Placental cell type deconvolution reveals that cell proportions drive preeclampsia gene expression differences.

The placenta mediates adverse pregnancy outcomes, including preeclampsia, which is characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue (n = 9 biological replicates) at term (n = 40,494 cells). We deconvoluted eight published microarray case-control studies of preeclampsia (n = 173 controls, 157 cases). Preeclampsia was associated with excess extravillous trophoblasts and fewer mesenchymal and Hofbauer cells. Adjustment for cellular composition reduced preeclampsia-associated differentially expressed genes (log2 fold-change cutoff = 0.1, FDR < 0.05) from 1154 to 0, whereas downregulation of mitochondrial biogenesis, aerobic respiration, and ribosome biogenesis were robust to cell type adjustment, suggesting direct changes to these pathways. Cellular composition mediated a substantial proportion of the association between preeclampsia and FLT1 (37.8%, 95% CI [27.5%, 48.8%]), LEP (34.5%, 95% CI [26.0%, 44.9%]), and ENG (34.5%, 95% CI [25.0%, 45.3%]) overexpression. Our findings indicate substantial placental cellular heterogeneity in preeclampsia contributes to previously observed bulk gene expression differences. This deconvolution reference lays the groundwork for cellular heterogeneity-aware investigation into placental dysfunction and adverse birth outcomes.

Probing prenatal bisphenol exposures and tissue-specific DNA methylation responses in cord blood, cord tissue, and placenta.

The early-gestational fetal epigenome establishes the landscape for fetal development and is susceptible to disruption via environmental stressors including chemical exposures. Research has explored how cell- and tissue-type-specific epigenomic signatures contribute to human disease, but how the epigenome in each tissue comparatively responds to environmental exposures is largely unknown. This pilot study compared DNA methylation in four previously identified genes across matched cord blood (CB), cord tissue (CT), and placental (PL) samples from 28 mother-infant pairs in tthe Michigan Mother Infant Pairs study; evaluated association between prenatal exposure to bisphenols (BPA, BPF, and BPS) and DNA methylation (DNAm) by tissue type; compared epigenome-wide DNAm of CB and PL; and explored associations between prenatal bisphenol exposures and epigenome-wide DNAm in PL. Bisphenol concentrations were quantified in first-trimester maternal urine. DNAm was assessed at four genes via pyrosequencing in three tissues; epigenome-wide DNAm analysis via Infinium MethylationEPIC array was completed on CB and PL. Candidate gene analysis revealed tissue-specific differences across all genes. In adjusted linear regression, BPA and BPF were associated with DNAm across candidate genes in PL but not CB and CT. Epigenome-wide comparison of matched CB and PL DNAm revealed tissue-specific differences at most CpG sites and modest associations between maternal first-trimester bisphenol exposures and PL but not CB DNAm. These data endorse inclusion of a variety of tissues in prenatal exposure studies. Overlapping and divergent responses in CB, CT, and PL demonstrate their utility in combination to capture a fuller picture of the epigenetic effect of developmental exposures.

Maternal and neonatal one-carbon metabolites and the epigenome-wide infant response.

Maternal prenatal status, as encapsulated by that to which a mother is exposed through diet and environment, is a key determinant of offspring health and disease. Alterations in DNA methylation (DNAm) may be a mechanism through which suboptimal prenatal conditions confer disease risk later in life. One-carbon metabolism (OCM) is critical to both fetal development and in supplying methyl donors needed for DNAm. Plasma concentrations of one-carbon metabolites across maternal first trimester (M1), maternal term (M3), and infant cord blood (CB) at birth were tested for association with DNAm patterns in CB from the Michigan Mother and Infant Pairs (MMIP) pregnancy cohort. The Illumina Infinium MethylationEPIC BeadChip was used to quantitatively evaluate DNAm across the epigenome. Global and single-site DNAm and metabolite models were adjusted for infant sex, estimated cell type proportions, and batch as covariates. Change in mean metabolite concentration across pregnancy (M1 to M3) was significantly different for S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), betaine, and choline. Both M1 SAH and CB SAH were significantly associated with the global distribution of DNAm in CB, with indications of a shift toward less methylation. M3 SAH and CB SAH also displayed significant associations with locus-specific DNAm in infant CB (FDR<0.05). Our findings underscore the role of maternal one-carbon metabolites in shifting the global DNAm pattern in CB and emphasizes the need to closely evaluate how dietary status influences cellular methylation potential and ultimately offspring health.

