Abstract To investigate the associations of otitis media with effusion (OME) with different socioeconomic status (SES) before during and after the coronavirus disease 2019 (COVID-19) outbreak in Northeast China. Three cross-sectional data on daily emergency and outpatient were included pre, during and post COVID-19 epidemic. We recorded the number of OME and symptoms and confirmed SARS-Cov-2 infection in patients with OME. We used logistic regression to evaluate the odds ratio (OR) for OME with COVID-19 infection, and employed an interrupted time series analysis to quantify the effect of COVID-19 outbreak on OME, and a time-stratified case-crossover analysis to evaluate the association of OME with SES before, during and after the COVID-19 outbreak, especially in the two months following the COVID-19 outbreak. During COVID-19 outbreak, the OME significantly increased by 50% (RR: 1.563, 95% CI 1.256–1.942) compared to the same period in other years, low SES was associated with an increased risk of OME, but this low SES-related risk elevation significantly increased during the outbreak of COVID-19, especially in the first month after COVID-19 infection. Individuals under 50 years old were still vulnerable to SES after COVID-19 infection in Liaoning. Lower SES might aggravate OME and greater efforts are needed to improve SES in post-COVID-19.

BACKGROUND:Per- and polyfluoroalkyl substances (PFAS) pose significant health risks to vulnerable populations such as pregnant women and children. Evidence on prenatal PFAS exposure and childhood respiratory allergic diseases (RAD) is scarce, particularly regarding how this relationship might be modified by prenatal PM2.5 exposure. OBJECTIVE:To assess the association between prenatal PFAS exposure and the risk of childhood RAD and evaluate whether prenatal PM2.5 exposure modifies this association. METHODS:We conducted a population-based prospective cohort study of 4,166 mother-child pairs from the Shanghai Birth Cohort Consortium to investigate this relationship. Data on RAD (including asthma and allergic rhinitis) in children under 8 years of age were collected from medical records or validated questionnaires. Concentrations of seven PFAS were measured in maternal blood collected during early pregnancy using ultra-high performance liquid chromatography/triple quadrupole tandem mass spectrometry. Generalized linear regression models were used to assess the associations between PFAS and childhood RAD after adjusting for potential confounders. RESULTS:Among the participants, 1,003 (23.9%) children were diagnosed with RAD. PFOA exhibited the highest median concentration (11.97 ng/mL), followed by PFOS (9.68 ng/mL). A doubling increment in PFOA was associated with an increased adjusted odds ratio (aOR) for childhood RAD (1.21, 95% CI: 1.03 to 1.41). The molar sum of five carboxylate PFAS (∑PFCAs) were also significantly associated with elevated RAD risk (aOR = 1.21, 95% CI: 1.03 to 1.42). Additionally, we observed that higher prenatal PM2.5 exposure appeared to enhance the adverse effects of PFAS on RAD, with a significant interaction specifically noted for PFOA in relation to allergic rhinitis (aOR = 1.35, 95% CI: 1.07 to 1.72). CONCLUSION:Prenatal exposure to individual and PFAS mixture was associated with an increased risk of childhood RAD, particularly allergic rhinitis. Children born to mothers with high PM2. 5 levels during pregnancy were more susceptible. Reducing prenatal PFAS and PM2.5 exposure may reduce the public health burden of childhood RAD.

