Association between prenatal exposure to per- and polyfluoroalkyl substances and infant anthropometry: A prospective cohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic organic chemicals with potential endocrine-disrupting effects, and have been found to impair the physical growth of offspring in both experimental and epidemiological studies. We aimed to investigate the effects of prenatal PFAS exposure on repeated measurements of multiple anthropometric indicators in infants. METHOD: PFAS were measured in serum samples collected from pregnant women at 12-16 gestational weeks. We calculated z-scores for the weight-for-age (WAZ), weight-for-length (WLZ), head circumference-for-age (HCZ), arm circumference-for-age (ACZ), triceps skinfold-for-age (TSZ), and subscapular skinfold-for-age (SSZ) at birth, 6 months, and 12 months of age according to the child growth standards of the World Health Organization (WHO) for anthropometric indicators. A total of 964 mother-infant pairs were included. A multivariate linear regression was performed to examine the associations between prenatal PFAS concentrations and anthropometric indicators at each time point. A generalized estimating equation (GEE) model was used to examine the longitudinal effects of PFAS exposure on repeated measurements of anthropometric indicators. Ultimately, a Bayesian kernel machine regression (BKMR) model was used to assess the joint effects of the PFAS mixture on anthropometric indicators. RESULTS: In GEE models, perfluorododecanoic acid (PFDoA) in the high tertile group was associated with increased WAZ/WLZ, with ß values (95% confidence intervals (CI)) of 0.12 (0.00, 0.23) and 0.18 (0.03, 0.32), respectively. Perfluorononanoic acid (PFNA) was associated with increased ACZ in the middle and high tertile groups. The BKMR models also presented the associations of the PFAS mixture with increased WAZ/WLZ throughout infancy, with more profound effects in females. Meanwhile, a pattern of inverse associations was observed between the perfluorooctanoic acid (PFOA) concentrations in the high tertile group and decreased WAZ, WLZ, and HCZ in males. In addition, the associations between PFAS and increased TSZ/SSZ at birth were identified by both linear regression and BKMR models. CONCLUSION: Prenatal PFAS exposure (PFNA and PFDoA) was associated with increased infant anthropometry, especially in female infants, while prenatal PFOA exposure was associated with decreased weight, and head and arm circumference in male infants. The findings indicate that prenatal PFAS exposure may impair the growth trajectory of offspring.

Prenatal exposure to Per- and polyfluoroalkyl substances and adiposity measures of children at 4 and 6 years: A prospective birth cohort in China.

There is growing evidence that prenatal exposure to Per- and polyfluoroalkyl substances (PFAS) was associated with childhood obesity, but evidence on multiple adiposity measures including arm circumference (AC), and waist circumference (WC) among Chinese children is limited. We investigated the associations of prenatal exposure to PFAS with adiposity measures of children at 4 and 6 years of age in the Shanghai-Minhang Birth Cohort Study. A total of 573 mother-child pairs with maternal PFAS concentrations and at least one measurement of adiposity measures of children were included in the present study. Eleven PFAS were assessed in maternal fasting blood samples. Information on children's weight, height, AC, and WC was collected at follow-ups. Weight for age Z score (WAZ), body mass index for age Z score (BMIz), and children overweight were calculated based on the World Health Organization Child Growth Standards. Multivariate linear regression, Poisson regression with robust error variance, and Bayesian Kernel Machine Regression (BKMR) models were used to examine the associations of prenatal exposure to PFAS with children's adiposity measures. Eight PFAS with detection rates above 85 % were included in the analyses. In the multivariate linear regression models, maternal PFNA concentrations were associated with a greater AC (ß = 0.29, 95 % Confidence Interval (CI): 0.04-0.55) in 4-year-old children and with an increase in WAZ (ß = 0.26, 95 % CI: 0.06-0.46), BMIz (ß = 0.31, 95 % CI: 0.09-0.53), AC (ß = 0.49, 95 % CI: 0.08-0.90), and WC (ß = 1.47, 95 % CI: 0.41-2.52) in 6-year-old children. We also observed the associations of maternal concentrations of PFOS, PFNA, PFUdA, and PFTrDA with the increased risk of children overweight in 6-year-old children. BKMR models further supported the findings from multivariate linear regression and Poisson regression models, and identified PFNA as the most important contributor. Moreover, the associations described above were generally more pronounced in girls. In conclusion, prenatal exposure to PFAS was associated with an increased risk of children's adiposity with a sex-specific manner, and PFNA contributed most to the associations after controlling for the effect of co-exposure to other PFAS compounds, especially among girls at 6 years of age.