Intestinal commensal microbiota and cytokines regulate Fut2+ Paneth cells for gut defense.

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2- Paneth cells were localized in the duodenum, whereas the majority of Fut2+ Paneth cells were in the ileum. Fut2+ Paneth cells showed higher granularity and structural complexity than did Fut2- Paneth cells, suggesting that Fut2+ Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2+ Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2+ Paneth cells as part of gut defense.

Association of Maternal-Neonatal Steroids With Early Pregnancy Endocrine Disrupting Chemicals and Pregnancy Outcomes.

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 subset of 56 dyads and the influence of body mass index (BMI), age, and offspring sex in modulating the EDC associations with steroids were determined. RESULTS: Steroid-specific positive or negative associations with pregnancy measures were evident; many maternal first trimester EDCs were negatively associated with estrogens and positively with androgen/estrogen ratios; EDC-steroid associations were influenced by maternal age, pre-pregnancy BMI, and fetal sex; and 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, prepregnancy 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.

Maternal lipodome across pregnancy is associated with the neonatal DNA methylome.

Aim: To classify the association between the maternal lipidome and DNA methylation in cord blood leukocytes. Materials & methods: Untargeted lipidomics was performed on first trimester maternal plasma (M1) and delivery maternal plasma (M3) in 100 mothers from the Michigan Mother-Infant Pairs cohort. Cord blood leukocyte DNA methylation was profiled using the Infinium EPIC bead array and empirical Bayes modeling identified differential DNA methylation related to maternal lipid groups. Results: M3-saturated lysophosphatidylcholine was associated with 45 differentially methylated loci and M3-saturated lysophosphatidylethanolamine was associated with 18 differentially methylated loci. Biological pathways enriched among differentially methylated loci by M3 saturated lysophosphatidylcholines were related to cell proliferation and growth. Conclusion: The maternal lipidome may be influential in establishing the infant epigenome.

Maternal lipid levels across pregnancy impact the umbilical cord blood lipidome and infant birth weight.

Major alterations in metabolism occur during pregnancy enabling the mother to provide adequate nutrients to support infant development, affecting birth weight (BW) and potentially long-term risk of obesity and cardiometabolic disease. We classified dynamic changes in the maternal lipidome during pregnancy and identified lipids associated with Fenton BW z-score and the umbilical cord blood (CB) lipidome. Lipidomics was performed on first trimester maternal plasma (M1), delivery maternal plasma (M3), and CB plasma in 106 mother-infant dyads. Shifts in the maternal and CB lipidome were consistent with the selective transport of long-chain polyunsaturated fatty acids (PUFA) as well as lysophosphatidylcholine (LysoPC) and lysophosphatidylethanolamine (LysoPE) species into CB. Partial correlation networks demonstrated fluctuations in correlations between lipid groups at M1, M3, and CB, signifying differences in lipid metabolism. Using linear models, LysoPC and LysoPE groups in CB were positively associated with BW. M1 PUFA containing triglycerides (TG) and phospholipids were correlated with CB LysoPC and LysoPE species and total CB polyunsaturated TGs. These results indicate that early gestational maternal lipid levels influence the CB lipidome and its relationship with BW, suggesting an opportunity to modulate maternal diet and improve long-term offspring cardiometabolic health.

Toxicant Disruption of Immune Defenses: Potential Implications for Fetal Membranes and Pregnancy.