Cellular senescence is a fundamental hallmark of aging and represents a major barrier to the scalable and reproducible application of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs). Senescent human umbilical cord mesenchymal stromal cells (hUCMSCs) exhibit impaired proliferative capacity, disrupted mitochondrial homeostasis, and altered secretory phenotypes, which may compromise the biological activity and therapeutic reliability of sEVs. Here, we investigated whether overexpression of human telomerase reverse transcriptase (hTERT) attenuates senescence-associated deterioration and stabilizes sEV functional properties. Late-passage hUCMSCs displayed canonical senescence features and mitochondrial dysfunction, all of which were markedly alleviated by hTERT expression. Functionally, sEVs derived from senescent cells exhibited impaired immunomodulatory activity, whereas sEVs from hTERT-expressing cells largely restored this function. Mechanistically, senescence was associated with altered sEV cargo, including enrichment of miR-217-5p, which contributed to diminished immunomodulatory potency, at least in part through modulation of SIRT1-associated inflammatory signaling in recipient macrophages. Proteomic profiling further showed that H11-sEVs retained a young-like protein cargo profile, particularly for proteins associated with immune and inflammatory regulation. In parallel, sEVs from all three groups retained primordial follicle-activating capacity, consistent with the broad retention of PI3K-Akt pathway-related proteins in their proteomic profiles and PI3K-Akt pathway activation in ovarian tissues. In aged female mice, H11-sEVs exhibited young-like ovarian protective activity. Collectively, these findings demonstrate that hTERT uncouples cellular senescence from sEV functional decline, supporting the development of potency-stabilized sEV sources for aging-related and regenerative applications and providing insight into the biological roles of senescent cell-derived sEVs.

BACKGROUND:There is limited information on the joint effect of multiple-metal(loid)s on infant development. OBJECTIVE:This study aimed to investigate the joint impact of maternal early pregnancy and newborn exposures to mercury (Hg), selenium (Se), manganese (Mn) and zinc (Zn) on early child neurodevelopment. METHODS:Included were 2771 mother-infant pairs from the Shanghai Birth Cohort who had maternal early pregnancy blood and newborn cord blood Hg, Mn, Se and Zn measured. Neurobehavior was assessed using the Ages and Stages Questionnaire (ASQ-3) instrument at age 6 months, and Bayley Scales of Infant & Toddler Development (BSID-III) at age 24 months. Linear regression was used to examine effect of metal(loid)s (in tertiles), and Bayesian kernel machine regression (BKMR) for exposures mixtures on child neurobehavior. RESULTS:The ASQ-3 communication score was 1.25 lower (95% CI: -2.11, -0.38) in the high tertile group of maternal Hg (> 2.09 μg/L), 1.36 lower (95% CI: -2.45, -0.246) in high cord blood Hg (> 2.64 μg/L), 1.61 lower ( 95% CI: -1.07, -0.15) in high maternal Mn, and 1.10 higher (95% CI: 0.04, 2.16) in high cord blood Se at age 6 months. High maternal Hg was also associated with 1.80 increased social-emotional (SE) scores (95%CI: 0.22, 3.37). At age 24 months, high maternal Zn (> 5.62 μg/L) was associated with 2.66 higher (95%CI 0.43, 4.89) cognition score. These associations were persistent with adjustment for the other metal(loid)s by using BKMR models. The overall effects of maternal blood and cord blood metal(loid) mixture were both adversely associated with communication score and SE at age 6 months, respectively. CONCLUSIONS:The early-pregnancy and newborn biomarkers of prenatal exposure to Hg show negative effect on early child development. The overall combined impact of maternal exposure to Hg, Mn, Se and Zn mixtures appear to be adverse in the first 24 months of life.

