Dietary Intake of Nutrients Involved in Serotonin and Melatonin Synthesis and Prenatal Maternal Sleep Quality and Affective Symptoms.

Poor sleep quality and psychological distress in pregnancy are important health concerns. Serotonin and melatonin levels may underlie variation in these adverse outcomes. In this study, we examined dietary nutrients involved in serotonin and melatonin synthesis in relation to maternal sleep quality and affective symptoms during pregnancy. Pregnant women at no greater than normal medical risk at enrollment completed 24-hour dietary recalls in mid-late pregnancy. Usual intakes of vitamin B6, vitamin D, eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), and tryptophan were estimated from dietary intake of foods and supplements using the National Cancer Institute (NCI) method. Sleep quality, depression, and anxiety were measured using validated questionnaires. Associations between nutrient intakes, sleep quality, and affective symptoms were estimated using generalized estimating equation models adjusting for potential confounding factors. In minimally adjusted models, EPA + DHA and tryptophan intakes were associated with a lower score indicating better sleep quality (b: -1.07, 95% CI: -2.09, -0.05) and (b: -12.40, 95% CI: -24.60, -0.21), respectively. EPA + DHA and tryptophan intakes were also associated with a lower odds of shorter sleep duration and sleep disturbances. In addition, tryptophan was associated with a lower odds of higher sleep latency. However, associations were attenuated and nonsignificant after adjustment for demographic and lifestyle factors. In conclusion, intakes of EPA + DHA and tryptophan were associated with improved sleep quality, but these associations were confounded by maternal demographic and lifestyle characteristics. This study highlights the need to consider dietary intake and pregnancy health in the context of demographic characteristics and lifestyle behaviors.

Systemic oxidative stress levels during the course of pregnancy: Associations with exposure to air pollutants.

Increased systemic oxidative stress, implicated in adverse pregnancy outcomes for both mothers and fetuses, has been associated with gestational exposure to air pollutants such as polycyclic aromatic hydrocarbons (PAHs), fine particulate matter (PM2.5), and nitrogen dioxide (NO2). However, it is unclear whether exposure to pollutants at levels below the current air quality standards can increase oxidative stress in pregnant women. In a cohort of 305 pregnant persons residing in western New York, we examined the association between exposure to PM2.5, NO2, and PAHs (measured as urinary 1-hydroxypyrene) and urinary biomarkers of oxidative stress (malondialdehyde [MDA] and 8-hydroxy-2'-deoxyguanosine [8-OHdG]) measured in each trimester. After controlling for gestational stage, maternal age, lifestyles, and socioeconomic factors, each interquartile range (IQR) increase in 1-hydroxypyrene concentration (65.8 pg/ml) was associated with a 7.73% (95%CI: 3.18%,12.3%) higher in MDA levels throughout the pregnancy and in the first and second trimester. An IQR increase in PM2.5 concentration (3.20 µg/m3) was associated with increased MDA levels in the first trimester (8.19%, 95%CI: 0.28%,16.1%), but not the 2nd (-7.99%, 95% CI: 13.8%, -2.23%) or 3rd trimester (-2.81%, 95% CI: 10.0%, 4.38%). The average cumulative PM2.5 exposures in the 3-7 days before urine collection were associated with increased 8-OHdG levels during the second trimester, with the largest difference (22.6%; 95% CI: 3.46%, 41.7%) observed in relation to a one IQR increase in PM2.5 concentration in the previous 7 days. In contrast, neither oxidative stress biomarker was associated with NO2 exposure. Observed in pregnant women exposed to low-level air pollution, these findings expanded previously reported associations between systemic oxidative stress and high-level PM2.5 and PAH concentrations. Further, the first and second trimesters may be a susceptible window during pregnancy for oxidative stress responses to air pollution exposure.

Associations between mycoestrogen exposure and sex steroid hormone concentrations in maternal serum and cord blood in the UPSIDE pregnancy cohort.