In addition to providing a physical compartment for gestation, the fetal membranes (FM) are an active immunological barrier that provides defense against pathogenic microorganisms that ascend the gravid reproductive tract. Pathogenic infection of the gestational tissues (FM and placenta) is a leading known cause of preterm birth (PTB). Some environmental toxicants decrease the capacity for organisms to mount an immune defense against pathogens. For example, the immunosuppressive effects of the widespread environmental contaminant trichloroethylene (TCE) are documented for lung infection with Streptococcus zooepidemicus. Group B Streptococcus (GBS; Streptococcus agalactiae) is a bacterial pathogen that is frequently found in the female reproductive tract and can colonize the FM in pregnant women. Work in our laboratory has demonstrated that a bioactive TCE metabolite, S-(1, 2-dichlorovinyl)-L-cysteine (DCVC), potently inhibits innate immune responses to GBS in human FM in culture. Despite these provocative findings, little is known about how DCVC and other toxicants modify the risk for pathogenic infection of FM. Infection of the gestational tissues (FM and placenta) is a leading known cause of PTB, therefore toxicant compromise of FM ability to fight off infectious microorganisms could significantly contribute to PTB risk. This Perspective provides the current status of understanding of toxicant-pathogen interactions in FM, highlighting knowledge gaps, challenges, and opportunities for research that can advance protections for maternal and fetal health.

Developmental programming: Prenatal testosterone-induced changes in epigenetic modulators and gene expression in metabolic tissues of female sheep.

Prenatal testosterone (T)-treated female sheep manifest peripheral insulin resistance and tissue-specific changes in insulin sensitivity with liver and muscle manifesting insulin resistance accompanied by inflammatory, oxidative and lipotoxic state. In contrast, visceral (VAT) and subcutaneous (SAT) adipose tissues are insulin sensitive in spite of VAT manifesting changes in inflammatory and oxidative state. We hypothesized that prenatal T-induced changes in tissue-specific insulin resistance arise from disrupted lipid storage and metabolism gene expression driven by changes in DNA and histone modifying enzymes. Changes in gene expression were assessed in liver, muscle and 4 adipose (VAT, SAT, epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep. Prenatal T-treatment increased lipid droplet and metabolism genes PPARA and PLIN1 in liver, SREBF and PLIN1 in muscle and showed a trend for decrease in PLIN2 in PRAT. Among epigenetic modifying enzymes, prenatal T-treatment increased expression of 1) DNMT1 in liver and DNMT3A in VAT, PRAT, muscle and liver; 2) HDAC1 in ECAT, HDAC2 in muscle with decrease in HDAC3 in VAT; 3) EP300 in VAT and ECAT; and 4) KDM1A in VAT with increases in liver histone acetylation. Increased lipid storage and metabolism genes in liver and muscle are consistent with lipotoxicity in these tissues with increased histone acetylation likely contributing to increased liver PPARA. These findings are suggestive that metabolic defects in prenatal T-treated sheep may arise from changes in key genes mediated, in part, by tissue-specific changes in epigenetic-modifying enzymes.

Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood.

Maternal prenatal exposures, including bisphenol A (BPA), are associated with offspring's risk of disease later in life. Alterations in DNA methylation may be a mechanism through which altered prenatal conditions (e.g. maternal exposure to environmental toxicants) elicit this disease risk. In the Michigan Mother and Infant Pairs Cohort, maternal first-trimester urinary BPA, bisphenol F, and bisphenol S concentrations were tested for association with DNA methylation patterns in infant umbilical cord blood leukocytes (N = 69). We used the Illumina Infinium MethylationEPIC BeadChip to quantitatively evaluate DNA methylation across the epigenome; 822 020 probes passed pre-processing and quality checks. Single-site DNA methylation and bisphenol models were adjusted for infant sex, estimated cell-type proportions (determined using cell-type estimation algorithm), and batch as covariates. Thirty-eight CpG sites [false discovery rate (FDR) <0.05] were significantly associated with maternal BPA exposure. Increasing BPA concentrations were associated with lower DNA methylation at 87% of significant sites. BPA exposure associated DNA methylation sites were enriched for 38 pathways significant at FDR <0.05. The pathway or gene-set with the greatest odds of enrichment for differential methylation (FDR <0.05) was type I interferon receptor binding. This study provides a novel understanding of fetal response to maternal bisphenol exposure through epigenetic change.