BACKGROUND:Early pregnancy exposure to organophosphate flame retardants (OPFRs) and pesticides (OPPs) may disrupt maternal thyroid function, but mixed effects remain unclear. METHODS:This study examined 403 pregnant women (<16 weeks of gestation) from the Shanghai Birth Cohort, measuring urinary metabolites of eight OPFRs and six OPPs using ultra-performance liquid chromatography-tandem mass spectrometry. Free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb) status were also assessed. Single-exposure effects were analyzed using multiple linear/logistic regressions, and mixture effects with quantile g-computation (Qgcomp) and Bayesian kernel machine regression (BKMR) models. RESULTS:Single-exposure analysis revealed significant associations between specific organophosphate metabolites and maternal thyroid function parameters: O,O-diethyl phosphate with suppressed TSH levels, O,O-diethyl thiophosphate with elevated FT3, and Di-o-tolyl-phosphate with increased risk of TPOAb positivity. Qgcomp analysis indicated non-significant mixture effects, including an overall trend toward TSH suppression, elevated FT3 and FT4 levels, and heightened TPOAb positivity risk. BKMR confirmed the presence of the aforementioned nonlinear correlation in the mixture. Stratified analysis revealed that mixed exposure significantly impacted FT3 and FT4 levels in multiparous women and FT4 levels in pregnant women with female fetuses. CONCLUSION:Early pregnancy exposure to OPFR/OPP mixtures is associated with potential disrupted maternal thyroid homeostasis and increases autoimmune risk.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants; however, their long-term neurodevelopmental effects following prenatal exposure remain incompletely characterized. This study examined associations between prenatal PFAS exposure and longitudinal neurodevelopment from birth to age 7 years old, with attention to sex-specific effects and thyroid hormone-mediated pathways. Using data from the Laizhou Wan Birth Cohort, 221 mother-infant pairs with at least three neurodevelopmental assessments were included. PFAS concentrations were quantified in cord blood at delivery, and neurodevelopment was evaluated using validated instruments. Generalized Linear Mixed-Effects Models and Bayesian Kernel Machine Regression were applied. Prenatal exposure to perfluorohexanesulfonic acid (PFHxS) (OR = 3.76, 95% CI: 1.10-11.24) and perfluorooctanoic acid (PFOA) (OR = 2.15, 95% CI: 1.01-4.62) was associated with below-average neurodevelopment. Female offspring showed greater sensitivity to PFHxS exposure (OR = 6.73, 95% CI: 1.19-38.19). Mediation analyses indicated that thyroid hormone disruption may partially mediate these associations, with stronger effects observed in females. Associations were most evident at ages 1-2 years. These findings suggest that prenatal PFAS exposure is associated with adverse neurodevelopmental outcomes and highlight thyroid hormone disruption and sex-specific susceptibility during early childhood.

BACKGROUND AND OBJECTIVE:Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent pollutants with potential neurotoxic effects, but evidence on short-chain and emerging PFASs remains scarce. To examine associations between prenatal PFAS exposure, particularly short-chain and emerging compounds, and cognitive outcomes in 2.5-year-old children, considering sex-specific effects and the potential mediating role of maternal thyroid hormones (THs). METHODS:In 202 mother-child pairs from the Wuxi Birth Cohort (2019-2021), 23 PFASs and maternal THs were measured in serum. Child cognition was assessed using the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition. Statistical models including linear regression, restricted cubic splines (RCS) and Bayesian kernel machine regression (BKMR) were used to examine both linear and non-linear associations between prenatal exposure to individual and combined PFASs and offspring neurodevelopment. Mediation analysis was conducted to investigate whether maternal thyroid function mediated these associations. RESULTS:Higher maternal PFBA (short-chain) levels were significantly associated with lower verbal comprehension index scores in boys [β = -2.13, 95 % confidence interval (CI): -4.05, -0.20]. Elevated maternal levels of the short-chain PFAS PFHxS were significantly associated with lower working memory index scores (β = -3.90, 95 % CI: -7.48, -0.32), with similar adverse associations also observed for long-chain PFASs such as PFOA (β = -5.20, 95 % CI: -10.20, -0.20) and PFOS (β = -2.03, 95 % CI: -3.50, -0.55). Notably, RCS models revealed several short-chain PFASs, including PFHxA and PFPeA, showed significant nonlinear associations with cognitive outcomes such as working memory index (WMI)and visual spatial index. In contrast, PFAS mixtures showed no significant effects. Although several PFASs was associated with maternal thyroid hormone levels, mediation was not supported. CONCLUSION:Prenatal exposure to specific short and long chain PFASs may impair early cognitive development, with sex-specific and nonlinear patterns. These findings highlight the need for further research and regulation of emerging PFASs.