Zearalenone (ZEN) is a fungal-derived toxin found in global food supplies including cereal grains and processed foods, impacting populations worldwide through diet. Because the chemical structure of ZEN and metabolites closely resembles 17ß-estradiol (E2), they interact with estrogen receptors α/ß earning their designation as 'mycoestrogens'. In animal models, gestational exposure to mycoestrogens disrupts estrogen activity and impairs fetal growth. Here, our objective was to evaluate relationships between mycoestrogen exposure and sex steroid hormone concentrations in maternal circulation and cord blood for the first time in humans. In each trimester, pregnant participants in the UPSIDE study (n = 297) provided urine for mycoestrogen analysis and serum for hormone analysis. At birth, placental mycoestrogens and cord steroids were measured. We fitted longitudinal models examining log-transformed mycoestrogen concentrations in relation to log-transformed hormones, adjusting for covariates. Secondarily, multivariable linear models examined associations at each time point (1st, 2nd, 3rd trimesters, delivery). We additionally considered effect modification by fetal sex. ZEN and its metabolite, α-zearalenol (α-ZOL), were detected in >93% and >75% of urine samples; >80% of placentas had detectable mycoestrogens. Longitudinal models from the full cohort exhibited few significant associations. In sex-stratified analyses, in pregnancies with male fetuses, estrone (E1) and free testosterone (fT) were inversely associated with ZEN (E1 %Δ: -6.68 95%CI: -12.34, -0.65; fT %Δ: -3.22 95%CI: -5.68, -0.70); while α-ZOL was positively associated with E2 (%Δ: 5.61 95%CI: -1.54, 9.85) in pregnancies with female fetuses. In analysis with cord hormones, urinary mycoestrogens were inversely associated with androstenedione (%Δ: 9.15 95%CI: 14.64, -3.30) in both sexes, and placental mycoestrogens were positively associated with cord fT (%Δ: 37.13, 95%CI: 4.86, 79.34) amongst male offspring. Findings support the hypothesis that mycoestrogens act as endocrine disruptors in humans, as in animal models and livestock. Additional work is needed to understand impacts on maternal and child health.

Maternal affective symptoms and sleep quality have sex-specific associations with placental topography.

BACKGROUND: The impacts of prenatal maternal affective symptoms on the placental structure are not well-established. Employing Geographic Information System (GIS) spatial autocorrelation, Moran's I, can help characterize placental thickness uniformity/variability and evaluate the impacts of maternal distress on placental topography. METHODS: This study (N = 126) utilized cohort data on prenatal maternal affective symptoms and placental 2D and 3D morphology. Prenatal maternal depression, stress, anxiety and sleep quality were scored for each trimester using the Edinburgh Postnatal Depression Scale (EPDS), Stressful Life Event Scale (SLE), Penn State Worry Questionnaire (PSWQ), and Pittsburgh Sleep Quality Index (PSQI), respectively. Placental shape was divided into Voronoi cells and thickness variability among these cells was computed using Moran's I for 4-nearest neighbors and neighbors within a 10 cm radius. Sex-stratified Spearman correlations and linear regression were used to study associations between mean placental thickness, placental GIS variables, placental weight and the average score of each maternal variable. RESULTS: For mothers carrying boys, poor sleep was associated with higher mean thickness (r = 0.308,p = 0.035) and lower placental thickness uniformity (r = -0.36,p = 0.012). Lower placental weight (r = 0.395,p = 0.003), higher maternal depression (r = -0.318,p = 0.019) and worry/anxiety (r = -0.362,p = 0.007) were associated with lower placental thickness uniformity for mothers carrying girls. LIMITATIONS: The study is exploratory and not all GIS models were developed. Excluding high-risk pregnancies prevented investigating pregnancy complications related hypotheses. A larger sample size is needed for greater confidence for clinical application. CONCLUSIONS: Placental topography can be studied using GIS theory and has shown that prenatal maternal affective symptoms and sleep have sex-specific associations with placental thickness.

Affective Symptoms in Pregnancy are Associated with the Vaginal Microbiome.

Composition of the vaginal microbiome in pregnancy is associated with adverse maternal, obstetric, and child health outcomes. Identifying the sources of individual differences in the vaginal microbiome is therefore of considerable clinical and public health interest. The current study tested the hypothesis that vaginal microbiome composition during pregnancy is associated with an individual's experience of affective symptoms and stress exposure. Data were based on a prospective longitudinal study of a diverse and medically healthy community sample of 275 mother-infant pairs. Affective symptoms and stress exposure and select measures of associated biomarkers (diurnal salivary cortisol, serum measures of sex hormones) were collected at each trimester; self-report, clinical, and medical records were used to collect detailed data on socio-demographic factors and health behavior, including diet and sleep. Vaginal microbiome samples were collected in the third trimester (34-40 weeks) and characterized by 16S rRNA sequencing. Identified taxa were clustered into three community state types (CST1-3) based on dissimilarity of vaginal microbiota composition. Results indicate that depressive symptoms during pregnancy were reliably associated with individual taxa and CST3 in the third trimester. Prediction of functional potential from 16S taxonomy revealed a differential abundance of metabolic pathways in CST1-3 and individual taxa, including biosynthetic pathways for the neuroactive metabolites, serotonin and dopamine. With the exception of bioavailable testosterone, no significant associations were found between symptoms- and stress-related biomarkers and CSTs. Our results provide further evidence of how prenatal psychological distress during pregnancy alters the maternal-fetal microbiome ecosystem that may be important for understanding maternal and child health outcomes.

