Endocrine disrupting chemicals (EDCs) are ubiquitous, and pregnancy is a sensitive window for toxicant exposure. EDCs may disrupt the maternal immune system, which may lead to poor pregnancy outcomes. Most studies investigate single EDCs, even though “real life” exposures do not occur in isolation. We tested the hypothesis that uniquely weighted mixtures of early pregnancy exposures are associated with distinct changes in the maternal and neonatal inflammasome. First trimester urine samples were tested for 12 phthalates, 12 phenols, and 17 metals in 56 women. Twelve cytokines were measured in first trimester and term maternal plasma, and in cord blood after delivery. Spearman correlations and linear regression were used to relate individual exposures with inflammatory cytokines. Linear regression was used to relate cytokine levels with gestational age and birth weight. Principal component analysis was used to assess the effect of weighted EDC mixtures on maternal and neonatal inflammation. Our results demonstrated that maternal and cord blood cytokines were differentially associated with (1) individual EDCs and (2) EDC mixtures. Several individual cytokines were positively associated with gestational age and birth weight. These observed associations between EDC mixtures and the pregnancy inflammasome may have clinical and public health implications for women of childbearing age.
Adolescents with consistently insufficient sleep could be at greater risk for obesity. The finding that insufficient-variable sleepers had only slightly higher adiposity suggests that opportunities for "catch-up" sleep may be protective.
Introduction/Purpose Limited studies have examined the association of physical activity with reproductive hormones, DNA methylation, and pubertal status among adolescents. Methods Among 248 boys and 271 girls, we estimated daily physical activity levels based on 7 d of wrist-worn accelerometer data. We used an isotemporal substitution paradigm and sex-stratified regression models to examine the association of physical activity levels with 1) testosterone, cortisol, progesterone, and androstenedione concentrations; 2) DNA methylation of long interspersed nucleotide (LINE-1) repeats and the genes H19, hydroxysteroid (11-Beta) dehydrogenase 2 (HSD11B2), and peroxisome proliferator-activated receptor alpha (PPARA) from blood leukocytes; and 3) Tanner stages, adjusted for age, BMI, and socioeconomic status. Results In boys, substituting 30 min of moderate physical activity for 30 min of sedentary behavior per day was associated with 29% (−49%, 0%) of lower testosterone and 29% (4%, 61%) of higher progesterone. Substituting 30 min of light physical activity for sedentary behavior was associated with 13% (−22%, −2%) of lower progesterone. Among girls, 30 min of additional sedentary behavior was associated with 8% (−15%, 0%) of lower testosterone and 24% (8%, 42%) of higher progesterone concentrations. Substituting 30 min of moderate physical activity for sedentary behavior was associated with 15% (0%, 31%) of higher cortisol, whereas substituting the same amount of light physical activity for sedentary behavior was associated with 22% (−39%, 0%) of lower progesterone. Substituting 30 min of vigorous physical activity for sedentary behavior per day was associated with almost six times higher levels (5.83, 95% confidence interval = 1.79–9.86) of HSD11B2 methylation in boys. Conclusions Accelerometer-measured daily physical activity was associated with reproductive hormones and HSD11B2 DNA methylation, differed by sex and activity intensity levels.
Context Early pregnancy exposure to endocrine disrupting chemicals (EDCs) may contribute to poor birth outcomes through oxidative stress (OS)-mediated disruption of the maternal and fetal milieu. Most studies have investigated the effect of single EDC exposures on OS. Objective Assess the association of uniquely weighted mixtures of early pregnancy exposures with the maternal and neonatal OS markers. Design Prospective analysis of mother–infant dyads Setting University hospital. Participants 56 mother–infant dyads. Main Outcome Measures The association of OS markers (nitrotyrosine, dityrosine, chlorotyrosine) in maternal first trimester and term, and cord blood plasma with maternal first trimester exposure levels of each of 41 toxicants (trace elements, metals, phenols, and phthalates) from 56 subjects was analyzed using Spearman correlations and linear regression. The association of OS markers with inflammatory cytokines and birth outcomes were analyzed by Spearman correlation and linear regression analysis, respectively. Weighted mixtures of early pregnancy exposures were created by principal component analysis and offspring sex-dependent and independent associations with oxidative stress markers were assessed. Results (1) An inverse relationship between levels of maternal/cord OS markers and individual EDCs was evident. In contrast, when assessed as EDC mixtures, both direct and inverse associations were evident in a sex-specific manner; (2) the maternal term OS marker, nitrotyrosine, was inversely associated with gestational age, and (3) both direct and inverse associations were evident between the 3 OS markers and individual cytokines. Conclusions Provides proof of concept that effects of exposures on OS varies when assessed as EDC mixtures versus individually.
Study Objectives Sleep deprivation and low sleep quality are widespread among adolescents, and associate with obesity risk. Plausible mediators include diet and physical activity. Another potential interrelated pathway, as yet unexplored in adolescents, could involve epigenetic modification of metabolism genes. Methods In a cohort of 351 Mexico City adolescents (47% male; mean [SD] age = 14 [2] years), 7-day actigraphy was used to assess average sleep duration, sleep fragmentation, and movement index. DNA isolated from blood leukocytes was bisulfite-converted, amplified, and pyrosequenced at four candidate regions. Linear mixed models evaluated sex-stratified associations between sleep characteristics (split into quartiles [Q]) and DNA methylation of each region, adjusted for potential confounders. Results Mean sleep duration was 8.5 [0.8] hours for boys and 8.7 [1] hours for girls. There were sex-specific associations between sleep duration and LINE-1 (long interspersed nuclear element) methylation. Boys with longer sleep duration (Q4) had lower LINE-1 methylation than boys in the 3rd quartile reference category, while girls with both longer and shorter sleep duration had higher LINE-1 methylation compared to Q3. Longer sleep duration was associated with higher H19 methylation among girls (comparing highest to third quartile, −0.9% [−2.2, 0.5]; p, trend = 0.047). Sleep fragmentation was inversely associated with peroxisome proliferator-activated receptor alpha (PPARA) methylation among girls (comparing highest to lowest fragmentation quartile, 0.9% [0.1 to 1.8]). Girls also showed an inverse association between sleep fragmentation and hydroxysteroid (11-beta) dehydrogenase 2 (HSD11B2; Q4 to Q1, 0.6% [−1.2%, 0%]). Conclusions Sleep duration and fragmentation in adolescents show sex-specific associations with leukocyte DNA methylation patterns of metabolism genes.