[Background]Attention-deficit/hyperactivity disorder(ADHD)is one of the most common neu-rodevelopmental disorders in children and adolescents.Current research suggests that environ-mental factors,such as per-and polyfluoroalkyl substances(PFAS),may be associated with an in-creased risk of ADHD in offspring.However,most epidemiological evidence originates from non-Chinese populations,with limited research investigating the association between prenatal PFAS and ADHD-like symptoms in Chinese school-aged children. [Objective]To examine the association between prenatal PFAS exposure and ADHD-like symptoms in 7-year-old children. [Methods]Based on the Shanghai Birth Cohort,this study included 488 mother-child pairs.PFAS were measured in maternal serum during the second trimester using ultra-performance liquid chromatography-tandem mass spectrometry.The analysis focused on eight specific compounds from three PFAS categories[perfluorooctanoic acid(PFOA),perfluorooctanesulfonic acid(PFOS),and perfluorohexanesulfonic acid(PFHxS)].The hyperactivity subscale of the Strengths and Difficulties Questionnaire(SDQ)was used to assess ADHD-like symptoms in children at age 7.Basic demographic information was collected via questionnaires and medical records.Negative binomial regression models were used to evaluate the relationship between individual exposures to the three typical PFAS categories(PFOA,PFOS,and PFHxS)and children's ADHD-like symptoms,while the bayesian kernel machine regression(BKMR)mixture model was employed to assess the overall effect of PFAS mixture exposure on ADHD-like symptoms. [Results]The detection rates of the eight target PFAS in maternal second-trimester serum were all above 85％,with PFOA exhibiting the highest median concentration(10.21 ng·mL-1).Overall,14.75％of the children exhibited ADHD-like symptoms.Results from the negative binomial regression models showed that second-trimester exposures to PFOA(IRR=1.15,95％CI:1.05,1.26),n-PFOS(IRR=1.08,95％CI:1.01,1.15),6m-PFOS(IRR=1.13,95％CI:1.05,1.21),and 1m-PFOS(IRR=1.11,95％CI:1.03,1.18)were associated with an increased risk of ADHD-like symptoms in 7-year-old children.Stratified analyses suggested potentially statistically significant associations in girls[e.g.,for PFOA,boys vs.girls:1.09(0.96,1.23)vs.1.25(1.09,1.44),P-int=0.31].The BKMR mixture model indicated that the risk of ADHD-like symptoms trended upward with increasing PFAS mixture concentrations,although this association was statistically significant only among girls(P<0.05). [Conclusion]Prenatal PFAS exposure may be associated with an increased risk of ADHD-like symptoms in 7-year-old children,and this adverse association appears to be more prominent in girls.

Previous studies indicate pesticides may disrupt female reproductive hormone levels. However, the combined effects of multiclass pesticides on these hormones and whether different types exert distinct effects in women undergoing assisted reproductive technology (ART) remain unclear. Thus, we examined associations between combined multiclass pesticide exposure and reproductive hormone levels in ART women. The study included 462 women enrolled in the sub-cohort of the China National Birth Cohort between July 2017 and December 2018. Blood and urine samples were collected before ART treatment. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and anti-Mullerian hormone (AMH) were obtained from medical records. Urine was quantified for organophosphates (OPs), pyrethroids (PYRs), neonicotinoids (NEOs), and their metabolites. Using hierarchical bayesian kernel machine regression models we found combined exposure to multiclass pesticides was associated with increased FSH (-12.35%, 95% CI: -22.41%, -0.97% for 30th vs. 50th percentile) and decreased AMH (-15.74%, 95% CI: -28.83%, -0.25% for 75th vs. 50th percentile) levels. 4-fluoro-3-phenoxybenzoic acid (4F-3PBA, a PYR metabolite, condPIP = 0.79) and nitenpyram (NIT, a NEO metabolite, condPIP = 0.45) contributed most to elevated FSH and reduced AMH levels, respectively. Furthermore, OPs and PYRs were mainly associated with increased FSH, and NEOs with decreased AMH. Our study suggests that combined exposure to multiclass pesticides may adversely affect female reproductive function.