Prenatal maternal immune activation predicts observed fearfulness in infancy.

Fear reactivity is an early emerging temperament trait that predicts longer term behavioral and health outcomes. The current analysis tests the hypothesis, an extension of prior research on maternal immune activation (MIA), that the prenatal maternal immune system is a reliable predictor of observed fear reactivity in infancy. The analysis is based on a prospective longitudinal cohort study that collected data from the first trimester and conducted observational assessments of temperament at approximately 12 months of age (n = 281 infants). MIA was assessed from immune biomarkers measured in maternal blood at each trimester; infant temperament was assessed using the Laboratory Temperament Assessment Battery assessment at 12 months; covariates included family and sociodemographic factors. Patterns of inflammatory markers across gestation reliably predicted observed temperament: elevated prenatal MIA was associated with high fear reactivity to novel stimuli. The findings provide novel evidence of prenatal origins of fear reactivity and suggest developmental mechanisms that may underlie early emerging individual differences in child temperament. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

PFAS alters placental arterial vasculature in term human placentae: A prospective pregnancy cohort study.

INTRODUCTION: Perfluoroalkyl substances (PFAS) are synthetic chemicals used in industrial and consumer goods that are widely detected in human populations and are associated with adverse health outcomes, including perinatal health risks and child health. One mechanism of influence may be the impact of PFAS exposure on placental structure and function. OBJECTIVES: The objective of this study is to investigate the relationship between maternal prenatal exposure to PFAS and measures of placental vascularization, and to assess whether changes in vascularization play a role in mediating the impact of PFAS on birth outcomes. METHODS: Using data from a prospective cohort study, we examined associations between second trimester PFAS (individually and as mixtures using Bayesian kernel machine regression) and placental arterial vasculature in term placentae (N = 158); secondarily we evaluated the degree to which alterations in placental arterial vasculature explained associations between PFAS exposure and birth outcomes. Placental arterial vasculature features were collected from arterial tracings of each placental image. RESULTS: In both linear regression and mixture models, natural log-transformed perfluorooctanoic acid concentrations were negatively associated with surface vasculature, indexed by the mean distance from arterial end point to perimeter (ß = -0.23, 95% CI: -0.41, -0.041); additionally, maximum arterial tortuosity was negatively associated with placental weight (ß = -0.19, 95% CI: -0.34, -0.051). There were no reliable differences in effect by fetal sex. DISCUSSION: The findings provide some of the first evidence of PFAS exposure shaping a key measure of placental vascular function, which may underlie the impact of PFAS on perinatal and child health risks.

Fetoplacental Disposition and Toxicity of Cadmium in Mice Lacking the Bcrp Transporter.

The environmental toxicant cadmium (Cd) impairs the growth of rodents and humans in utero which in turn heightens susceptibility to diseases later in life. We previously demonstrated that the maternal-facing efflux transporter, breast cancer resistance protein (human BCRP/ABCG2, mouse Bcrp/Abcg2) confers resistance against Cd toxicity in human trophoblasts. In the current study, we sought to determine whether the absence of Bcrp alters the fetoplacental disposition and toxicity of Cd in mice. Pregnant female wild-type (WT) and Bcrp-null mice (n = 9-10/group) were administered a single injection of saline (5 ml/kg) or CdCl2 (5 mg/kg) on gestational day (GD) 9. Following Cd treatment, Bcrp-null offspring were shorter and accumulated more Cd in their placentas on GD 17 compared to WT mice. Because Cd can adversely impact placentation and transplacental nutrient delivery in mice, multiple pathways were assessed using morphometrics and immunohistochemistry including placenta zonation, vasculature development, and nutrient transporter expression. Most notably, the placentas of Bcrp-null mice had reduced immunostaining of the cell adhesion marker, ß-catenin, and the trophoblast marker, cytokeratin, as well as decreased expression of divalent metal nutrient transporters (Dmt1, Zip14, and ZnT1) following Cd treatment. In summary, the absence of Bcrp expression increased placental concentrations of Cd which was associated with shorter fetal size that may be related to differential changes in molecular patterns of placental development and nutrition.

Associations between neighborhood stress and maternal sex steroid hormones in pregnancy.

