Context: Phthalates may disrupt maternal-fetal-placental endocrine pathways, affecting pregnancy outcomes and child development. Placental corticotropin releasing hormone (pCRH) is critical for healthy pregnancy and child development, but understudied as a target of endocrine disruption. Objective: To examine phthalate metabolite concentrations (as mixtures and individually) in relation to pCRH. Design: Secondary data analysis from a prospective cohort study. Setting: Prenatal clinics in Tennessee, USA. Patients: 1018 pregnant women (61.4% non-Hispanic Black, 32% non-Hispanic White, 6.6% other) participated in the CANDLE study and provided data. Inclusion criteria included: low-medical-risk singleton pregnancy, age 16–40, and gestational weeks 16–29. Intervention: None. Main outcome measures: Plasma pCRH at two visits (mean gestational ages 23.0 and 31.8 weeks) and change in pCRH between visits (ΔpCRH). Results: In weighted quantile sums (WQS) regression models, phthalate mixtures were associated with higher pCRH at Visit 1 (β = 0.07, 95 %CI: 0.02, 0.11) but lower pCRH at Visit 2 (β = −0.08, 95 %CI: −0.14, −0.02). In stratified analyses, among women with gestational diabetes (n = 59), phthalate mixtures were associated with lower pCRH at Visit 1 (β = −0.17, 95 %CI: −0.35, 0.0006) and Visit 2 (β = −0.35, 95 %CI: −0.50, −0.19), as well as greater ΔpCRH (β = 0.16, 95 %CI: 0.07, 0.25). Among women with gestational hypertension (n = 102), phthalate mixtures were associated with higher pCRH at Visit 1 (β = 0.20, 95 %CI: 0.03, 0.36) and Visit 2 (β = 0.42; 95 %CI: 0.19, 0.64) and lower ΔpCRH (β = −0.17, 95 %CI: −0.29, −0.06). Significant interactions between individual phthalate metabolites and pregnancy complications were observed. Conclusions: Phthalates may impact placental CRH secretion, with differing effects across pregnancy. Differences in results between women with and without gestational diabetes and gestational hypertension suggest a need for further research examining whether women with pregnancy complications may be more vulnerable to endocrine-disrupting effects of phthalates.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: β = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study – United Kingdom Biobank – PTSD symptoms were negatively associated with SBP levels (β = −1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (β = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

The infant gut microbiome has lifelong implications on health and immunity but there is still limited understanding of the microbiome differences and similarities between children in low- and middle-income countries (LMICs) vs. high-income countries (HICs). Here, we describe and compare the microbiome profile of children aged under 48 months in two urban areas: Maputo, Mozambique and Atlanta, USA using shotgun metagenomics. The gut microbiome of American children showed distinct development, characterized by higher alpha diversity after infancy, compared to the same age group of African children, and the microbiomes clustered separately based on geographic location or age. The abundances of antibiotic resistance genes (ARGs) and virulence factors (VFs) were significantly higher in Maputo children, driven primarily by several primary and opportunistic pathogens. Most notably, about 50% of Maputo children under the age of two were positive for enterotoxigenic (ETEC) and typical enteropathogenic (EPEC) Escherichia coli diagnostic genes while none of the Atlanta age-matched children showed such a positive signal. In contrast, commensal species such as Phocaeicola vulgatus and Bacteroides caccae were more abundant in Atlanta, potentially reflecting diets rich in animal protein and susceptibility to inflammatory diseases. Overall, our results suggest that the different environments characterizing the two cities have significant, distinctive signatures on the microbiota of children and its development over time. Lack of safe water, sanitation, and hygiene (WASH) conditions and/or unsafe food sources may explain the higher enteric pathogen load among children in Maputo.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous endocrine-disrupting combustion by-products that have been linked to preterm birth. One possible mechanism is through disruption of placental corticotropin releasing hormone (pCRH), a key hormone implicated in parturition. As an extension of recent research identifying pCRH as a potential target of endocrine disruption, we examined maternal PAH exposure in relation to pCRH in a large, diverse sample. Participants, drawn from the CANDLE cohort, part of the ECHO-PATHWAYS Consortium, completed study visits at 16-29 weeks (V1) and 22-39 weeks (V2) gestation (n=812). Seven urinary mono-hydroxylated PAH metabolites (OH-PAHs) were measured at V1 and serum pCRH at V1 and V2. Associations between individual log-transformed OH-PAHs (as well as two summed PAH measures) and log(pCRH) concentrations across visits were estimated using mixed effects models. Minimally-adjusted models included gestational age and urinary specific gravity, while fully-adjusted models also included sociodemographic characteristics. We additionally evaluated effect modification by pregnancy complications, fetal sex, and maternal childhood trauma history. We observed associations between 2-OH-Phenanthrene (2-OH-PHEN) and rate of pCRH change that persisted in fully adjusted models (β=0.0009, 0.00006, 0.0017), however, positive associations with other metabolites (most notably 3-OH-Phenanthrene and 1-Hydroxypyrene) were attenuated after adjustment for sociodemographic characteristics. Associations tended to be stronger at V1 compared to V2 and we observed no evidence of effect modification by pregnancy complications, fetal sex, or maternal childhood trauma history. In conclusion, we observed modest evidence of association between OH-PAHs, most notably 2-OH-PHEN, and pCRH in this sample. Additional research using serial measures of PAH exposure is warranted, as is investigation of alternative mechanisms that may link PAHs and timing of birth, such as inflammatory, epigenetic, or oxidative stress pathways.