Prenatal exposure to per- and polyfluoroalkyl substances and DNA methylation in the placenta: A prospective cohort study.

Epidemiological studies regarding the relationship between per- and polyfluoroalkyl substances (PFAS) and DNA methylation were limited. We investigated the associations of maternal PFAS concentrations with placental DNA methylation and examined the mediating role of methylation changes between PFAS and infant development. We measured the concentrations of 11 PFAS in maternal plasma during early pregnancy and infant development at six months of age. We analyzed genome-wide DNA methylation in 16 placental samples using reduced representation bisulfite sequencing. Additionally, we measured DNA methylation levels using bisulfite amplicon sequencing in 345 mother-infant pairs for five candidate genes, including carbohydrate sulfotransferase 7 (CHST7), fibroblast growth factor 13 (FGF13), insulin receptor substrate 4 (IRS4), paired like homeobox 2Ap (PHOX2A), and plexin domain containing 1 (PLXDC1). We found that placental DNA methylation profiles related to PFOA mainly enriched in angiogenesis and neuronal signaling pathways. PFOA was associated with hypomethylation of IRS4 and PLXDC1, and PFNA was associated with PLXDC1 hypomethylation. There were positive associations of CHST7 methylation with PFTrDA and IRS4 methylation with PFDoA and PFTrDA. PLXDC1 hypomethylation mediated the association between PFOA and suspected developmental delay in infants. Future studies with larger sample sizes are warranted to confirm these findings.

Prenatal per- and polyfluoroalkyl substances exposure and gut microbiota of infants: A prospective cohort study.

Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) has been reported to be linked to a series of adverse health outcomes in mothers and their children. As the gut microbiota is a sensitive biomarker for assessing the toxicity of environmental contaminants, this study attempted to investigate whether prenatal PFASs exposure was associated with the gut microbiota of infants. Based on the Shanghai-Minhang Birth Cohort Study, this prospective cohort study included 69 mother-infant pairs. Fasting blood samples were collected from pregnant women for the PFASs assay. We collected fecal samples of infants at 1 year of age and analyzed the V3-V4 hypervariable region of the bacterial 16 S rRNA gene by high-throughput sequencing. Among the detected 11 PFASs, the concentration of perfluorooctanoic acid (22.19 ng/mL) was the highest, followed by perfluorooctane sulfonic acid (12.08 ng/mL). Compared with infants whose mothers' total PFASs concentrations during pregnancy were at the 40th percentile or lower (reference group), the species richness and diversity of microbiota were lower in infants prenatally exposed to a high level of PFASs (the sum of PFASs concentrations above the 60th percentile). Prenatal exposure to PFASs was associated with a higher proportion of Acidaminococcaceae, Acidaminococcus, Megamonas, Megasphaera micronuciformis and Megamonas funiformis in infants. The changes of the species have been suggested to be associated with immune and metabolic dysfunction in humans. Functional alterations of gut microbiota due to PFASs exposure were dominated by an enrichment of butanoate metabolism. Our preliminary findings may shed light on the potential role of the microbiota underlying the well-known impact of prenatal PFASs exposure on health outcomes of humans in later life.

Per- and Poly-fluoroalkyl Substances and Bile Acid Profiles in Pregnant Women.