BACKGROUND: Neighborhood stressors (e.g., crime and deprivation) have been associated with adverse pregnancy outcomes including preterm birth and low birth weight. A potential mechanism is disruption of maternal endocrine pathways. While stress hormones (e.g., cortisol) have received much attention, other relevant hormones, including sex steroids, have been overlooked. METHODS: Pregnant women in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaires, and medical record data (n = 262). In each trimester, maternal serum total testosterone [TT], estrone, estradiol, and estriol were measured using LC/MS-MS and serum free testosterone was measured by equilibrium dialysis. In the third trimester, participants reported on neighborhood stress over the last year through the validated City Stress Inventory. We examined two subscales: 11-item neighborhood disorder (e.g., vacant buildings, crime) and 7-item exposure to violence (personal experiences of violence). Composite scores were calculated and examined categorically (quartile (Q) for neighborhood disorder and any/none for exposure to violence). We fitted linear mixed models examining associations between neighborhood stressors and sex steroid hormones across pregnancy as well as trimester-specific linear regression models, all adjusting for confounders. Secondarily, we stratified by fetal sex. Results are presented as percentage change (∆%) and 95% confidence interval (CI) in hormones. RESULTS: Most participants (73%) reported one or more exposures to neighborhood disorder; 22% reported any exposure to violence. In adjusted models, neighborhood disorder was associated with higher TT across pregnancy (Q2: %∆= 37.3, 95%CI: 13.2, 66.5; Q3: %∆= 22.2, 95%CI: 1.2, 47.5; and Q4: %∆= 25.7, 95%CI: 1.6, 55.3), with the strongest associations observed in the third trimester (Q2: %∆= 38.0, 95%CI: 10.6, 72.1; Q3: %∆= 29.2, 95%CI: 4.4, 59.9; and Q4: %∆=33.4, 95%CI: 4.9, 69.6). In stratified models, neighborhood disorder was associated with higher TT among women carrying male fetuses (%∆ range: 48.2-84.8). Exposure to violence was not associated with any hormones. CONCLUSION: Neighborhood disorder is associated with higher maternal testosterone levels, which may have implications for maternal and child health. Additional research is needed to understand the mechanisms by which neighborhood stress impacts endocrine physiology.

Per- and polyfluoroalkyl substances, gestational weight gain, postpartum weight retention and body composition in the UPSIDE cohort.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals found in drinking water and consumer products, resulting in ubiquitous human exposure. PFAS have been linked to endocrine disruption and altered weight gain across the lifespan. A limited and inconsistent body of research suggests PFAS may impact gestational weight gain (GWG) and postpartum body mass index (BMI), which are important predictors of overall infant and maternal health, respectively. METHODS: In the Understanding Pregnancy Signals and Infant Development (UPSIDE/UPSIDE-MOMs) study (n = 243; Rochester, NY), we examined second trimester serum PFAS (PFOS: perfluorooctanesulfonic acid, PFOA: perfluorooctanoic acid, PFNA: perfluorononanoic acid, PFHxS: perfluorohexanesulfonic acid, PFDA: perfluorodecanoic acid) in relation to GWG (kg, and weekly rate of gain) and in the postpartum, weight retention (PPWR (kg) and total body fat percentage (measured by bioelectrical impedance)). We fit multivariable linear regression models examining these outcomes in relation to log-transformed PFAS in the whole cohort as well as stratified by maternal pre-pregnancy BMI (< 25 vs. = > 25 kg/m2), adjusting for demographics and lifestyle factors. We used weighted quantile sum regression to find the combined influence of the 5 PFAS on GWG, PPWR, and body fat percentage. RESULTS: PFOA and PFHxS were inversely associated with total GWG (PFOA: ß = -1.54 kg, 95%CI: -2.79, -0.30; rate ß = -0.05 kg/week, 95%CI: -0.09, -0.01; PFHxS: ß = -1.59 kg, 95%CI: -3.39, 0.21; rate ß = -0.05 kg/week, 95%CI: -0.11, 0.01) and PPWR at 6 and 12 months (PFOA 6 months: ß = -2.39 kg, 95%CI: -4.17, -0.61; 12 months: ß = -4.02 kg, 95%CI: -6.58, -1.46; PFHxS 6 months: ß = -2.94 kg, 95%CI: -5.52, -0.35; 12 months: ß = -5.13 kg, 95%CI: -8.34, -1.93). PFOA was additionally associated with lower body fat percentage at 6 and 12 months (ß = -1.75, 95%CI: -3.17, -0.32; ß = -1.64, 95%CI: -3.43, 0.16, respectively) with stronger associations observed in participants with higher pre-pregnancy BMI. The PFAS mixture was inversely associated with weight retention at 12 months (ß = -2.030, 95%CI: -3.486, -0.573) amongst all participants. CONCLUSION: PFAS, in particular PFOA and PFHxS, in pregnancy are associated with altered patterns of GWG and postpartum adiposity with potential implications for fetal development and long-term maternal cardiometabolic health.

Association between sex steroid hormones and subsequent hyperglycemia during pregnancy.