Maternal Exposure to Environmental Disruptors and Sexually Dimorphic Changes in Maternal and Neonatal Oxidative Stress.

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.

Fucosyltransferase 2 induces lung epithelial fucosylation and exacerbates house dust mite-induced airway inflammation.

BACKGROUND: One of the pathognomonic features of asthma is epithelial hyperproduction of mucus, which is composed of a series of glycoproteins; however, it remains unclear how glycosylation is induced in lung epithelial cells from asthmatic patients and how glycan residues play a role in the pathogenesis of asthma. OBJECTIVE: The objective of this study was to explore comprehensive epithelial glycosylation status induced by allergic inflammation and reveal its possible role in the pathogenesis of asthma. METHODS: We evaluated the glycosylation status of lung epithelium using a lectin microarray. We next searched for molecular mechanisms underlying epithelial glycosylation. We also examined whether epithelial glycosylation is involved in induction of allergic inflammation. RESULTS: On allergen inhalation, lung epithelial cells were heavily α(1,2)fucosylated by fucosyltransferase 2 (Fut2), which was induced by the IL-13-signal transducer and activator of transcription 6 pathway. Importantly, Fut2-deficient (Fut2-/-) mice, which lacked lung epithelial fucosylation, showed significantly attenuated eosinophilic inflammation and airway hyperresponsiveness in house dust mite (HDM)-induced asthma models. Proteome analyses and immunostaining of the HDM-challenged lung identified that complement C3 was accumulated in fucosylated areas. Indeed, Fut2-/- mice showed significantly reduced levels of C3a and impaired accumulation of C3a receptor-expressing monocyte-derived dendritic cells in the lung on HDM challenge. CONCLUSION: Fut2 induces epithelial fucosylation and exacerbates airway inflammation in asthmatic patients in part through C3a production and monocyte-derived dendritic cell accumulation in the lung.

Early pregnancy exposure to endocrine disrupting chemical mixtures are associated with inflammatory changes in maternal and neonatal circulation.

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.

First trimester maternal exposures to endocrine disrupting chemicals and metals and fetal size in the Michigan Mother-Infant Pairs study.

Exposures to endocrine disrupting chemicals and metals are near ubiquitous worldwide, and their potential impact on children is a major public health concern. This pilot study was designed to characterize exposures to phthalates, phenols and metals among pregnant women in the first trimester, and to examine associations with fetal biometrics and birth weight. A total of 41 chemicals and elements were analyzed in urine from 56 mothers with full-term newborns from the Michigan Mother-Infant Pairs study. Bivariate analyses identified predictors of exposure biomarkers. Associations between birth weight, Fenton z-scores and second trimester fetal biometrics with toxicants were examined via multivariable linear regression. An average of 30 toxicants were detected in maternal urine. Fast food consumption was associated with several phthalate metabolites, phenols and metals, and canned food consumption with bisphenol F (P <0.05). Mono (3-carboxypropyl) phthalate was significantly associated with higher birth weight and Fenton z-score while the opposite was observed for bisphenol S. Estimated femur length from ultrasonography was significantly inversely associated with arsenic, barium and lead. While limited by sample size, this study is one of the first to evaluate birth outcomes with respect to emerging endocrine disrupting chemicals and to examine associations between toxicants and fetal biometrics. Exposure assessment was provided by the National Institute of Environmental Health Sciences' Children's Health Exposure Analysis Resource (NIEHS CHEAR), a resource available to children's studies with the goal of combining data across cohorts in an effort to characterize the impact of toxicants on child health from birth and beyond.

Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation.