Alterations in bile acid (BA) profiles are closely associated with adverse outcomes in pregnant women and their offspring and may be one potential pathway underlying the related metabolic effects of per- and poly-fluoroalkyl substances (PFAS) exposure. However, evidence of associations between PFAS exposure and BA profiles in pregnant women is scarce. This study examined the associations of individual PFAS and PFAS mixture with BA profiles of pregnant women. We obtained quantitative data on the plasma concentrations of 13 PFAS and 15 BAs in 645 pregnant women from the Jiashan birth cohort. In Bayesian kernel machine regression models, the PFAS mixture was associated with increased plasma CA, TCA, TCDCA, and GLCA levels but with decreased GCA and LCA concentrations. Furthermore, the PFAS mixture was associated with increased concentrations of total BAs and the secondary/primary BA ratio but with decreased conjugated/unconjugated and glycine/taurine-conjugated BA ratios. PFHxS, PFUdA, PFOS, PFNA, and PFDA were the dominant contributors. The results of the linear regression analysis of individual PFAS were generally similar. Our findings provide the first epidemiological evidence for the associations of a PFAS mixture with BA profiles in pregnant women and may provide explanatory insights into the biological pathways underlying the related metabolic effects of PFAS exposure.

Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia.

Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.

Prenatal bisphenol exposure and intelligence quotient in children at six years of age: A prospective cohort study.

The effects of prenatal bisphenol A (BPA) exposure on children's cognitive development have been reported; however, relevant evidence on BPA analogues was limited, with rare evidence of the joint effect of their mixture. Among 424 mother-offspring pairs from the Shanghai-Minhang Birth Cohort Study, maternal urinary concentrations of five bisphenols (BPs) were quantified, and children's cognitive function was assessed by the Wechsler Intelligence Scale at six years of age. We assessed the associations of prenatal exposure to individual BPs with children's intelligence quotient (IQ) and analyzed the joint effect of BPs mixture by the Quantile g-computation model (QGC) and Bayesian kernel machine regression model (BKMR). QGC models showed that higher maternal urinary BPs mixture concentrations were associated with lower scores among boys in a non-linear way; however, no association was observed in girls. For individual effects, BPA and BPF were associated with decreased IQ scores in boys and were identified as important contributors to the joint effect of BPs mixture. However, associations of BPA with increased IQ scores in girls, and TCBPA with increased IQ scores in both sexes were observed. Our findings suggested prenatal exposure to BPs mixture may affect children's cognitive function in a sex-specific pattern and provided evidence of the neurotoxicity of BPA and BPF.

Distribution of serum uric acid concentration and its association with lipid profiles: a single-center retrospective study in children aged 3 to 12 years with adenoid and tonsillar hypertrophy.

BACKGROUND: Presently, there is no consensus regarding the optimal serum uric acid (SUA) concentration for pediatric patients. Adenoid and tonsillar hypertrophy is considered to be closely associated with pediatric metabolic syndrome and cardiovascular risk and is a common condition in children admitted to the hospital. Therefore, we aimed to evaluate the relationship between SUA and dyslipidemia and propose a reference range for SUA concentration that is associated with a healthy lipid profile in hospitalized children with adenoid and tonsillar hypertrophy. METHODS: Preoperative data from 4922 children admitted for elective adenoidectomy and/or tonsillectomy surgery due to adenoid and tonsillar hypertrophy were collected. SUA concentrations were scaled to standard deviation (SD), and SUA deviations were expressed as SD from the mean SUA of children without dyslipidemia. RESULTS: The mean SUA concentration of the participants was 4.27 ± 1.01 mg/dL, and the prevalence of hyperuricemia was 1.6% when it was defined using an SUA of ≥ 7.0 mg/dL. Participants with dyslipidemia (856, 17.4%) had a higher prevalence of hyperuricemia (3.4% vs. 1.2%, P < 0.001) and higher SUA concentrations (4.51 ± 1.15 vs. 4.22 ± 0.97 mg/dL, P < 0.001) than those with ortholiposis. The circulating lipid status of participants with SUAs < 1 SD below the mean value for the participants with ortholiposis (range 1.80-3.28 mg/dL) was more normal. Each 1-SD increase in SUA was associated with a 27% increase in the risk of dyslipidemia (OR = 1.270, 95% CI, 1.185-1.361). Adjustment for a number of potential confounders reduced the strength of the relationship, but this remained significant (OR = 1.125, 95% CI, 1.042-1.215). The higher risk of dyslipidemia was maintained for participants with SUAs > 1 SD above the mean value of the participants with ortholiposis. CONCLUSIONS: SUA was independently associated with dyslipidemia in children with adenoid and tonsillar hypertrophy, and an SUA < 1 SD below the mean value for patients with ortholiposis was associated with a healthy lipid profile.