Objective: Sex steroid hormones may play a role in insulin resistance and glucose dysregulation. However, evidence regarding associations between early-pregnancy sex steroid hormones and hyperglycemia during pregnancy is limited. The primary objective of this study was to assess the relationships between first trimester sex steroid hormones and the subsequent development of hyperglycemia during pregnancy; with secondary evaluation of sex steroid hormones levels in mid-late pregnancy, concurrent with and subsequent to diagnosis of gestational diabetes. Methods: Retrospective analysis of a prospective pregnancy cohort study was conducted. Medically low-risk participants with no known major endocrine disorders were recruited in the first trimester of pregnancy (n=319). Sex steroid hormones in each trimester, including total testosterone, free testosterone, estrone, estradiol, and estriol, were assessed using high-performance liquid chromatography and tandem mass spectrometry. Glucose levels of the 1-hour oral glucose tolerance test and gestational diabetes diagnosis were abstracted from medical records. Multivariable linear regression models were fitted to assess the associations of individual first trimester sex steroids and glucose levels. Results: In adjusted models, first trimester total testosterone (ß=5.24, 95% CI: 0.01, 10.46, p=0.05) and free testosterone (ß=5.98, 95% CI: 0.97, 10.98, p=0.02) were positively associated with subsequent glucose concentrations and gestational diabetes diagnosis (total testosterone: OR=3.63, 95% CI: 1.50, 8.78; free testosterone: OR=3.69; 95% CI: 1.56, 8.73). First trimester estrone was also positively associated with gestational diabetes (OR=3.66, 95% CI: 1.56, 8.55). In mid-late pregnancy, pregnant people with gestational diabetes had lower total testosterone levels (ß=-0.19, 95% CI: -0.36, -0.02) after adjustment for first trimester total testosterone. Conclusion: Early-pregnancy sex steroid hormones, including total testosterone, free testosterone, and estrone, were positively associated with glucose levels and gestational diabetes in mid-late pregnancy. These hormones may serve as early predictors of gestational diabetes in combination with other risk factors.

Prenatal Cadmium Exposure and Maternal Sex Steroid Hormone Concentrations across Pregnancy.

Cadmium exposure has been associated with adverse perinatal outcomes. One possible mechanism is endocrine disruption. Studies of non-pregnant adults suggest that cadmium impacts androgen production; here, we examined these associations during pregnancy. Participants in the Understanding Pregnancy Signals and Infant Development (UPSIDE) cohort provided biospecimens and questionnaire data in each trimester (n = 272). We quantified urinary cadmium, serum total testosterone (TT), estrone, estradiol, and estriol and serum free testosterone (fT). In adjusted longitudinal models, we examined sex steroid concentrations across pregnancy in relation to specific gravity-adjusted, ln-transformed cadmium concentrations. Additionally, we examined trimester-specific associations and stratified models by fetal sex. Results are presented as percent change (%∆) in hormone concentrations. In longitudinal models, higher cadmium concentrations were associated with lower fT across pregnancy (%∆ = -5.19, 95%CI: -8.33, -1.93), with no differences in other hormones observed. In trimester-specific models, higher cadmium concentrations were associated with lower TT in trimester 2 (%∆ = -15.26, 95%CI: -25.15, -4.06) and lower fT in trimester 3 (%∆ = -14.35, 95%CI: -19.75, -8.59). Associations with TT were stronger in pregnancies carrying female fetuses. Maternal cadmium exposure may be associated with reduced testosterone in pregnancy. Additional work is necessary to understand how alterations in gestational testosterone activity may impact pregnancy and child health.

Cadmium reduces growth of male fetuses by impairing development of the placental vasculature and reducing expression of nutrient transporters.

In utero exposure to the toxic metal cadmium (Cd) alters fetoplacental growth in rodents and has been inversely associated with birth weight and infant size in some birth cohorts. Moreover, studies suggest that Cd may have differential effects on growth and development according to offspring sex. The purpose of the current study was to evaluate changes in male and female fetoplacental development following a single injection of saline (5 ml/kg ip) or cadmium chloride (CdCl2, 2.5, 5 mg/kg, ip) on gestational day (GD) 9. By GD18, no changes in fetal or placental weights were observed after treatment with 2.5 mg/kg CdCl2. By comparison, the weight and length of male fetuses and their placentas were reduced following treatment with 5 mg/kg CdCl2 whereas no change was observed in females. In addition, the area of maternal and fetal blood vessels as well as the expression of the glucose transporters, Glut1 and Glut3, and the endothelial marker, CD34, were reduced in the placentas of CdCl2-treated male offspring compared to females. Interestingly, the placentas of females accumulated 80% more Cd than males after CdCl2 (5 mg/kg) administration. Female placentas also had higher concentrations of zinc and the zinc transporter Znt1 compared to males which may explain the limited changes in fetal growth observed following CdCl2 treatment. Taken together, disruption of vasculature development and reduced expression of glucose transporters in the placenta provide potential mechanisms underlying reduced fetal growth in male offspring despite the greater accumulation of Cd in female placentas.

