PCSK9 Inhibitor Added to High-Intensity Statin Therapy to Prevent Cardiovascular Events in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: A Randomized, Double- Blind, Placebo-Controlled, Multicenter SHAWN Study.

BACKGROUND: It is currently uncertain whether the combination of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and high-intensity statin treatment can effectively reduce cardiovascular events in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) for culprit lesions. METHODS: This study protocol describes a double-blind, randomized, placebo-controlled, multicenter study aiming to investigate the efficacy and safety of combining a PCSK9 inhibitor with high-intensity statin therapy in patients with ACS following PCI. A total of 1212 patients with ACS and multiple lesions will be enrolled and randomly assigned to receive either PCSK9 inhibitor plus high-intensity statin therapy or high-intensity statin monotherapy. The randomization process will be stratified by sites, diabetes, initial presentation and use of stable (≥4 weeks) statin treatment at presentation. PCSK 9 inhibitor or its placebo is injected within 4 hours after PCI for the culprit lesion. The primary endpoint is the composite of cardiovascular death, myocardial infarction, stroke, re-hospitalization due to ACS or heart failure, or any ischemia-driven coronary revascularization at one-year follow-up between two groups. Safety endpoints mean PCSK 9 inhibitor and statin intolerance. CONCLUSION: The SHAWN study has been specifically designed to evaluate the effectiveness and safety of adding a PCSK9 inhibitor to high-intensity statin therapy in patients who have experienced ACS following PCI. The primary objective of this study is to generate new evidence regarding the potential benefits of combining a PCSK9 inhibitor with high-intensity statin treatment in reducing cardiovascular events among these patients.

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 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 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.

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.

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.

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.

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.

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.

Hypothalamic CDK4 regulates thermogenesis by modulating sympathetic innervation of adipose tissues.

This study investigated the role of CDK4 in the oxidative metabolism of brown adipose tissue (BAT). BAT from Cdk4-/- mice exhibited fewer lipids and increased mitochondrial volume and expression of canonical thermogenic genes, rendering these mice more resistant to cold exposure. Interestingly, these effects were not BAT cell-autonomous but rather driven by increased sympathetic innervation. In particular, the ventromedial hypothalamus (VMH) is known to modulate BAT activation via the sympathetic nervous system. We thus examined the effects of VMH neuron-specific Cdk4 deletion. These mice display increased sympathetic innervation and enhanced cold tolerance, similar to Cdk4-/- mice, in addition to browning of scWAT. Overall, we provide evidence showing that CDK4 modulates thermogenesis by regulating sympathetic innervation of adipose tissue depots through hypothalamic nuclei, including the VMH. This demonstrates that CDK4 not only negatively regulates oxidative pathways, but also modulates the central regulation of metabolism through its action in the brain.

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.

Association of pre-pregnancy body mass index and gestational weight gain with neonatal anogenital distance in a Chinese birth cohort.

BACKGROUND: This study aimed to investigate the associations of pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with anogenital distance (AGD) among newborns. METHODS: The study included 556 mother-newborn pairs from the Jiashan birth cohort. AGD was measured as AGDAP (from the center of the anus to the anterior base of the penis, where the penile tissue meets the pubic bone) and AGDAS (from the center of the anus to the posterior base of the scrotum, where the skin changes from rugate to smooth) in males and AGDAC (from the center of the anus to the clitoris) and AGDAF (from the center of the anus to the posterior convergence of the fourchette) in females. Multiple linear regression models were used to estimate the associations of pre-pregnancy BMI and GWG, with AGD. RESULTS: After adjusting for pre-pregnancy BMI and other potential confounders, male newborns whose mothers had excessive GWG had shorter AGDAP than those whose mothers had normal GWG. Male newborns whose mothers had normal pre-pregnancy BMI and inadequate/excessive GWG had shorter AGDAP than the reference group where mothers had normal pre-pregnancy BMI and GWG in stratified analyses. CONCLUSION: Gestational weight gain during pregnancy was associated with AGD in newborns in this birth cohort.