Maternal per- and poly-fluoroalkyl substances exposure and child adiposity measures: A birth cohort study.

Maternal exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy may have a programming effect on the physical development of the offspring. However, the findings of the association between PFAS and the physical development of offspring were inconsistent, and the overall effects of the PFAS mixture were unclear. In this study, we examined the associations between maternal PFAS exposure and offspring adiposity during the first two years of life. A total of 937 mother-child pairs from the Jiashan Birth Cohort Study were investigated. Thirteen PFASs were analyzed in maternal blood samples. Child weight and length were measured at birth, 1, 3, 6, 8, 12, and 24 months, and the ponderal index (PI) and weight-for-age z-scores (WAZ) were calculated. Longitudinal associations of PFAS concentrations (by quartile) with repeated data of PI and WAZ were examined using linear mixed model, and the overall effect of the PFAS mixture on adiposity measures was evaluated using quantile g-computation (QGC). Maternal PFAS exposure was associated with increased PI in both the linear mixed model and the QGC model. Among the PFAS examined, the associations between maternal PFTrDA exposure and PI were the strongest. Maternal PFAS and WAZ showed similar patterns of association. In the longitudinal cohort study, we found that adiposity in young children is increased by maternal PFAS exposure. The associations between maternal PFASs concentrations and child adiposity may be chemical-specific.

Prenatal exposure to ambient PM2.5 and its chemical constituents and child intelligence quotient at 6 years of age.

There are limited studies on the associations between prenatal exposure to constituents of fine particulate matter (PM2.5) and children's intelligence quotient (IQ). Our study aimed to explore the associations between prenatal PM2.5 and its six constituents and the IQ levels of 6-year-old children. We included 512 mother-child pairs. We used a satellite-based modelling framework to estimate prenatal PM2.5 and its six constituents (ammonium, sulfate, nitrate, organic carbon, soil dust, and black carbon). We assessed the children's IQ using the short form of the Wechsler Intelligence Scale. Perceptual Reasoning Index (PRI), Verbal Comprehension Index (VCI), and Full Scale IQ (FSIQ) scores were computed. The multiple informant model (MIM) was applied to explore the trimester specific effects of PM2.5 and its six constituents' exposure on children's PRI, VCI, and FSIQ. To examine whether the duration of breastfeeding and physical activity (PA) could modify the effects of PM2.5 on children's IQ, we stratified the analyses according to the duration of breastfeeding (≤6 and >6 months) and time of outdoor activities after school (≤2 and >2 h/week). The first trimester PM2.5 and its five constituents' exposures were inversely associated with FSIQ [ß = -1.34, 95 % confidence interval [CI] (-2.71, 0.04) for PM2.5] and PRI [ß = -2.18, 95 %CI (-3.80, -0.57) for PM2.5] in children. The associations were magnified among boys and those with less outdoor activities or shorter breastfeeding duration. Our results indicate that prenatal PM2.5 and several of its main constituents' exposure may disrupt cognitive development in children aged 6 years. More PA and longer breastfeeding duration may alleviate the detrimental effects of prenatal PM2.5 exposure on children's cognitive function.

The associations between concentrations of gestational bisphenol analogues and thyroid related hormones in cord blood: A prospective cohort study.

Animal studies indicated that Bisphenol analogues (BPs) exhibited potential thyroid toxicity. However, little is known of the associations between maternal BPs exposure and offspring's thyroid related hormones in humans. On the basis of Shanghai-Minhang Birth Cohort study, we analyzed BPs in maternal urine collected at the third trimester of pregnancy. Thyroid related hormones (THs), including total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were measured in cord blood samples. We performed multiple linear regression and Bayesian kernel machine regression (BKMR) models to explore the single and joint effects of gestational BPs exposure on thyroid related hormones in cord blood among 258 mother-child pairs. Statistically significant inverse associations of categorized BPA with FT3 and TT4 concentrations were observed. We also found a significant association between the mixture of BPs in maternal urine and increased concentration of TT3 in cord blood and a marginally significant association between BPs mixture and increased FT3 concentrations. Further associations of BPA with lower TT4/FT4 and of Bisphenol AF (BPAF) with higher TT3/FT3 were also suggestive, by BKMR model, when other BPs were fixed at 25th percentiles. It was concluded that prenatal BPs exposure was associated with THs in cord blood. Exposure to BPA and BPAF might have large contributions to the effects on thyroid function than other bisphenols.