Context Adrenal-derived 11-oxygenated androgens (11oAs) are known important contributors to human physiology and disease but have not been studied in pregnancy. Objective We characterize 11oAs in normal human pregnancy and neonatal period and assess the ratios between 11oAs and compare with ratios of other steroids that undergo placental metabolism. Design Prospective cohort study, 2010-2018. Setting Academic institution. Patients Pairs of pregnant women and newborns (n = 120) were studied. Inclusion criteria were maternal age between 18 and 42 years old, spontaneous singleton pregnancies, and intention to deliver at University of Michigan. Intervention Maternal venous blood was collected during first trimester and at term. Neonatal cord blood was collected following delivery. Steroids were measured via liquid chromatography-tandem mass spectrometry. Main Outcome Measures Levels of 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone, and 11-ketotestoterone (11KT) in maternal first trimester, maternal term, and neonatal cord blood were compared. 11OHA4-to-11KA4 ratios were correlated with cortisol-to-cortisone ratios. Results Dominant 11oAs in pregnancy and the cord blood are 11OHA4 and 11KA4, compared to 11OHA4 and 11KT in adult men and nonpregnant women. We found a rise in 11oA concentrations, particularly 11KA4, from first to third trimester. In cord blood, the concentration of 11KA4 exceeded those of both 11OHA4 and 11KT, reflecting placental 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and 17β-hydroxysteroid dehydrogenase (17βHSD2) activities, respectively. 11OHA4-to-11KA4 ratios are concordant with cortisol-to-cortisone ratios across all maternal and fetal compartments, reflecting placental 11βHSD2 activity. Conclusions Placental 17βHSD2 activity defends the fetus against the androgen 11KT. Our normative values may be used in future studies of 11oAs in complicated pregnancies.
Context Steroids play an important role in fetal development and parturition. Gestational exposures to endocrine disrupting chemicals (EDCs) affect steroidal milieu and pregnancy outcomes, raising the possibility of steroids serving as biomarkers. Most studies have not addressed the impact of EDC mixtures, which are reflective of real life scenarios. Objective Assess the association of maternal and neonatal steroids with pregnancy outcomes and early pregnancy EDC levels. Design Prospective analysis of mother-infant dyads. Setting University hospital. Participants 121 mother-infant dyads. Main Outcome Measures The associations of maternal and neonatal steroidal hormones from 121 dyads with pregnancy outcomes, the associations of first trimester EDCs individually and as mixtures with maternal and neonatal steroids in a sub-set of 56 dyads and the influence of BMI, age and offspring sex in modulating the EDC associations with steroids were determined. Results (1) Steroid-specific positive or negative associations with pregnancy measures were evident; (2) many maternal first trimester EDCs were negatively associated with estrogens and positively with androgen/estrogen ratios; (3) EDC-steroid associations were influenced by maternal age, pre-pregnancy BMI, and fetal sex and (4) EDCs individually and as mixtures showed direct and inverse fetal sex-dependent associations with maternal and neonatal steroids. Conclusions This proof-of-concept study indicates association of steroids with pregnancy outcomes depending on maternal age, pre-pregnancy BMI, and fetal sex, with the effects of EDCs differing when considered individually or as mixtures. These findings suggest that steroidal hormonal measures have potential to serve as biomarkers of impact of EDC exposures and pregnancy outcome.
Summary Background Alterations in body composition (BC) during adolescence relates to future metabolic risk, yet underlying mechanisms remain unclear. Objectives To assess the association between the metabolome with changes in adiposity (body mass index [BMI], waist circumference [WC], triceps skinfold [TS], fat percentage [BF%]) and muscle mass (MM). Methods In Mexican adolescents (n = 352), untargeted serum metabolomics was profiled at baseline. and data were reduced by pairing hierarchical clustering with confirmatory factor analysis, yielding 30 clusters with 51 singleton metabolites. At the baseline and follow‐up visits (1.6–3.5 years apart), anthropometry was collected to identify associations between baseline metabolite clusters and change in BC (∆) using seemingly unrelated and linear regression. Results Between visits, MM increased in boys and adiposity increased in girls. Sex differences were observed between metabolite clusters and changes in BC. In boys, aromatic amino acids (AAA), branched chain amino acids (BCAA) and fatty acid oxidation metabolites were associated with increases in ∆BMI, and ∆BF%. Phospholipids were associated with decreases in ∆TS and ∆MM. Negative associations were observed for ∆MM in boys with a cluster including AAA and BCAA, whereas positive associations were found for a cluster containing tryptophan metabolites. Few associations were observed between metabolites and BC change in girls, with one cluster comprising methionine, proline and lipids associated with decreases in ∆BMI, ∆WC and ∆MM. Conclusion Sex‐specific associations between the metabolome and change in BC were observed, highlighting metabolic pathways underlying adolescent physical growth.
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