Association between Maternal Perinatal Stress and Depression on Infant DNA Methylation in the First Year of Life.

Maternal stress and depression during pregnancy and the first year of the infant's life affect a large percentage of mothers. Maternal stress and depression have been associated with adverse fetal and childhood outcomes as well as differential child DNA methylation (DNAm). However, the biological mechanisms connecting maternal stress and depression to poor health outcomes in children are still largely unknown. Here we aim to determine whether prenatal stress and depression are associated with changes in cord blood mononuclear cell DNAm (CBMC-DNAm) in newborns (n = 119) and whether postnatal stress and depression are associated with changes in peripheral blood mononuclear cell DNAm (PBMC-DNAm) in children of 12 months of age (n = 113) from the Canadian Healthy Infant Longitudinal Development (CHILD) cohort. Stress was measured using the 10-item Perceived Stress Scale (PSS) and depression was measured using the Center for Epidemiologic Studies Depression Questionnaire (CESD). Both stress and depression were measured at 18 weeks and 36 weeks of pregnancy and six months and 12 months postpartum. We conducted epigenome-wide association studies (EWAS) using robust linear regression followed by a sensitivity analysis in which we bias-adjusted for inflation and unmeasured confounding using the bacon and cate methods. To investigate the cumulative effect of maternal stress and depression, we created composite prenatal and postnatal adversity scores. We identified a significant association between prenatal stress and differential CBMC-DNAm at 8 CpG sites and between prenatal depression and differential CBMC-DNAm at 2 CpG sites. Additionally, we identified a significant association between postnatal stress and differential PBMC-DNAm at 8 CpG sites and between postnatal depression and differential PBMC-DNAm at 11 CpG sites. Using our composite scores, we further identified 2 CpG sites significantly associated with prenatal adversity and 7 CpG sites significantly associated with postnatal adversity. Several of the associated genes, including PLAGL1, HYMAI, BRD2, and ERC2 have been implicated in adverse fetal outcomes and neuropsychiatric disorders. This suggested that differential DNAm may play a role in the relationship between maternal mental health and child health.

Metabolic Perturbations Associated with an Exposure Mixture of Per- and Polyfluoroalkyl Substances in the Atlanta African American Maternal-Child Cohort.

Prenatal exposure to single chemicals belonging to the per- and polyfluoroalkyl substances (PFAS) family is associated with biological perturbations in the mother, fetus, and placenta, plus adverse health outcomes. Despite our knowledge that humans are exposed to multiple PFAS, the potential joint effects of PFAS on the metabolome remain largely unknown. Here, we leveraged high-resolution metabolomics to identify metabolites and metabolic pathways perturbed by exposure to a PFAS mixture during pregnancy. Targeted assessment of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS), along with untargeted metabolomics profiling, were conducted on nonfasting serum samples collected from pregnant African Americans at 6-17 weeks gestation. We estimated the overall mixture effect and partial effects using quantile g-computation and single-chemical effects using linear regression. All models were adjusted for maternal age, education, parity, early pregnancy body mass index, substance use, and gestational weeks at sample collection. Our analytic sample included 268 participants and was socioeconomically diverse, with the majority receiving public health insurance (78%). We observed 13.3% of the detected metabolic features were associated with the PFAS mixture (n = 1705, p < 0.05), which was more than any of the single PFAS chemicals. There was a consistent association with metabolic pathways indicative of systemic inflammation and oxidative stress (e.g., glutathione, histidine, leukotriene, linoleic acid, prostaglandins, and vitamins A, C, D, and E metabolism) across all metabolome-wide association studies. Twenty-six metabolites were validated against authenticated compounds and associated with the PFAS mixture (p < 0.05). Based on quantile g-computation weights, PFNA contributed the most to the overall mixture effect for γ-aminobutyric acid (GABA), tyrosine, and uracil. In one of the first studies of its kind, we demonstrate the feasibility and utility of using methods designed for exposure mixtures in conjunction with metabolomics to assess the potential joint effects of multiple PFAS chemicals on the human metabolome. We identified more pronounced metabolic perturbations associated with the PFAS mixture than for single PFAS chemicals. Taken together, our findings illustrate the potential for integrating environmental mixture analyses and high-throughput metabolomics to elucidate the molecular mechanisms underlying human health.

Differential DNA Methylation in the Brain as Potential Mediator of the Association between Traffic-related PM2.5 and Neuropathology Markers of Alzheimer's Disease.

INTRODUCTION: Growing evidence indicates fine particulate matter (PM2.5) as risk factor for Alzheimer's' disease (AD), but the underlying mechanisms have been insufficiently investigated. We hypothesized differential DNA methylation (DNAm) in brain tissue as potential mediator of this association. METHODS: We assessed genome-wide DNAm (Illumina EPIC BeadChips) in prefrontal cortex tissue and three AD-related neuropathological markers (Braak stage, CERAD, ABC score) for 159 donors, and estimated donors' residential traffic-related PM2.5 exposure 1, 3 and 5 years prior to death. We used a combination of the Meet-in-the-Middle approach, high-dimensional mediation analysis, and causal mediation analysis to identify potential mediating CpGs. RESULTS: PM2.5 was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty-six CpG sites were identified as mediators of the association between PM2.5 exposure and neuropathology markers, several located in genes related to neuroinflammation. DISCUSSION: Our findings suggest differential DNAm related to neuroinflammation mediates the association between traffic-related PM2.5 and AD.

Intergenerational transmission of trauma: A biological perspective.