Individual and joint effects of phthalates exposure on the risk of early miscarriage.

BACKGROUND: The exposure levels of phthalates in humans have dropped dramatically. Little is known about the individual and joint effects of phthalates exposure at low levels on the risk of early miscarriage. OBJECTIVE: To examine the association between exposure to phthalates individually or as a mixture and early miscarriage. METHODS: A case-control study was conducted in Shanghai, China during 2019-2020. A total of 291 women seeking medical services due to miscarriage (cases) and 308 women planning to terminate an unintended pregnancy (controls) within 12 gestational weeks were recruited. Urinary concentrations of eight phthalate metabolites were determined by ultra-performance liquid chromatography. We included 534 women in the main analysis who had available data on both phthalates exposure and complete information on potential confounders. We used logistic regression and Bayesian kernel machine regression (BKMR) to examine the associations of concentrations of phthalates with miscarriage. RESULTS: Among the phthalate metabolites, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) had the highest concentration (8.10 ng/mL), followed by mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, 2.68 ng/mL) and monobutyl phthalate (MBP, 2.24 ng/mL). Higher concentrations of MBP, mono(2-ethylhexyl) phthalate (MEHP), MEHHP, MEOHP and the molar sum of di(2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHPm) were associated with an increased risk of miscarriage exhibiting a dose-response relationship. The most evident association of miscarriage was found with ∑DEHPm, with adjusted odds ratio (95% confidence interval) of 1.94 (1.14, 3.31) for the second quartile, 2.83 (1.67, 4.79) for the third quartile and 4.28 (2.49, 7.37) for the fourth quartile compared to the first quartile. Consistently, the phthalate mixture was positively associated with the risk of miscarriage and DEHP was the predominant contributor to the joint effect in BKMR model. IMPACT: Phthalates are a family of synthetic chemicals mainly used as plasticizers, solvents and additives in a large variety of industrial and consumer products, including food packing materials, toys, gloves, medical devices and personal care products. Although exposure levels of phthalates of pregnant women have declined sharply over the past few decades, phthalates exposure was still associated with an increased risk of early miscarriage. Our findings suggest that future researchers and policy makers might need to take low-dose effects of phthalates into account regarding the reproductive toxicity of phthalates exposure in humans. SIGNIFICANCE: Our findings contribute to the awareness of the reproductive toxic potential of phthalates at low levels in humans and support the ongoing efforts to further reduce exposure to phthalates.

Associations between maternal urinary isoflavone concentrations and anogenital distance of offspring throughout infancy: a prospective cohort study.