Limited evidence is available for the association between prenatal per- and polyfluoroalkyl substances (PFAS) exposure and childhood bone mineral density (BMD). Among 755 mother-child pairs in the Shanghai Birth Cohort, ten PFAS were measured in first-trimester maternal plasma using high-performance liquid chromatography/tandem mass spectrometry, and childhood lumbar spine BMD was assessed using dual-energy X-ray absorptiometry. Multivariable linear regression, Bayesian kernel machine regression (BKMR) and quantile g-computation (qgcomp) were applied. In the overall analyses, PFHpA was suggestively associated with higher total BMD (β = 0.13; 95% CI: 0.00, 0.27). Sex-stratified analyses indicated possible differences by sex. Among girls, PFDA and PFDoA showed inverse associations with total BMD (β = -0.29; 95% CI: -0.57, 0.00 and β = -0.27; 95% CI: -0.50, -0.04, respectively). Among boys, PFHpA showed a positive association with total BMD (β = 0.20; 95% CI: 0.04, 0.37). BKMR analyses suggested that mixture effects tended to be inverse among girls and positive among boys at higher quantiles. In qgcomp models, the positive association was most evident for L3 BMD among boys (β = 0.23; 95% CI: 0.00, 0.45). Our findings provide preliminary evidence that prenatal PFAS exposure may be associated with childhood BMD, with possible sex-specific patterns.

Hypertensive disorders of pregnancy (HDP) are major pregnancy complications, yet their environmental correlates and associated metabolic profiles remain incompletely characterized. In this prospective study of 1,432 pregnant women from the Shanghai Birth Cohort, we integrated exposome-wide prioritization, mixture analyses, untargeted metabolomics, meet-in-the-middle (MITM), and exploratory mediation analyses to investigate prenatal exposures and metabolic profiles associated with HDP, gestational hypertension (GH), and preeclampsia (PE). Eighty-one exposures were ranked using ExWAS, elastic net, random forest, sparse partial least squares, and XGBoost. Among the measured exposure domains, phenols were prominently represented among the top 15 exposures, accounting for eight, seven, and six exposures for HDP, GH, and PE, respectively. Among 10 prioritized phenols, BP-1, BP-8, 4-HBP, and BPS showed generally consistent positive associations, with supportive evidence from weighted quantile sum regression and Bayesian kernel machine regression. In 1,156 women with metabolomics data, metabolome-wide association analyses identified metabolic profiles associated with prioritized phenols and HDP outcomes. MITM and exploratory mediation analyses highlighted lipid-related candidate processes, particularly biosynthesis of unsaturated fatty acids and plasmalogen synthesis, which were consistently retained across the outcomes. These findings highlight prenatal phenols as an HDP-associated exposure family and lipid metabolism as a candidate biological link.

China, home to over 250 million children, has witnessed remarkable economic development in recent decades, successfully addressing many issues related to basic hygiene and sanitation in children, thereby altering the childhood disease spectrum. However, the emergence of environment-related disorders among children has become a significant concern. Despite the rapid accumulation of scientific knowledge on the adverse effects of environmental pollution on child health, the availability of children-specific protective strategies and actions remains alarmingly low. This commentary synthesizes the information and viewpoints presented and discussed by experts at the International Forum on Children's Environmental Health in China. It summarizes the strategies and actions proposed to reduce adverse environmental exposure and protect children's short- and long-term health and a call for more children-centered evidence-action transformation. The following four specific actions were proposed: (1) strengthen health education in parents, caregivers, and children, and personal protection for children; (2) monitor child exposure and environment-related health status; (3) set up child-specific interventions and regulations; and (4) conduct more research on environment exposures and child health.

Previous studies on prenatal environmental factors and early-life growth generally applied the single-exposure strategy, mostly relying on cross-sectional growth indicators. No attempt has been made to explore the environmental effects on longitudinal growth at the exposome level. Further, the underlying bio-mechanisms and gene-environment interactions are poorly understood. Within 1,944 mother-child pairs from the Shanghai Birth Cohort, neonatal sex-specific z-scores of weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) were used as the fetal growth outcomes. The growth trajectories of WAZ, LAZ, and WLZ before 2 years old were used as the child growth outcomes. We combined multiple exposome analysis strategies to screen for prenatal environmental factors that continuously affect the first 1000-day growth, based on which maternal metabolome and genome were incorporated to explore the underlying bio-mechanisms and effect modification by genetic predisposition. We found that phenols were the environmental factors that had a lasting growth impact, showing negative associations with neonatal WAZ, LAZ, and WLZ and positive associations with the risks of slow WAZ and LAZ growth trajectories and rapid WLZ growth trajectory in children. Metabolomic and gene-environment interaction analyses suggested the chemicals may exert such lasting effects by upregulating maternal glucose and lipid metabolism during pregnancy, and the effects were specifically more pronounced in mothers with high glucose and low lipid genetic predispositions. Our study suggests that prenatal exposure to phenols has lasting effects on offspring's first-1000-day growth by disturbing maternal glucose and lipid metabolism. The effects may be aggravated by maternal high glucose and low lipid genetic predispositions.