Adverse social exposures (ASEs) such as low income, low educational attainment, and childhood/adult trauma exposure are associated with variability in brain region measurements of gray matter volume (GMV), surface area (SA), and cortical thickness (CT). These CNS morphometries are associated with stress-related psychiatric illnesses and represent endophenotypes of stress-related psychiatric illness development. Epigenetic mechanisms, such as 5-methyl-cytosine (5mC), may contribute to the biological embedding of the environment but are understudied and not well understood. How 5mC relates to CNS endophenotypes of psychiatric illness is also unclear. In 97 female, African American, trauma-exposed participants from the Grady Trauma Project, we examined the associations of childhood trauma burden (CTQ), adult trauma burden, low income, and low education with blood-derived 5mC clusters and variability in brain region measurements in the amygdala, hippocampus, and frontal cortex subregions. To elucidate whether peripheral 5mC indexes central nervous system (CNS) endophenotypes of psychiatric illness, we tested whether 73 brain/blood correlated 5mC clusters, defined by networks of correlated 5mC probes measured on Illumina’s HumanMethylation Epic Beadchip, mediated the relationship between ASEs and brain measurements. CTQ was negatively associated with rostral middle frontal gyrus (RMFG) SA (β =−0.231, p = 0.041). Low income and low education were also associated with SA or CT in a number of brain regions. Seven 5mC clusters were associated with CTQ (pmin = 0.002), two with low education (pmin = 0.010), and three with low income (pmin = 0.007). Two clusters fully mediated the relation between CTQ and RMFG SA, accounting for 47 and 35% of variability, respectively. These clusters were enriched for probes falling in DNA regulatory regions, as well as signal transduction and immune signaling gene ontology functions. Methylome-network analyses showed enrichment of macrophage migration (p = 9 × 10–8), T cell receptor complex (p = 6 × 10–6), and chemokine-mediated signaling (p = 7 × 10–4) pathway enrichment in association with CTQ. Our results support prior work highlighting brain region variability associated with ASEs, while informing a peripheral inflammation-based epigenetic mechanism of biological embedding of such exposures. These findings could also serve to potentiate increased investigation of understudied populations at elevated risk for stress-related psychiatric illness development.