STUDY QUESTION: Are maternal urinary isoflavone (ISO) concentrations during pregnancy associated with anogenital distance (AGD) in infants at birth, and at 6 and 12 months of age? SUMMARY ANSWER: Higher maternal urinary ISO concentrations during pregnancy were associated with longer AGD in infants of both sexes, and equol (EQU) and daidzein (DAD) were identified as the important ISO mixture components in the observed associations. WHAT IS KNOWN ALREADY: Evidence of the association of prenatal exposure to ISO with offspring's AGD is mainly derived from animal studies, which used different study designs and had inconsistent results. Only one human study has been reported and it found null associations between maternal ISO exposure during pregnancy and AGD among boys at birth, with a small sample size and a wide range of exposure windows. No human study on girls was found. STUDY DESIGN, SIZE, DURATION: Prospective cohort study (Shanghai-Minhang Birth Cohort Study), with pregnant women recruited at 12-16 weeks of gestation in Shanghai, China between April and December 2012. One thousand two hundred and twenty-five live singletons were left in the cohort at delivery of which 480 mother-infant pairs had data on both maternal urinary ISO concentrations and at least one AGD measurement and were included in the present study. Anopenile distance (AGDAP) and anoscrotal distance (AGDAS) of boys and anoclitoral distance (AGDAC) and anofourchette distance (AGDAF) of girls were measured at birth and at 6 and 12 months of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Multiple linear regression models were used to examine the associations between maternal ISO concentrations and AGD. Bayesian kernel machine regression (BKMR) was implemented to examine both the overall effects of ISO mixture and the single effect of each ISO and identify important components of ISO mixture. MAIN RESULTS AND THE ROLE OF CHANCE: A general profile of higher concentrations of maternal ISO associated with longer AGD in infants of both sexes was observed, when maternal education, parity, BMI before pregnancy (BMI, categorical variable), passive smoking during early pregnancy, age at delivery, gestational weeks and infant body size were adjusted for. Among boys, EQU was associated with increased AGDAS at birth and at 6 and 12 months, and DAD was associated with increased AGDAP at birth. Among girls, the associations of EQU and DAD with increased AGDAC and AGDAF at birth were found. When gestational weight gain and feeding patterns of infants in the first 6 months were additionally adjusted for, and maternal BMI was adjusted for as a continuous variable, more pronounced associations were observed, especially for associations of genistein (GEN), DAD and glycitein (GLY) with increased AGDAP and AGDAS at 6 months in boys. However, these associations were not always observed in the highest tertile group, and no consistent dose-response relationships were found. Similar results were observed in BKMR models, showing positive correlations of concentration of ISO mixture with increased AGDAS at both 6 and 12 months among boys, and increased AGDAC and AGDAF at birth among girls. Statistically significant increments of 4.96 mm (95% credible interval (CrI): 1.40, 8.52) and 1.07 mm (95% CrI: 0.02, 2.13) in AGDAS at 6 months among boys and AGDAC at birth among girls, respectively, were observed at the 75th percentile of ISO mixture, compared with 25th percentile. EQU and DAD were identified as the important components among ISO-AGD associations. LIMITATIONS, REASONS FOR CAUTION: First, due to the short half-lives of ISO, the accuracy of a single spot urine sample reflecting ISO exposure during pregnancy may be limited, and thus may cause non-differential misclassification. Second, despite the adjustments for several important covariates in the study, unmeasured and residual confounding factors may remain a concern. Third, false discovery due to multiple testing may remain. Finally, the reduced sample sizes attributed to the loss of follow-up and missing data of confounders may limit our ability to detect an association, if any existed. WIDER IMPLICATIONS OF THE FINDINGS: Prenatal ISO exposure may affect the reproductive development of offspring. As ISO can be widely detected in pregnant women, especially in Eastern countries, more studies are warranted to provide evidence of the effects of prenatal ISO exposure on long-term reproductive outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Key Research and Development Program of China (2021YFC2701003), the National Natural Science Foundation of China (22076123), the Science and Technology Commission of Shanghai Municipality (21ZR1454700 and 20ZR1448000), the Shanghai Municipal Health Commission (20194Y0160) and Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2022-04). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Prenatal exposure to organophosphate esters is associated with decreased anogenital distance in offspring.

BACKGROUND: Evidence from in vitro and rodent studies suggests that organophosphate esters (OPEs) may disrupt sex steroid hormone homeostasis, but no human studies, to date, have examined the effects of in utero exposure to OPEs on offspring reproductive development. OBJECTIVE: Anogenital distance (AGD) is a sensitive biomarker of fetal hormonal milieu and has been used to assess reproductive toxicity. We evaluated the longitudinal effects of prenatal exposure to OPEs on the AGD of offspring from birth to 4 years. METHODS: Based on Shanghai-Minhang Birth Cohort Study, pregnant women provided urine samples at a gestational age of 12-16 weeks, which were analyzed for eight OPE metabolites. AGD was measured in offspring at birth and 0.5, 1, and 4 years of age. We used generalized estimating equations (GEE) and Bayesian kernel machine regression (BKMR) models to estimate the associations of prenatal exposure to individual OPE metabolites and OPE mixtures with AGD stratified by sex. RESULTS: A total of 733 mother-infant pairs were analyzed. Prenatal exposure to diphenyl phosphate and bis-(2-ethylhexyl) phosphate was associated with decreased AGD in boys in GEE models. Bis-(1-chloro-2-propyl) phosphate (BCIPP) showed a similar but marginally significant effect. Prenatal exposure to most OPE metabolites was associated with decreased AGD in girls, with the most profound association observed for bis (2-butoxyethyl) phosphate (BBOEP) and alkyl-OPEs. The OPE mixture was also inversely associated with AGD in both sexes. The single-exposure effects of BKMR models were largely consistent with those observed in the GEE models. In addition, alkyl-OPEs, particularly BBOEP, contributed the most to the decreased AGD in girls, while BCIPP contributed the most to the decreased AGD in boys. CONCLUSIONS: This study provides the first human evidence that prenatal exposure to OPEs is associated with decreased AGD in offspring. The magnitude of these effects may vary depending on the structure of OPEs.