Gadolinium during human pregnancy following administration of gadolinium chelate before pregnancy.

Gadolinium (Gd), a toxic rare earth element, has been shown to dissociate from chelating agents and bioaccumulate within tissues, raising concerns about the possibility of their remobilization during pregnancy with subsequent free Gd exposures to developing fetuses. Gd chelates are among the most commonly used magnetic resonance imaging (MRI) contrast agents. This investigation was undertaken after the detection of elevated Gd (800-1000× higher than the usual rare earth element levels) in preliminary unpublished studies from the placentae of subjects in the NIH ECHO/UPSIDE Rochester Cohort Study and unpublished studies from placentae analyzed in formalin-fixed placental specimens from Surgical Pathology at the University of Rochester. Fifteen pregnancies with elevated Gd were studied (12 first pregnancies and 3 second pregnancies). Maternal bloods were collected from all three trimesters, maternal, and cord (fetal) bloods at delivery as well as placental tissue. Breastmilk was also collected from selected mothers. It was determined that Gd was present in maternal bloods from all three trimesters, and in cord bloods and breastmilk in both first and second pregnancies. These results emphasize the need to fully appreciate the implications of pre-pregnancy exposure to Gd chelates and its potential effects on maternal and fetal health.

Adverse Childhood Experiences Predict Diurnal Cortisol Throughout Gestation.

OBJECTIVE: Adverse childhood experiences (ACEs) are associated with negative prenatal and perinatal health outcomes and may, via these pathways, have intergenerational effects on child health and development. We examine the impact of ACEs on maternal salivary cortisol, a key measure of prenatal biology previously linked with pregnancy-related health outcomes. METHODS: Leveraging assessments across three trimesters, we used linear mixed-effects models to analyze the influence of ACEs on maternal prenatal diurnal cortisol patterns in a diverse cohort of pregnant women (analytic sample, n = 207). Covariates included comorbid prenatal depression, psychiatric medications, and sociodemographic factors. RESULTS: Maternal ACEs were significantly associated with flatter diurnal cortisol slopes (i.e., less steep decline), after adjusting for covariates, with effects consistent across gestation (estimate = 0.15, standard error = 0.06, p = .008). CONCLUSIONS: ACEs experienced before pregnancy may have a robust and lasting influence on maternal prenatal hypothalamic-pituitary-adrenal activity throughout gestation, a key biological marker associated with perinatal and child health outcomes. The findings suggest one route of intergenerational transmission of early adverse experiences and underscore the potential value of assessing prepregnancy adverse experiences for promoting perinatal and maternal and child health.

Urinary 1-hydroxypyrene in pregnant women in a Northeastern U.S. city: socioeconomic disparity and contributions from air pollution sources.

BACKGROUND: Maternal exposure to polycyclic aromatic hydrocarbons (PAHs), ubiquitous constituents of air pollution, has been associated with adverse birth outcomes. Yet it remains unclear whether and how socioeconomic status (SES) affects gestational PAH exposure. OBJECTIVE: To examine whether there are socioeconomic disparities in PAHs exposure among pregnant women from Rochester, NY, and if so, to what extent disproportionate proximity to air pollution sources, measured by residential distance to transportation-related sources, contributed to the exposure disparity. METHODS: We measured 1-hydroxypyrene concentrations in 726 urine samples collected from 305 pregnant women up to three samples throughout pregnancy. Residential distances to transportation-related sources were calculated based on participants' home addresses. We used linear mixed-effects models with random intercepts of participants to examine associations between 1-hydroxypyrene, SES indicators, and distance to transportation-related sources. We used structural equation modelling to assess to what extent distance to transportation-related sources contributes to the socioeconomic disparity in 1-hydroxypyrene concentrations. RESULTS: Reduced household income and maternal education level were both significant SES predictors of 1-hydroxypyrene concentrations, after the adjustment for other maternal demographic characteristics. Each interquartile range (IQR) increases in residential proximity to the airport (from 14.3 to 6.0 km), the railroad yard (from 22.3 to 6.0 km), and annual average daily traffic within 300 m (from 3796 to 99,933 vehicles/year) were associated with 15.0% (95%CI: 7.0-22.2%), 15.4% (95%CI: 6.5-23.5%), and 13.6% (95%CI: 4.7-23.3%) increases in 1-hydroxypyrene concentrations, respectively. Proximity to these sources jointly explained 10% (95%CI: 1.6-18.4%) of the 1-hydroxypyrene concentration change associated with decreases in SES as a latent variable defined by both household income and education level. IMPACT STATEMENT: Our findings suggest that efforts to address disproportionate residential proximity to transportation-related sources may reduce the socioeconomic disparity in PAH exposure.