Endocrine disrupting chemicals (EDCs) pose a public health risk through disruption of normal biological processes. Identifying toxicoepigenetic mechanisms of developmental exposure-induced effects for EDCs, such as phthalates or bisphenol A (BPA), is essential. Here, we investigate whether maternal exposure to EDCs is predictive of infant DNA methylation at candidate gene regions. In the Michigan Mother-Infant Pairs (MMIP) cohort, DNA was extracted from cord blood leukocytes for methylation analysis by pyrosequencing (n = 116) and methylation changes related to first trimester levels of 9 phthalate metabolites and BPA. Growth and metabolism-related genes selected for methylation analysis included imprinted (IGF2, H19) and non-imprinted (PPARA, ESR1) genes along with LINE-1 repetitive elements. Findings revealed decreases in methylation of LINE-1, IGF2, and PPARA with increasing phthalate concentrations. For example, a log unit increase in ΣDEHP corresponded to a 1.03 [95% confidence interval (CI): -1.83, -0.22] percentage point decrease in PPARA methylation. Changes in DNA methylation were also inversely correlated with PPARA gene expression determined by RT-qPCR (r = -0.34, P = 0.02), thereby providing evidence in support of functional relevance. A sex-stratified analysis of EDCs and DNA methylation showed that some relationships were female-specific. For example, urinary BPA exposure was associated with a 1.35 (95%CI: -2.69, -0.01) percentage point decrease in IGF2 methylation and a 1.22 (95%CI: -2.27, -0.16) percentage point decrease in PPARA methylation in females only. These findings add to a body of evidence suggesting epigenetically labile regions may provide a conduit linking early exposures with disease risk later in life and that toxicoepigenetic susceptibility may be sex specific.

Lipid metabolism is associated with developmental epigenetic programming.

Maternal diet and metabolism impact fetal development. Epigenetic reprogramming facilitates fetal adaptation to these in utero cues. To determine if maternal metabolite levels impact infant DNA methylation globally and at growth and development genes, we followed a clinical birth cohort of 40 mother-infant dyads. Targeted metabolomics and quantitative DNA methylation were analyzed in 1st trimester maternal plasma (M1) and delivery maternal plasma (M2) as well as infant umbilical cord blood plasma (CB). We found very long chain fatty acids, medium chain acylcarnitines, and histidine were: (1) stable in maternal plasma from pregnancy to delivery, (2) significantly correlated between M1, M2, and CB, and (3) in the top 10% of maternal metabolites correlating with infant DNA methylation, suggesting maternal metabolites associated with infant DNA methylation are tightly controlled. Global DNA methylation was highly correlated across M1, M2, and CB. Thus, circulating maternal lipids are associated with developmental epigenetic programming, which in turn may impact lifelong health and disease risk. Further studies are required to determine the causal link between maternal plasma lipids and infant DNA methylation patterns.

Maternal phthalate exposure during early pregnancy and at delivery in relation to gestational age and size at birth: A preliminary analysis.

Epidemiologic studies of in utero phthalate exposure and birth outcomes have had conflicting findings. The objective of this study was to characterize maternal phthalate exposure across pregnancy, examine associations between maternal phthalate levels and infant size and gestational age at birth, and investigate relationships between concurrent bisphenol A (BPA) and phthalate exposure and birth outcomes. Women in the Michigan Mother-Infant Pairs cohort provided urine and blood samples during their first trimester and at delivery. Urinary phthalate metabolites and serum BPA were measured at both time points, and birth weight, length, head circumference, and gestational age were recorded from medical records. Maternal DEHP metabolite concentrations were significantly higher at delivery compared to the first trimester (p<0.05), suggesting increased DEHP exposure late in pregnancy. A number of phthalate metabolites were associated with birth size and gestational age in patterns that varied by sex and timing of exposure, independent of BPA exposure.

Gender-Specific Effects on Gestational Length and Birth Weight by Early Pregnancy BPA Exposure.