In China, the prevalence of underweight and overweight/obesity remained high among women. Appropriate pre-pregnancy body mass index (BMI) and gestation weight gain (GWG) were critical to reduce the risk of adverse birth outcomes. The anogenital distance (AGD) was measured as an indicator of neonatal reproductive function and was associated with adverse reproductive outcomes in adults. Thus, we investigated the associations of both sub-optimal pre-pregnancy BMI, as well as GWG, with AGD among newborns to draw a picture about their effect on offspring reproductive health.A total of 556 mother-newborns were included in the study from the Jiashan birth cohort in China. We extracted information about maternal lifestyles, social demographic characteristics, diet, and medical history from questionnaires conducted during 8­16 gestational weeks and medical records. AGD among newborns was measured within 3 days of delivery.We found that maternal excessive GWG was associated with shorter AGD in male newborns after adjusting for maternal pre-pregnancy BMI in multiple linear regression models. The study also suggested that maternal inadequate GWG was associated with a shorter AGD in male newborns, which needed to be corroborated in further studies with a larger sample size.In conclusion, health professionals shall implement sufficient intervention to prevent suboptimal GWG during prenatal checkups.

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.

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.

Zinc as a countermeasure for cadmium toxicity.

Cadmium (Cd) is an important environmental pollutant and long-term Cd exposure is closely related to autoimmune diseases, cancer, cardiovascular diseases (CVD), and hepatic dysfunction. Zinc (Zn) is an essential metal that plays key roles in protein structure, catalysis, and regulation of their function. Numerous studies have shown that Zn can reduce Cd toxicity; however, the underlying mechanisms have not been extensively explored. Preclinical studies have revealed direct competition for sarcolemmal uptake between these two metals. Multiple sarcolemmal transporters participate in Cd uptake, including Zn transporters, calcium channels, and DMT1 (divalent metal transporter 1). Zn also induces several protective mechanisms, including MT (metallothionein) induction and favorable redox homeostasis. This review summarizes current knowledge related to the role of Zn and metal transporters in reducing Cd toxicity and discusses potential future directions of related research.

Risk of intellectual disability and maternal history of spontaneous abortion: a nationwide cohort study.

AIM: To investigate the association between a maternal history of spontaneous abortion and intellectual disability in children. METHOD: This cohort study included 1 778 786 children (913 340 males, 865 085 females, 361 missing data; mean age 15y 2mo, SD 8y 11mo, range birth to 40y) born in Denmark between 1977 and 2016. Cox proportional hazard regression was used to estimate the hazard ratios (HRs) of intellectual disability. RESULTS: The overall HR of intellectual disability for children with a maternal history of spontaneous abortion was 1.17 (95% confidence interval [CI] 1.12-1.22) and the risk for multiple spontaneous abortions (HR=1.30, 95% CI 1.20-1.40) was higher than for a single spontaneous abortion (HR=1.13, 95% CI 1.07-1.18). When only cases of inpatient intellectual disability were included, the estimates increased slightly: the overall HR was 1.22 (95% CI 1.12-1.32), the HR for multiple spontaneous abortions was 1.37 (95% CI 1.20-1.58), and the HR for a single spontaneous abortion was 1.17 (95% CI 1.07-1.28). The risks were similar regardless of whether spontaneous abortion occurred before or after the index delivery. Estimates were nearly unchanged after adjusting for preterm birth, low birthweight, or Apgar score. INTERPRETATION: Children born to mothers with spontaneous abortion, especially multiple spontaneous abortions, may be at a higher risk of intellectual disability in later life, regardless of whether spontaneous abortion occurred before or after the index delivery. The findings have clinical implications for targeted early intervention of children with intellectual disability. What this paper adds A maternal history of spontaneous abortion was associated with a risk of intellectual disability in offspring. The risk was higher in children whose mothers previously had multiple spontaneous abortions. Similar risks were observed regardless of whether spontaneous abortion occurred before or after childbirth.

Maternal spontaneous abortion and the risk of attention-deficit/hyperactivity disorder in offspring: a population-based cohort study.