Protective role of the placental efflux transporter BCRP/ABCG2 in the relationship between prenatal cadmium exposure, placenta weight, and size at birth.

BACKGROUND AND AIM: Placental efflux transporter proteins, such as BCRP, reduce the placental and fetal toxicity of environmental contaminants but have received little attention in perinatal environmental epidemiology. Here, we evaluate the potential protective role of BCRP following prenatal exposure to cadmium, a metal that preferentially accumulates in the placenta and adversely impacts fetal growth. We hypothesized that individuals with a reduced function polymorphism in ABCG2, the gene encoding BCRP, would be most vulnerable to the adverse impacts of prenatal cadmium exposure, notably, smaller placental and fetal size. METHODS: We measured cadmium in maternal urine samples at each trimester and in term placentas from UPSIDE-ECHO study participants (NY, USA; n = 269). We fit adjusted multivariable linear regression and generalized estimating equation models to examine log-transformed urinary and placental cadmium concentrations in relation to birthweight, birth length, placental weight, and fetoplacental weight ratio (FPR) and stratified models by ABCG2 Q141K (C421A) genotype. RESULTS: Overall 17% of participants expressed the reduced-function ABCG2 C421A variant (AA or AC). Placental cadmium concentrations were inversely associated with placental weight (ß = -19.55; 95%CI: -37.06, -2.04) and trended towards higher FPR (ß = 0.25; 95%CI: -0.01, 0.52) with stronger associations in 421A variant infants. Notably, higher placental cadmium concentrations in 421A variant infants were associated with reduced placental weight (ß = -49.42; 95%CI: 98.87, 0.03), and higher FPR (ß = 0.85, 95%CI: 0.18, 1.52), while higher urinary cadmium concentration was associated with longer birth length (ß = 0.98; 95%CI: 0.37, 1.59), lower ponderal index (ß = -0.09; 95%CI: 0.15, -0.03), and higher FPR (ß = 0.42; 95%CI: 0.14, 0.71). CONCLUSIONS: Infants with reduced function ABCG2 polymorphisms may be particularly vulnerable to the developmental toxicity of cadmium as well as other xenobiotics that are BCRP substrates. Additional work examining the influence of placental transporters in environmental epidemiology cohorts is warranted.

Yolk sac development, function and role in rodent pregnancy.

During the early phases of embryonic development, the yolk sac serves as an initial placenta in many animal species. While in some, this role subsides around the end of active organogenesis, it continues to have important functions in rodents, alongside the chorio-allantoic placenta. The yolk sac is the initial site of hematopoiesis in many animal species including primates. Cells of epiblastic origin form blood islands that are the forerunners of hematopoietic cells and of the primitive endothelial cells that form the vitelline circulation. The yolk sac is also a major route of embryonic and fetal nutrition apparently as long as it functions. In mammals and especially rodents, macro and micronutrients are absorbed by active pinocytosis into the visceral yolk sac, degraded and the degradation products (i.e., amino acids) are then transferred to the embryo. Interference with the yolk sac function may directly reflect on embryonic growth and development, inducing congenital malformations or in extreme damage, causing embryonic and fetal death. In rodents, many agents were found to damage the yolk sac (i.e., anti-yolk sac antibodies or toxic substances interfering with yolk sac pinocytosis) subsequently affecting the embryo/fetus. Often, the damage to the yolk sac is transient while embryonic damage persists. In humans, decreased yolk sac diameter was associated with diabetic pregnancies and increased diameter was associated with pregnancy loss. In addition, culture of rat yolk sacs in serum obtained from pregnant diabetic women or from women with autoimmune diseases induced severe damage to the visceral yolk sac epithelium and embryonic malformations. It can be concluded that as a result of the crucial role of the yolk sac in the well-being of the early embryo, any damage to its normal function may severely and irreversibly affect further development of the embryo/fetus.

Intergenerational transmission of the effects of maternal exposure to childhood maltreatment in the USA: a retrospective cohort study.