CONTEXT AND OBJECTIVE: Effects of prenatal exposure to bisphenol A (BPA) on gestational and birth outcomes are controversial. The aim of the study was to evaluate the relationship between prenatal exposure to BPA and birth and gestational outcomes. design, setting, participants, and outcome: Levels of unconjugated (uBPA) and BPA glucuronide in 80 matching samples of pregnant women during the first trimester of pregnancy and at delivery and matching term cord blood obtained from a prospective study conducted at the University of Michigan Hospitals were determined using a methodology validated in the National Institutes of Environmental Health Sciences funded Round Robin study and related to pregnancy outcomes. RESULTS: Highest levels of uBPA were found in maternal term samples followed by first trimester maternal (M1) samples and cord blood. A 2-fold increase in M1 uBPA was associated with 55-g less birth weight when male and female pregnancies were combined and 183-g less birth weight with only female pregnancies. A 2-fold increase in maternal term uBPA was associated with an increased gestational length of 0.7 days for all pregnancies and 1.1 days for only female pregnancies. CONCLUSION: Higher uBPA exposure levels during first trimester and term are associated with sex-specific reduction in birth weight and increase in gestational length, respectively. Race, parity, and employment have an effect on BPA exposure. Because low birth weight is associated with adverse health outcomes, effect of early pregnancy BPA levels on reducing birth weight highlights the risk posed by developmental exposure to BPA.

A key role for Fut1-regulated angiogenesis and ICAM-1 expression in K/BxN arthritis.

OBJECTIVES: Angiogenesis contributes to the pathogenesis of rheumatoid arthritis. Fucosyltransferases (Futs) are involved in angiogenesis and tumour growth. Here, we examined the role of Fut1 in angiogenesis and K/BxN serum transfer arthritis. METHODS: We examined Fut1 expression in human dermal microvascular endothelial cells (HMVECs) by quantitative PCR. We performed a number of angiogenesis assays to determine the role of Fut1 using HMVECs, Fut1 null (Fut1(-/-)), and wild type (wt) endothelial cells (ECs) and mice. K/BxN serum transfer arthritis was performed to determine the contribution of Fut1-mediated angiogenesis in Fut1(-/-) and wt mice. A static adhesion assay was implemented with RAW264.7 (mouse macrophage cell line) and mouse ECs. Quantitative PCR, immunofluorescence and flow cytometry were performed with Fut1(-/-) and wt ECs for adhesion molecule expression. RESULTS: Tumour necrosis factor-α induced Fut1 mRNA and protein expression in HMVECs. HMVECs transfected with Fut1 antisense oligodeoxynucleotide and Fut1(-/-) ECs formed significantly fewer tubes on Matrigel. Fut1(-/-) mice had reduced angiogenesis in Matrigel plug and sponge granuloma angiogenesis assays compared with wt mice. Fut1(-/-) mice were resistant to K/BxN serum transfer arthritis and had decreased angiogenesis and leucocyte ingress into inflamed joints. Adhesion of RAW264.7 cells to wt mouse ECs was significantly reduced when Fut1 was lacking. Fut1(-/-) ECs had decreased intercellular adhesion molecule-1 (ICAM-1) expression at mRNA and protein levels compared with wt ECs. ICAM-1 was also decreased in Fut1(-/-) arthritic ankle cryosections compared with wt ankles. CONCLUSIONS: Fut1 plays an important role in regulating angiogenesis and ICAM-1 expression in inflammatory arthritis.

Innate lymphoid cells regulate intestinal epithelial cell glycosylation.

Fucosylation of intestinal epithelial cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host-microbiota symbiosis. Commensal bacteria induce epithelial fucosylation, and epithelial fucose is used as a dietary carbohydrate by many of these bacteria. However, the molecular and cellular mechanisms that regulate the induction of epithelial fucosylation are unknown. Here, we show that type 3 innate lymphoid cells (ILC3) induced intestinal epithelial Fut2 expression and fucosylation in mice. This induction required the cytokines interleukin-22 and lymphotoxin in a commensal bacteria-dependent and -independent manner, respectively. Disruption of intestinal fucosylation led to increased susceptibility to infection by Salmonella typhimurium. Our data reveal a role for ILC3 in shaping the gut microenvironment through the regulation of epithelial glycosylation.