This commentary is based on an invited panel for the 2022 International Society of Traumatic Stress Studies (ISTSS) annual meeting entitled "Perspective Discourses On…Intergenerational Transmission of Trauma: A Biological Perspective." This was a new format introduced by ISTSS to facilitate discussion around timely topics. This session included scholars from different backgrounds (e.g., epidemiology, neuroscience, environmental health) who shared their approaches to understanding the biological bases of the intergenerational transmission of trauma. Specifically, the panel presented information about putative direct and indirect mechanisms of transmission, including epigenetic and environmental factors, and pointed to behavioral and neurobiological outcomes in offspring. This commentary synthesizes some of the current knowledge gained by these different approaches and identifies key areas to advance in future work.

Fine particulate air pollution and neuropathology markers of Alzheimer's disease in donors with and without APOE ε4 alleles - results from an autopsy cohort.

Introduction: Higher fine particulate matter (PM2.5) exposure has been found to be associated with Alzheimer's disease (AD). PM2.5 has been hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. A major genetic risk factor of AD, the apolipoprotein E (APOE) gene, has also been hypothesized to modify the association between PM2.5 and AD. However, little prior research exisits to support these hypotheses. Therefore, this paper aims to investigate the association between traffic-related PM2.5 and AD hallmark pathology, including effect modification by APOE genotype, in an autopsy cohort. Methods: Brain tissue donors enrolled in the Emory Goizueta Alzheimer's Disease Research Center (ADRC) who died before 2020 (n=224) were assessed for AD pathology including Braak Stage, Consortium to Establish a Registry for AD (CERAD) score, and the combined AD neuropathologic change (ABC score). Traffic-related PM2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250m. One-, 3-, and 5-year average PM2.5 concentrations prior to death were matched to participants home address. We assessed the association between traffic-related PM2.5 and AD hallmark pathology, as well as effect modification by APOE genotype, using adjusted ordinal logistic regression models. Results: Traffic-related PM2.5 was significantly associated with CERAD score for the 1-year exposure window (OR: 1.92; 95% CI: 1.12, 3.30), and the 3-year exposure window (OR: 1.87; 95%-CI: 1.01, 3.17). PM2.5 had harmful, but non-significant associations on Braak Stage and ABC score. The strongest associations between PM2.5 and neuropathology markers were among those without APOE ε4 alleles (e.g., for CERAD and 1-year exposure window, OR: 2.31; 95% CI: 1.36, 3.94), though interaction between PM2.5 and APOE genotype was not statistically significant. Conclusions: Our study found traffic-related PM2.5 exposure was associated with CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM2.5 affects Aß deposition in the brain. This association was particularly strong among donors without APOE ε4 alleles. Future studies should further investigate the biological mechanisms behind this assocation.

Genetic Variants in Telomerase Reverse Transcriptase Contribute to Solar Lentigines.

Solar lentigines (SLs) are a hallmark of human skin aging. They result from chronic exposure to sunlight and other environmental stressors. Recent studies also imply genetic factors, but findings are partially conflicting and lack of replication. Through a multi-trait based analysis strategy, we discovered that genetic variants in telomerase reverse transcriptase were significantly associated with non-facial SL in two East Asian (Taizhou longitudinal cohort, n = 2,964 and National Survey of Physical Traits, n = 2,954) and one Caucasian population (SALIA, n = 462), top SNP rs2853672 (P-value for Taizhou longitudinal cohort = 1.32 × 10‒28 and P-value for National Survey of Physical Traits = 3.66 × 10‒17 and P-value for SALIA = 0.0007 and Pmeta = 4.93 × 10‒44). The same variants were nominally associated with facial SL but not with other skin aging or skin pigmentation traits. The SL-enhanced allele/haplotype upregulated the transcription of the telomerase reverse transcriptase gene. Of note, well-known telomerase reverse transcriptase‒related aging markers such as leukocyte telomere length and intrinsic epigenetic age acceleration were not associated with SL. Our results indicate a previously unrecognized role of telomerase reverse transcriptase in skin aging‒related lentigines formation.

Association of exposure to ambient particulate matter with maternal thyroid function in early pregnancy.

BACKGROUND: It is known that maternal thyroid dysfunction during early pregnancy can cause adverse pregnancy complications and birth outcomes. This study was designed to examine the association between ambient particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) and particulate matter with aerodynamic diameters ≤10 µm (PM10) exposure and maternal thyroid function during early pregnancy. METHODS: This study was based on data from a birth cohort study of 921 pregnant women in China. We estimated associations between ambient PM2.5 and PM10 exposure during the first trimester of pregnancy (estimated with land-use regression models) and maternal thyroid hormone concentrations (free thyroxine (FT4), free tri-iodothyronine (FT3), and thyroid-stimulating hormone (TSH)) collected between weeks 10 and 17 of gestation using linear regression models adjusting for potential confounders. Ambient PM2.5 and PM10 concentrations were modeled per interquartile range (IQR) increment and as tertiles based on the distribution of the exposure levels. RESULTS: An IQR increment (68 µg/m3) in PM2.5 exposure was associated with a significant decrease in maternal FT4 levels (ß = -0.60, 95% CI: -1.07, -0.12); and a significant decrease in FT4/FT3 ratio (ß = -0.13, 95% CI: -0.25, -0.02). Further analyses showed that, relative to the lowest tertile, women in both the middle and highest tertiles of PM2.5 had significantly lower concentrations of maternal FT4 and FT4/FT3 ratio. No significant associations were found between PM2.5 and FT3 or TSH levels. PM10 exposure was not significantly associated with maternal thyroid function. CONCLUSIONS: Our study suggested that higher ambient PM2.5, not PM10, exposed during the first trimester of pregnancy were associated with a significant decrease in maternal serum FT4 concentrations and FT4/FT3 ratio. Studies in populations with different exposure levels are needed to replicate our study results.