BACKGROUND: Childhood maltreatment is associated with adverse health outcomes and this risk can be transmitted to the next generation. We aimed to investigate the association between exposure to maternal childhood maltreatment and common childhood physical and mental health problems, neurodevelopmental disorders, and related comorbidity patterns in offspring. METHODS: We conducted a retrospective cohort study using data from the Environmental influences on Child Health Outcomes (ECHO) Program, which was launched to investigate the influence of early life exposures on child health and development in 69 cohorts across the USA. Eligible mother-child dyads were those with available data on maternal childhood maltreatment exposure and at least one child health outcome measure (autism spectrum disorder, attention-deficit hyperactivity disorder [ADHD], internalising problems, obesity, allergy, and asthma diagnoses). Maternal history of childhood maltreatment was obtained retrospectively from the Adverse Childhood Experiences or Life Stressor Checklist questionnaires. We derived the prevalence of the specified child health outcome measures in offspring across childhood and adolescence by harmonising caregiver reports and other relevant sources (such as medical records) across cohorts. Child internalising symptoms were assessed using the Child Behavior Checklist. Associations between maternal childhood maltreatment and childhood health outcomes were measured using a series of mixed-effects logistic regression models. Covariates included child sex (male or female), race, and ethnicity; maternal and paternal age; maternal education; combined annual household income; maternal diagnosis of depression, asthma, ADHD, allergy, or autism spectrum disorder; and maternal obesity. Two latent class analyses were conducted: to characterise patterns of comorbidity of child health outcomes; and to characterise patterns of co-occurrence of childhood maltreatment subtypes. We then investigated the association between latent class membership and maternal childhood maltreatment and child health outcomes, respectively. FINDINGS: Our sample included 4337 mother-child dyads from 21 longitudinal cohorts (with data collection initiated between 1999 and 2016). Of 3954 mothers in the study, 1742 (44%) had experienced exposure to abuse or neglect during their childhood. After adjustment for confounding, mothers who experienced childhood maltreatment were more likely to have children with internalising problems in the clinical range (odds ratio [OR] 2·70 [95% CI 1·95-3·72], p<0·0001), autism spectrum disorder (1·70 [1·13-2·55], p=0·01), ADHD (2·09 [1·63-2·67], p<0·0001), and asthma (1·54 [1·34-1·77], p<0·0001). In female offspring, maternal childhood maltreatment was associated with a higher prevalence of obesity (1·69 [1·17-2·44], p=0·005). Children of mothers exposed to childhood maltreatment were more likely to exhibit a diagnostic pattern characterised by higher risk for multimorbidity. Exposure to multiple forms of maltreatment across all subtypes of maternal childhood maltreatment was associated with the highest risk increases for most offspring health outcomes, suggesting a dose-response relationship. INTERPRETATION: Our findings suggest that maternal childhood maltreatment experiences can be a risk factor for disease susceptibility in offspring across a variety of outcomes and emphasise the need for policies focusing on breaking the intergenerational transmission of adversity. FUNDING: Environmental influences on Child Health Outcomes Program, Office of the Director, National Institutes of Health.

Prenatal perfluoroalkyl substances exposure and maternal sex steroid hormones across pregnancy.

BACKGROUND: Poly- and perfluoroalkyl substances (PFAS) are ubiquitous and persistent environmental contaminants that may act as endocrine disruptors in utero, but the specific endocrine pathways are unknown. OBJECTIVE: We examined associations between maternal serum PFAS and sex steroid hormones at three time points during pregnancy. METHODS: Pregnant women participating in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaire, and medical record data in each trimester (n = 285). PFAS (including perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA)) were analyzed in second-trimester serum samples by high-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Total testosterone [TT], free testosterone [fT], estrone [E1], estradiol [E2], and estriol [E3]) were measured by LC-MS/MS in serum samples from each trimester. Linear mixed models with random intercepts were used to examine associations between log-transformed PFAS concentrations and hormone levels, adjusting for covariates, and stratifying by fetal sex. Results are presented as the mean percentage difference (Δ%) in hormone levels per ln-unit increase in PFAS concentration. RESULTS: In adjusted models, PFHxS was associated with higher TT (%Δ = 20.0, 95%CI: 1.7, 41.6), particularly among women carrying male fetuses (%Δ = 15.3, 95%CI: 1.2, 30.7); this association strengthened as the pregnancy progressed. PFNA (%Δ = 7.9, 95%CI: 3.4, 12.5) and PFDA (%Δ = 7.2, 95%CI: 4.9, 9.7) were associated with higher fT, with associations again observed only in women carrying male fetuses. PFHxS was associated with higher levels of E2 and E3 in women carrying female fetuses (%Δ = 13.2, 95%CI: 0.5, 29.1; %Δ = 17.9, 95%CI: 3.2, 34.8, respectively). No associations were observed for PFOS and PFOA. CONCLUSION: PFHxS, PFNA, and PFDA may disrupt androgenic and estrogenic pathways in pregnancy in a sex-dependent manner.