BACKGROUND:Dietary intake, especially foods of animal-origin, is an important source of per- and polyfluoroalkyl substances (PFAS) exposure to the general population. However, the distribution of legacy and emerging PFAS in different food categories is unclear, as well as their potential health risk for children. OBJECTIVES:To investigate dietary sources of PFAS and evaluate the risk for 7-year-old children in Laizhou Wan, a region with high PFAS exposure in Shandong, China. METHODS:We sampled participants from the Laizhou Wan Birth Cohort study. We administered a dietary questionnaire to the parents of 7-year-old children and measured PFAS compounds in the serum of the children (n = 154) and meat and seafood samples (n = 45). We calculated the Mann-Whitney U test to compare serum PFAS levels between children who frequently consumed a specific type of marine fish or shrimp/shellfish and those who did not. Children's dietary PFAS intake was calculated through multiplying food consumption and PFAS concentrations, and health risks were assessed by comparing the intake of PFAS with health-based guideline values. RESULTS:In seafood, perfluorooctanic acid (PFOA) (0.52 ng/g wet weight (ww)), perfluoro-6-methylheptanesulfonic acid (iso-PFOS) (0.02 ng/g ww), and 6:2 chlorinated polyfluoroethersulfonic acid (0.06 ng/g ww) had the highest median concentrations among 10 linear PFAS, 8 branched isomers of PFOA and perfluorooctanesulfonic acid (PFOS), and 3 alternatives, respectively. Particularly, PFOA levels (median, 87.80 ng/g) in Zoarces slongatus (one type of marine fish), were approximately 10-100 times of those in other seafood species. Children who frequently consumed Zoarces slongatus had higher serum PFAS levels, especially PFOA, than those who did not. Seafood intake accounted for more than 80% of the total estimated daily intake of PFAS. The dietary estimated weekly intake values of four PFAS (PFOA, PFOS, perfluorononanoic acid, and perfluorohexanesulfonic acid) for children (7.4 ng/kg of body weight (bw)/week) exceeded the tolerable weekly intake (4.4 ng/kg bw/week) as recommended by the European Food Safety Authority. CONCLUSION:Seafood was widely contaminated by both legacy PFAS and their alternatives in Laizhou Wan area. Intake of seafood, especially Zoarces slongatus, may contribute greatly to PFAS exposure in 7-year-old children. Avoiding intake of high PFAS polluted seafood may be an important strategy to protect local children. https://doi.org/10.1289/EHP15157.

Breastfeeding is an important source of Per- and polyfluoroalkyl substances (PFAS) exposure for breastfed infants. However, compared to prenatal exposures, health effects related to postnatal exposure to PFAS are less studied. In this study, we investigated PFAS exposure risk via breastfeeding and evaluate their associations with the physical growth of one-year-old infants in Laizhou Wan, a region with high PFAS exposure in Shandong, China. We included 117 mother-infant pairs who provided both human milk and maternal plasma samples for PFAS measurements. Among them, 99 one-year-old children were followed up for anthropometry measurement. We found that both legacy PFAS and their alternatives were widely detected in human milk samples. PFAS can be transferred from maternal serum to human milk. Perfluorooctanoic acid (PFOA) (median: 0.970 ng/mL) was the dominant PFAS compound in human milk, while perfluoro-6-methylheptanoic acid (6 m-PFOA) (0.013 ng/mL) and 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA) (0.018 ng/mL) had the highest median concentrations among branched isomers and alternatives, respectively. PFOA (77.35 ng/kg bw/d) had the highest median estimated daily intake (EDI) and contributed the most to the total median EDI of the Sigma 4PFAS (82.26 ng/kg bw/d). The daily exposure of infants to PFAS through breastfeeding has exceeded the health-based guidance value (HBGV) set by the European Food Safety Authority (EFSA) and the Agency for Toxic Substances and Disease Registry (ATSDR). Sex-specific effects might exist in the association between infants' physical growth and PFAS exposures via human milk, with the PFAS mixtures showing negative associations with heightfor-age z-score (HAZ) ((3 = -0.49, 95 % CI: -0.92, -0.06) and head circumference-for-age z-score (HCZ) ((3 = -0.61, 95 % CI: -1.02, -0.20), and a positive association with body mass index-for-age z-score (BMIZ) ((3 = 0.73, 95% CI: 0.02, 1.44) only in female infants. Further longitudinal studies are warranted to verify our results.