Background: Human and animal exposure to bisphenol A (BPA) has been associated with adverse developmental and reproductive effects. The molecular mechanisms by which BPA exposure exerts its effects are not well-understood, even less known about its analogues bisphenol F (BPF). To address these knowledge gaps, we conducted an untargeted metabolome-wide association study (MWAS) to identify metabolic perturbations associated with BPA/BPF exposures in a pregnant African American cohort. Methods: From a subset of study participants enrolled in the Atlanta African American Maternal-Child cohort, we collected both urine samples, for targeted exposure assessment of BPA (N = 230) and BPF (N = 48), and serum samples, for high-resolution metabolomics (HRM) profiling (N = 230), during early pregnancy (8–14 weeks’ gestation). Using an established untargeted HRM workflow consisting of MWAS modeling, pathway enrichment analysis, and chemical annotation and confirmation, we investigated the potential metabolic pathways and features associated with BPA/BPF exposures. Results: The geometric mean creatinine-adjusted concentrations of urinary BPA and BPF were 0.85 ± 2.58 and 0.70 ± 4.71 µg/g creatinine, respectively. After false positive discovery rate correction at 20 % level, 264 and 733 unique metabolic features were significantly associated with urinary BPA and BPF concentrations, representing 10 and 12 metabolic pathways, respectively. Three metabolic pathways, including steroid hormones biosynthesis, lysine and lipoate metabolism, were significantly associated with both BPA and BPF exposure. Using chemical standards, we have confirmed the chemical identity of 16 metabolites significantly associated with BPA or BPF exposure. Conclusions: Our findings support that exposure to BPA and BPF in pregnant women is associated with the perturbation of aromatic amino acid metabolism, xenobiotics metabolism, steroid biosynthesis, and other amino acid metabolism closely linked to stress responses, inflammation, neural development, reproduction, and weight regulation.

Exposure to stress triggers biological changes throughout the body. Accumulating evidence indicates that alterations in immune system function are associated with the development of stress-associated illnesses such as major depressive disorder and post-traumatic stress disorder, increasing interest in identifying immune markers that provide insight into mental health. Recombination events during T-cell receptor rearrangement and T-cell maturation in the thymus produce circular DNA fragments called T-cell receptor excision circles (TRECs) that can be utilized as indicators of thymic function and numbers of newly emigrating T-cells. Given data suggesting that stress affects thymus function, we examined whether blood levels of TRECs might serve as a quantitative peripheral index of cumulative stress exposure and its physiological correlates. We hypothesized that chronic stress exposure would compromise thymus function and produce corresponding decreases in levels of TRECs. In male mice, exposure to chronic social defeat stress (CSDS) produced thymic involution, adrenal hypertrophy, and decreased levels of TRECs in blood. Extending these studies to humans revealed robust inverse correlations between levels of circulating TRECs and childhood emotional and physical abuse. Cell-type specific analyses also revealed associations between TREC levels and blood cell composition, as well as cell-type specific methylation changes in CD4T + and CD8T + cells. Additionally, TREC levels correlated with epigenetic age acceleration, a common biomarker of stress exposure. Our findings demonstrate alignment between findings in mice and humans and suggest that blood-borne TRECs are a translationally-relevant biomarker that correlates with, and provides insight into, the cumulative physiological and immune-related impacts of stress exposure in mammals.