Multivessel vs. culprit vessel-only percutaneous coronary intervention in ST-segment elevation myocardial infarction with and without cardiogenic shock.

Background: Early revascularization of the culprit vessel is the most effective treatment for reducing the risk of mortality from acute STEMI with and without cardiogenic shock. However, the most recent trends and impact of multivessel percutaneous coronary intervention (PCI) during the index hospitalization on in-hospital outcomes are unknown. Methods: The National Inpatient Sample was queried from October 2015 to 2019 for hospitalizations with STEMI. The impact of multivessel PCI on in-hospital outcomes of patients with and without cardiogenic shock was evaluated. Results: Of 624,605 STEMI hospitalizations treated with PCI, 12.5% were complicated by cardiogenic shock. Among hospitalizations without cardiogenic shock, 15.7% were treated by multivessel PCI, which declined from 20.8% in 2015 to 13.9% in 2019 (P trend < 0.001). Multivessel and culprit-only PCI had similar rates of In-hospital mortality (2.4 vs. 2.3%, p = 0.027) and major adverse cardiac and cerebrovascular events (MACCE; 7.4 vs. 7.2%, p = 0.072). Among hospitalizations with cardiogenic shock, 22.1% were treated by multivessel PCI, which declined from 29.2% in 2015 to 19.4% in 2019 (P trend < 0.001). Multivessel PCI was associated with higher rates of in-hospital mortality (30.9 vs. 28.4%, p < 0.001) and MACCE (39.9 vs. 36.5%, p < 0.001) than culprit-only PCI. Conclusion: The frequency of multivessel PCI for STEMI with and without cardiogenic shock is declining. Multivessel PCI is associated with worse in-hospital outcomes for STEMI with cardiogenic shock but not for STEMI without cardiogenic shock.

Association between prenatal exposure to perfluoroalkyl substances and anogenital distance in female neonates.

BACKGROUND: Perfluoroalkyl substances (PFASs) have been reported to exert reproductive toxicity. Anogenital distance (AGD) is a biomarker of intrauterine androgen exposure and an indicator of genital development. An animal study reported that female neonatal rats exposed to perfluorooctanoic acid or perfluorooctane sulfonate (PFOS) during postnatal days 1-5 exhibited a longer AGD, while epidemiological studies have shown inconsistent results. This study aimed to examine the effects of prenatal exposure to PFASs on the AGD in female neonates. METHODS: PFAS levels were measured in plasma samples obtained from pregnant women at 12-16 gestational weeks using high-performance liquid chromatography/mass spectrometry. The AGD of each female neonate was measured within 3 days after delivery. The anogenital index (AGI), calculated as AGD divided by weight, was also determined. A total of 362 motherinfant pairs were included in this study. A multivariate linear regression model was used to examine the association between prenatal ln-transformed concentrations of PFASs and AGD/AGI. In addition, weighted quantile sum regression (WQSR) and Bayesian kernel machine regression (BKMR) models were used to assess the overall effects of a mixture of PFASs on the AGD/AGI and to identify important contributors to the overall effect. RESULTS: There was a consistent pattern of association between maternal PFAS concentrations and increased AGDanus to posterior fourchette (AF), AGDanus to clitoris (AC), and AGIAF lengths at birth. Statistical significance was found between maternal ln-transformed concentrations of perfluorohexane sulfonate (PFHxS), perfluorododecanoic acid, and perfluorotridecanoic acid and AGDAF, with ß values (95% confidence interval [CI]) of 0.83 (0.16, 1.51), 0.32 (0.05, 0.59), and 0.25 (0.00, 0.51) mm, respectively; between PFOS and AGDAC, with a ß value (95% CI) of 0.63 (0.04, 1.21) mm; and between PFHxS and AGIAF, with a ß value (95% CI) of 0.22 (0.02, 0.43) mm/kg. Similarly, the WQSR and BKMR models showed that an increase in the AGDAF/AGIAF at birth was associated with co-exposure to a mixture of PFASs. CONCLUSION: High maternal concentrations of PFASs were associated with increased AGD in female neonates, indicating that PFASs may impair reproductive development in female offspring in early life.