Background:Emerging evidence suggests vitamin D plays a dual role in immune regulation, yet its interplay with genetic susceptibility in early-life allergy development remains poorly understood. This prospective cohort study investigated whether cord blood 25-hydroxyvitamin D [25(OH)D] levels interact with immunoregulatory gene variants to influence childhood food allergy risk. Methods:A total of 1,049 mother-infant pairs from the Shanghai Allergy Cohort were stratified by cord blood 25(OH)D concentrations (<15, 15-25, >25 ng/mL). Food allergy diagnoses at 6, 12, and 24 months followed standardized clinical criteria. Five single-nucleotide polymorphisms (SNPs) (IL4, IL4R, IL13, MS4A2) were genotyped using MALDI-TOF MS. Multivariable logistic regression evaluated associations between vitamin D, genetic polymorphisms, and allergy outcomes, adjusting for birth season, maternal allergy history, and environmental confounders. Gene-vitamin D interactions were tested via stratified analyses. Results:A U-shaped relationship was observed between cord blood serum25(OH)D levels and the risk of developing childhood food allergies. Both deficient (<15 ng/mL) and elevated (>25 ng/mL) 25(OH)D levels at birth independently increased 6-month food allergy risk (adjusted OR = 2.55 and 2.38, respectively). By 24 months, only deficient levels showed attenuated effects (OR = 1.14, p = 0.779). IL4R rs1801275 AA, IL13 rs20541 GG, and IL-4 rs2243250 CC genotypes synergistically amplified allergy risk under vitamin D deficiency (adjusted OR = 26.14, p = 0.019; OR = 6.51, p = 0.025; OR = 4.13, p = 0.007). Notably, the protective effect of MS4A2 rs569108 GG genotype observed at reference vitamin D levels (adjusted OR = 0.55, p = 0.016) was attenuated at high levels (OR = 0.68, p = 0.149). Conclusion:Genetic susceptibility in Th2 pathway genes (IL4R, IL-4, IL13) dramatically amplified food allergy risk under vitamin D deficiency, with AA/GG/CC genotypes conferring 4- to 26-fold increased susceptibility. Conversely, the protective effect of MS4A2 rs569108 GG genotype was compromised at high vitamin D levels (>25 ng/mL). Our findings underscore that personalized vitamin D thresholds during pregnancy must account for fetal genetic background to mitigate allergy risk.

Bisphenol AF (BPAF), a widely used substitute for bisphenol A (BPA), has been widely detected in pregnant women, raising concerns about its potential effects on reproductive health. However, studies on the reproductive toxicity of BPAF in mammals remain limited. This study aimed to investigate the reproductive toxicity and underlying mechanisms of BPAF exposure during gestation and lactation. Pregnant Sprague-Dawley rats were randomly assigned to four groups (n = 10/group) and administered BPAF by oral gavage (0, 2, 10, or 50 mg/kg/d in corn oil) from gestational day (GD) 0 to postnatal day (PND) 21. Female offspring [first filial generation (F1)] were examined at PND21 and PND70 for reproductive outcomes and steroidogenic alterations. Gestational and lactational BPAF exposure significantly reduced anogenital distance (AGD) at PND21, from 12.05 +/- 0.59 mm in controls to 11.54 +/- 0.50 mm in the 50 mg/kg group (P < 0.001). At PND21, serum estradiol (E2) levels were decreased in the 2 and 10 mg/kg BPAF groups compared with controls (P < 0.05). By PND70, all BPAF-exposed offspring showed reduced E2 and testosterone (T) levels (P < 0.05). In addition, BPAF exposure increased follicular atresia and downregulated the mRNA expression of key steroidogenic genes (StAR, CYP11A1, 17 beta-HSD, and CYP19A1; P < 0.05) at PND70. Our findings indicate that BPAF exposure during gestation and lactation impairs reproductive function in F1 females and may exert long-term effects through disruption of ovarian steroidogenesis. Further research is warranted to confirm these outcomes.