Introduction: Maternally derived antibodies are crucial for neonatal immunity. Understanding the binding and cross-neutralization capacity of maternal and cord antibody responses to SARS-CoV-2 variants following COVID-19 vaccination in pregnancy can inform neonatal immunity. Methods: Here we characterized the binding and neutralizing antibody profile at delivery in 24 pregnant individuals following two doses of Moderna mRNA-1273 or Pfizer BNT162b2 vaccination. We analyzed for SARS-CoV-2 multivariant cross-neutralizing antibody levels for wildtype Wuhan, Delta, Omicron BA1, BA2, and BA4/BA5 variants. In addition, we evaluated the transplacental antibody transfer by profiling maternal and umbilical cord blood. Results: Our results reveal that the current COVID-19 vaccination induced significantly higher RBD-specific binding IgG titers in cord blood compared to maternal blood for both the Wuhan and Omicron BA1 strain. Interestingly, the binding IgG antibody levels for the Omicron BA1 strain were significantly lower when compared to the Wuhan strain in both maternal and cord blood. In contrast to the binding, the Omicron BA1, BA2, and BA4/5 specific neutralizing antibody levels were significantly lower compared to the Wuhan and Delta variants. It is interesting to note that the BA4/5 neutralizing capacity was not detected in either maternal or cord blood. Discussion: Our data suggest that the initial series of COVID-19 mRNA vaccines were immunogenic in pregnant women, and vaccine-elicited binding antibodies were detectable in cord blood at significantly higher levels for the Wuhan and Delta variants but not for the Omicron variants. Interestingly, the vaccination did not induce neutralizing antibodies for Omicron variants. These results provide novel insight into the impact of vaccination on maternal humoral immune response and transplacental antibody transfer for SARS-CoV-2 variants and support the need for bivalent boosters as new variants emerge.

Recent evidence suggests that maternal childhood adversity may have an intergenerational impact, with children of adversity-exposed mothers exhibiting elevated symptoms of psychopathology. At the same time, many children demonstrate resilience to these intergenerational effects. Among the variety of factors that likely contribute to resilience, the composition of the gut microbiome may play a role in buffering the negative impacts of trauma and stress. The current prospective cohort study tested the novel hypothesis that offspring gut microbiome composition is a potential moderator in the relationship between maternal exposure to childhood adversity and offspring symptomatology (i.e., internalizing, externalizing, and posttraumatic stress symptoms). Maternal childhood adversity was self-reported during pregnancy via the Childhood Trauma Questionnaire and Adverse Childhood Experiences (ACEs) survey, and offspring symptomatology was assessed with the Child Behavior Checklist/1.5–5 when offspring were 2–4 years old. Offspring fecal samples were collected between these timepoints (i.e., during 6- to 24-month follow-up visits) for microbiome sequencing. Results indicated that maternal ACEs and the relative abundances of Bifidobacterium, Lactobacillus, and Prevotella were associated with offspring symptomatology. However, there was little evidence that microbial abundance moderated the association between maternal adversity and offspring symptoms. Overall, these findings further our understanding of how the gut microbiome associates with psychopathology, and informs future studies aimed at targeting modifiable factors that may buffer the intergenerational effects of childhood adversity.

Pregnancy can exacerbate or prompt the onset of stress-related disorders, such as post-traumatic stress disorder (PTSD). PTSD is associated with heightened stress responsivity and emotional dysregulation, as well as increased risk of chronic disorders and mortality. Further, maternal PTSD is associated with gestational epigenetic age acceleration in newborns, implicating the prenatal period as a developmental time period for the transmission of effects across generations. Here, we evaluated the associations between PTSD symptoms, maternal epigenetic age acceleration, and infant gestational epigenetic age acceleration in 89 maternal-neonatal dyads. Trauma-related experiences and PTSD symptoms in mothers were assessed during the third trimester of pregnancy. The MethylationEPIC array was used to generate DNA methylation data from maternal and neonatal saliva samples collected within 24 h of infant birth. Maternal epigenetic age acceleration was calculated using Horvath’s multi-tissue clock, PhenoAge and GrimAge. Gestational epigenetic age was estimated using the Haftorn clock. Maternal cumulative past-year stress (GrimAge: p = 3.23e-04, PhenoAge: p = 9.92e-03), PTSD symptoms (GrimAge: p = 0.019), and difficulties in emotion regulation (GrimAge: p = 0.028) were associated with accelerated epigenetic age in mothers. Maternal PTSD symptoms were associated with lower gestational epigenetic age acceleration in neonates (p = 0.032). Overall, our results suggest that maternal cumulative past-year stress exposure and trauma-related symptoms may increase the risk for age-related problems in mothers and developmental problems in their newborns.