STUDY QUESTION: Is a maternal history of spontaneous abortion (SA) associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring? SUMMARY ANSWER: Our results suggest an association between maternal history of SA and ADHD in offspring, with the risk increasing with the number of maternal SA and highest in the firstborn children whose mothers had had recurrent SAs after adjusting for a number of potential confounders. WHAT IS KNOWN ALREADY: A history of SA has been associated with more complications in next pregnancies and adverse childbirth outcomes, which are risk factors for ADHD in the offspring. However, no previous study has investigated whether maternal SA increases risk of ADHD in the offspring. STUDY DESIGN, SIZE, DURATION: This population-based study included all live-born children in Denmark from 1 January 1995 to 31 December 2012 (n = 1 062 667). All children were followed from 3 years of age until the day of ADHD diagnosis, death, emigration or 31 December 2016, whichever came first. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 130 206 (12.2%) children born to mothers who had at least one SA. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). MAIN RESULTS AND THE ROLE OF CHANCE: During a median follow-up of 9.4 years (interquartile range, 5.4-14.3), 25 747 children were diagnosed with ADHD. Overall, children of mothers with a history of SA had an increased rate of ADHD (HR, 1.11; 95% CI, 1.07 to 1.15). The HRs increased with the number of maternal SA, 1.09 (95% CI, 1.05 to 1.13) for one SA and 1.22 (95% CI, 1.12 to 1.33) for at least two SAs, respectively. These findings were consistent when we took into consideration a number of factors, such as maternal socioeconomic status, type of SA, birth order, parental history of psychiatric disorders, pregnancy characteristics and adverse birth outcomes. LIMITATIONS, REASONS FOR CAUTION: Misclassification of SA was possible as we used population-based register data to capture maternal history of SA. However, any misclassification of maternal history of SA would be non-differential with regard to the diagnosis of ADHD in offspring, which generally leads to underestimation of the associations. Furthermore, probabilistic sensitivity analysis suggested that only 1% of change in the estimate may have been due to misclassification of SA. WIDER IMPLICATIONS OF THE FINDINGS: SA is quite frequent (varying from 15 to 20%), and a small increase of neurodevelopmental problems in offspring could have major public health implications. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Natural Science Foundation of China (No. 81703237, No. 81530086 and No. 81761128035), National Key Research and Development Program (2018YFC1002801, 2016YFC1000505), Shanghai Municipal Commission of Health and Family Planning (No. 2017ZZ02026, No. 2017EKHWYX-02), the Novo Nordisk Foundation (NNF18OC0052029), the Danish Council for Independent Research (DFF-6110-00019), the Nordic Cancer Union (176673, 186200 and R217-A13234-18-S65), Karen Elise Jensens Fond (2016) and Xinhua Hospital of Shanghai Jiao Tong University School of Medicine (2018YJRC03). All authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NA.

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms.

Cadmium (Cd) is a nonessential heavy metal and a prevalent environmental toxin that has been shown to induce significant cardiomyocyte apoptosis in neonatal murine engineered cardiac tissues (ECTs). In contrast, zinc (Zn) is a potent metallothionein (MT) inducer, which plays an important role in protection against Cd toxicity. In this study, we investigated the protective effects of Zn against Cd toxicity in ECTs and explore the underlying mechanisms. ECTs were constructed from neonatal ventricular cells of wild-type (WT) mice and mice with global MT gene deletion (MT-KO). In WT-ECTs, Cd (5-20 µM) caused a dose-dependent toxicity that was detected within 8 h evidenced by suppressed beating, apoptosis, and LDH release; Zn (50-200 µM) dose-dependently induced MT expression in ECTs without causing ECT toxicity; co-treatment of ECT with Zn (50 µM) prevented Cd-induced toxicity. In MT-KO ECTs, Cd toxicity was enhanced; but unexpectedly, cotreatment with Zn provided partial protection against Cd toxicity. Furthermore, Cd, but not Zn, significantly activated Nrf2 and its downstream targets, including HO-1; inhibition of HO-1 by a specific HO-1 inhibitor, ZnPP (10 µM), significantly increased Cd-induced toxicity, but did not inhibit Zn protection against Cd injury, suggesting that Nrf2-mediated HO-1 activation was not required for Zn protective effect. Finally, the ability of Zn to reduce Cd uptake provided an additional MT-independent mechanism for reducing Cd toxicity. Thus, Zn exerts protective effects against Cd toxicity for murine ECTs that are partially MT-mediated. Further studies are required to translate these findings towards clinical trials.

Maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances during pregnancy and anogenital distance in male infants.

STUDY QUESTION: Are maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances (PFASs) during pregnancy associated with anogenital distance (AGD) in male infants at birth, 6, and 12 months of age? SUMMARY ANSWER: Higher maternal plasma concentrations of some PFASs were associated with shorter AGD in male infants at birth and 6 months of age. WHAT IS KNOWN ALREADY: Two animal studies have found that exposure to PFASs was associated with shorter AGD in male rat fetuses and wild male minks. There is only one human study on the topic that did not identify consistent patterns between maternal serum concentrations of PFASs during pregnancy and AGD in male infants. STUDY DESIGN, SIZE, DURATION: In the prospective cohort study, a total of 1292 eligible pregnant women were recruited at 12-16 weeks of gestation between April and December 2012 at the Maternal and Child Health Hospital of Minhang district in Shanghai, China. At delivery, 667 male singletons were born. They were then followed up at birth (n = 439) and at 6 (n = 411) and 12 months (n = 376) of age when anopenile distance (AGDAP) and anoscrotal distance (AGDAS) were measured. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 500 male infants who had both maternal plasma concentrations of PFASs and at least one AGD measurement of at three time points were included in the present study. Multiple linear regression models were used to evaluate the potential linear associations between maternal concentrations of PFASs and AGD. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal plasma concentrations (ln-transformed) of perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUdA) were inversely associated with AGDAS or AGDAP at birth (AGDAS: per ln unit increase in PFAS concentrations: ß (95% CI): -0.65 (-1.27 to -0.02) mm for PFOS; -0.58 (-1.11 to -0.06) mm for PFDA; and -0.57 (-1.09 to -0.06) mm for PFUdA; AGDAP: per ln unit increase in PFAS concentrations: ß (95% CI): -0.63 (-1.24 to -0.01) mm for PFDA and - 0.76 (-1.36 to -0.16) mm for PFUdA). At 6 months of age, per unit increase in maternal ln concentrations of PFOS and perfluorotridecanoic acid (PFTrDA), AGDAS decreased on average by -2.21 (95% CI: -4.28 to -0.14) and -1.11 (95% CI: -2.17 to -0.06) mm, respectively. Additionally, ln-transformed perfluorooctanoic acid (PFOA) showed nonsignificant but inverse associations with both AGDAS and AGDAP at 6 months of age. We found no significant associations between ln-transformed maternal concentrations of PFASs and either AGDAS or AGDAP at 12 months of age. However, significantly inverse association of ln-transformed PFOA with AGDAP was observed in male infants who never or shortly breastfed (<3 months) at 12 months of age. LIMITATIONS, REASONS FOR CAUTION: AGD measurements were performed by different examiners at each follow-up visit, and the intra-examiner variation was not assessed, which might cause intra-rater and inter-rater measurement errors. Additionally, our study may have selection bias since a considerable number of participants withdrew from the cohort although the differences in demographic characteristics were not statistically significant between included mother-infant pairs and those excluded. No statistical correction was made for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may have important implications for the early development of genital health in male infants since PFASs can be detected in almost all pregnant women and infants worldwide. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Key Research and Development program of China (2018YFC1002801 and 2016YFC1000505), the Science and Technology Commission of Shanghai Municipality (16ZR1430100), the National Natural Science Foundation of China (81428011), and the Innovation-Oriented Science and Technology Grant from National Health Commission Key Laboratory of Reproduction Regulation (CX2017-06). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.