Associations of perfluoroalkyl and polyfluoroalkyl substances with gestational hypertension and blood pressure during pregnancy: A cohort study.

Previous studies have reported inconsistent associations between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and gestational hypertension (GH) and blood pressure (BP) during pregnancy. Herein, we aimed to evaluate individual and overall effects of PFAS on GH and longitudinal BP measures during pregnancy. We included 826 pregnant women from the Jiashan Birth Cohort established between 2016 and 2018. Concentrations of thirteen PFAS were quantified using plasma samples collected within 16 weeks of gestation. Longitudinal BP measures were obtained from medical records, and more than nine measurements were available for 85.60% of participants. GH was defined as new-onset hypertension occurring after 20 weeks of gestation. Logistic regression models were used to examine the effect of PFAS on GH, while generalized estimating equation models evaluated the average effect of PFAS on BP in each trimester. The potential effect modification by fetal sex was also examined. Bayesian kernel machine regression (BKMR) and quantile g-computation (QgC) were implemented to explore the overall effect of the PFAS mixture. PFOA, PFOS, and PFHxS presented the highest median concentrations of 11.99, 8.81 and 5.43 ng/mL, respectively. Overall, 5.57% of subjects developed GH. PFOS, PFDA, PFUdA, and PFDoA were significantly associated with lower GH odds, and odds ratios ranged between 0.62 and 0.68. We noted associations between PFAS and lower systolic BP and diastolic BP in the third trimester, with PFDA and PFUdA exhibiting the effect on systolic BP only in pregnant women carrying a female fetus. These associations were further confirmed by BKMR and QgC, showing an inverse overall effect of the PFAS mixture. Higher concentrations of PFAS during early pregnancy were associated with lower GH risk and longitudinal BP measures in the third trimester in a population with relatively high exposure levels. Fetal sex might modify the effects of PFDA and PFUdA on systolic BP in the third trimester.

Associations between prenatal exposure to perfluoroalkyl substances and neurobehavioral development in early childhood: A prospective cohort study.

Findings from epidemiological studies on the associations between prenatal perfluoroalkyl substances (PFASs) exposure and children's neurodevelopment were inconclusive, and most studies did not account for the co-exposure to multiple PFASs with strong inter-correlations. The present study aimed to assess the effects of prenatal multiple PFAS exposure on children's neurobehavioral development based on 614 mother-infant pairs in the Shanghai-Minhang Birth Cohort Study. Eight PFAS concentrations were measured in maternal plasma at 12-16 weeks of gestation. Children's neurobehavioral development at 2 and 4 years of age was assessed by the Child Behavior Checklist for Ages 1.5-5. In Bayesian kernel machine regression (BKMR) analyses that could address the inter-correlations between multiple PFASs, PFAS mixture appeared to be associated with fewer Somatic Complaints and more Externalizing Problems in boys, but more Somatic Complaints and Sleep Problems in girls. There were suggestive associations of PFNA and PFOS with decreased risk of Somatic Complaints and of PFUdA and PFTrDA with increased risk of Externalizing Problems in boys; trends of increased risk in girls were observed between PFUdA and Somatic Complaints and between PFTrDA and Sleep Problems. Overall, we found no clear evidence that prenatal exposure to PFASs had negative effects on neurobehavioral development in children. However, the modest associations still suggested the potential developmental neurotoxicity of prenatal PFAS exposure.