PURPOSE. This study aimed to elucidate how Pax6 directly regulates Raver2 and sFlt-1 expression in corneal epithelial cells to maintain the cornea's avascular privilege during normal development. METHODS. The expression levels of Pax6, Raver2, and sFlt-1 in both the mouse cornea and human corneal epithelial cell line (HCE-T) were evaluated. Changes in Raver2 and sFlt-1 expression following Pax6 knockdown were also assessed. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR), electrophoresis mobility shift assay (EMSA), and dual-luciferase reporter (DLR) assay were conducted to ascertain the regulatory relationship between Pax6 and Raver2. The impact on vascular endothelial cell proliferation, migration, and tube formation was examined after coculturing with siPax6- HCE-T conditioned culture medium. Additionally, corneal neovascularization (CoNV) was monitored following corneal epithelial scraping or injection of the AAV-siPax6 vector into the limbus. RESULTS. Pax6, Raver2, and sFlt-1 were highly expressed in both HCE-T cells and normal mouse corneal epithelial layer. Interference with Pax6 expression resulted in decreased levels of Raver2 and sFlt-1 both in vivo and in vitro. TFBS1 and TFBS2 in the Raver2 promoter region were identified as potential Pax6 binding sites. ChIP-qPCR and EMSA assays confirmed the direct interaction between Pax6 and Raver2. The DLR assay demonstrated that Pax6 binding to the TFBS1 and TFBS2 regulated Raver2 expression. Vascular endothelial cell proliferation, migration, and tube formation were enhanced when cocultured with siPax6-HCE-T conditioned culture medium. CoNV progressed after corneal epithelial scraping and AAV-siPax6 vector injection. CONCLUSIONS. Pax6 directly regulates Raver2/sFlt-1 expression in corneal epithelial cells, thus preserving the cornea's avascular privilege during normal development.

Prenatal PFAS exposure and maternal psychological distress may adversely affect child neurodevelopment through shared biological pathways, such as hypothalamic-pituitary-adrenal (HPA) axis disruption and pro-inflammatory responses. However, whether psychological distress modifies PFAS-related neurodevelopmental risks remains unclear. Using data from the Shanghai Birth Cohort including 1779 mother-child pairs, we measured maternal PFAS levels during the first trimester and assessed maternal psychological distress (perceived stress, depression, and anxiety) during the second trimester. Child neurodevelopment was evaluated at 6 months of age using the Ages & Stages Questionnaires-Third Edition (ASQ-3). Multivariable regression models and quantile g-computation were conducted to evaluate the associations of ASQ-3 scores with individual and mixture PFAS. Stratified analyses were conducted between the psychological distress positive group (experienced any one type of stressor) and negative group (experienced no stressors). We found that 41 % of pregnant women experienced at least one type of psychological distress. Among the overall participants, maternal PFAS exposure was associated with reduced gross motor scores in children. Maternal psychological distress status modified the association between PFAS and gross motor scores. Specifically, the adverse associations of PFAS with gross motor development were only observed in the psychological distress positive group, while no association was found in the negative group. Significant interaction effects were observed between maternal psychological distress and most PFAS compounds (all P for interaction <0.1). Furthermore, the adverse associations of prenatal PFAS exposure with gross motor development intensified in women experiencing multiple types of psychological stressors. This study indicates that maternal psychological distress may increase the risk of PFAS-related adverse gross motor development in six-month-old children. Investigating maternal psychological distress could be crucial for identifying vulnerable populations and guiding intervention measures.