß = -0.015; P = 0.036) and infant RSA across the SFP. No direct relation was found between placental TL and RSA, however composite placental TL moderated the relation between ACE score and both infant RSA reactivity (ß = 0.025; P = 0.005) and RSA recovery (ß = -0.028; P = 0.032). In infants with shorter composite placental TL, higher ACE score predicted greater RSA suppression during the still-face epoch relative to play period 1 and greater RSA augmentation during play period 2 relative to the still-face epoch. CONCLUSIONS: These data are the first, to our knowledge, to report that changes in placental TL influence the transgenerational impact of maternal early life adversity on the development of her offspring's autonomic nervous system.

Differences in placental telomere length suggest a link between racial disparities in birth outcomes and cellular aging.

BACKGROUND: Health disparities begin early in life and persist across the life course. Despite current efforts, black women exhibit greater risk for pregnancy complications and negative perinatal outcomes compared with white women. The placenta, which is a complex multi-tissue organ, serves as the primary transducer of bidirectional information between the mother and fetus. Altered placental function is linked to multiple racially disparate pregnancy complications; however, little is known about racial differences in molecular factors within the placenta. Several pregnancy complications, which include preeclampsia and fetal growth restriction, exhibit racial disparities and are associated with shorter placental telomere length, which is an indicator of cellular stress and aging. Cellular senescence and telomere dynamics are linked to the molecular mechanisms that are associated with the onset of labor and parturition. Further, racial differences in telomere length are found in a range of different peripheral tissues. Together these factors suggest that exploration of racial differences in telomere length of the placenta may provide novel mechanistic insight into racial disparities in birth outcomes. OBJECTIVE: This study examined whether telomere length measured in 4 distinct fetally derived tissues were significantly different between black and white women. The study had 2 hypotheses: (1) that telomere length that is measured in different placental tissue types would be correlated and (2) that across all sampled tissues telomere length would differ by race. STUDY DESIGN: In a prospective study, placental tissue samples were collected from the amnion, chorion, villus, and umbilical cord from black and white singleton pregnancies (N=46). Telomere length was determined with the use of monochrome multiplex quantitative real-time polymerase chain reaction in each placental tissue. Demographic and pregnancy-related data were also collected. Descriptive statistics characterized the sample overall and among black and white women separately. The overall impact of race was assessed by multilevel mixed-effects linear regression models that included empirically relevant covariates. RESULTS: Telomere length was correlated significantly across all placental tissues. Pairwise analyses of placental tissue telomere length revealed significantly longer telomere length in the amnion compared with the chorion (t=-2.06; P=.043). Overall telomere length measured in placenta samples from black mothers were significantly shorter than those from white mothers (ß=-0.09; P=.04). Controlling for relevant maternal and infant characteristics strengthened the significance of the observed racial differences (ß=-0.12; P=.02). Within tissue analyses revealed that the greatest difference by race was found in chorionic telomere length (t=-2.81; P=.007). CONCLUSION: These findings provide the first evidence of racial differences in placental telomere length. Telomere length was significantly shorter in placental samples from black mothers compared with white mothers. Given previous studies that have reported that telomere length, cellular senescence, and telomere dynamics are molecular factors that contribute to the rupture of the amniotic sac, onset of labor, and parturition, our findings of shorter telomere length in placentas from black mothers suggest that accelerated cellular aging across placental tissues may be relevant to the increased risk of preterm delivery in black pregnancies. Our results suggest that racial differences in cellular aging in the placenta contribute to the earliest roots of health disparities.

Diurnal and stress-reactive dehydroepiandrosterone levels and telomere length in youth.

The current investigation examined the association between the aging-related biomarkers dehydroepiandrosterone (DHEA) and telomere length (TL) in community-recruited African-American youth. The examination of DHEA included stress reactive, basal and diurnal sampling, in order to elucidate the underlying physiological process that may overlap with TL. One hundred and two participants completed the Trier Social Stressor Test for children (TSST-C). TL was obtained from all youth from buccal swabs on the same day as the TSST-C. Saliva samples from 83 participants were obtained over the course of two additional days to measure waking and diurnal levels of DHEA. DHEA diurnal slope was a robust predictor of TL (B=0.516, P<0.05), while other DHEA values were not significantly associated with TL. This study is one of the first studies to examine basal, diurnal and reactivity measurements of DHEA in youth. Furthermore, this is the first study, to our knowledge, to demonstrate a positive association between DHEA, a putative anti-aging hormone, and TL, an indicator of cellular aging.

Variation in CACNA1C is Associated with Amygdala Structure and Function in Adolescents.

OBJECTIVE: Genome-wide association studies have identified allelic variation in CACNA1C as a risk factor for multiple psychiatric disorders associated with limbic system dysfunction, including bipolar disorder, schizophrenia, and depression. The CACNA1C gene codes for a subunit of L-type voltage-gated calcium channels, which modulate amygdala function. Although CACNA1C genotype appears to be associated with amygdala morphology and function in adults with and without psychopathology, whether genetic variation influences amygdala structure and function earlier in development has not been examined. METHODS: In this first investigation of the neural correlates of CACNA1C in young individuals, we examined associations between two single nucleotide polymorphisms in CACNA1C (rs1006737 and rs4765914) with amygdala volume and activation during an emotional processing task in 58 adolescents and young adults 13-20 years of age. RESULTS: Minor (T) allele carriers of rs4765914 exhibited smaller amygdala volume than major (C) allele homozygotes (ß=-0.33, p=0.006). Furthermore, minor (A) allele homozygotes of rs1006737 exhibited increased blood-oxygen-level-dependent (BOLD) signal in the amygdala when viewing negative (vs. neutral) stimuli (ß=0.29, p=0.040) and decreased BOLD signal in the amygdala when instructed to downregulate their emotional response to negative stimuli (ß=-0.38, p=0.009). Follow-up analyses indicated that childhood trauma did not moderate the associations of CACNA1C variation with amygdala structure and function (ps>0.170). CONCLUSIONS: Findings indicate that CACNA1C-related differences in amygdala structure and function are present by adolescence. However, population stratification is a concern, given the racial/ethnic heterogeneity of our sample, and our findings do not have direct clinical implications currently. Nevertheless, these results suggest that developmentally informed research can begin to shed light on the time course by which genetic liability may translate into neural differences associated with vulnerability to psychopathology.

Arsenic mediated disruption of promyelocytic leukemia protein nuclear bodies induces ganciclovir susceptibility in Epstein-Barr positive epithelial cells.

Promyelocytic leukemia protein nuclear bodies (PML NBs) have been implicated in host immune response to viral infection. PML NBs are targeted for degradation during reactivation of herpes viruses, suggesting that disruption of PML NB function supports this aspect of the viral life cycle. The Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1) has been shown to suppress EBV reactivation. Our finding that LMP1 induces PML NB immunofluorescence intensity led to the hypothesis that LMP1 may modulate PML NBs as a means of maintaining EBV latency. Increased PML protein and morphometric changes in PML NBs were observed in EBV infected alveolar epithelial cells and nasopharyngeal carcinoma cells. Treatment with low dose arsenic trioxide disrupted PML NBs, induced expression of EBV lytic proteins, and conferred ganciclovir susceptibility. This study introduces an effective modality to induce susceptibility to ganciclovir in epithelial cells with implications for the treatment of EBV associated pathologies.