Association of plasma trans fatty acid concentrations with blood pressure and hypertension in U.S. adults.

Objective: The present study aimed to evaluate the association of plasma trans fatty acids (TFAs) biomarkers with the risk of hypertension. Methods: Using data from the National Health and Nutrition Examination Surveys (NHANES 2009-2010), we conducted a thorough analysis using both the traditional regression model and the Bayesian Kernel Machine Regression (BKMR) model to investigate the associations of individual TFAs and their mixtures with systolic blood pressure (SBP), diastolic blood pressure (DBP), and the risk of hypertension in a sample of 1,970 American adults. Results: The concentrations of TFAs were natural logarithms (ln) transformed to approximate a normal distribution. Multivariate linear regression models showed that each 1-unit increase in ln-transformed plasma concentrations of palmitelaidic, elaidic, vaccenic, and linolelaidic acids was associated with separate 2.94-, 3.60-, 2.46- and 4.78-mm Hg and 2.77-, 2.35-, 2.03-, and 3.70- mm Hg increase in SBP and DBP, respectively (P < 0.05). The BKMR model showed positive associations between the four TFAs mixtures and SBP and DBP. In addition, linolelaidic acid contributed the most to an increased blood pressure. Similar results were observed with the threshold of hypertension (≥130/80 mm Hg). Conclusion: Our findings provide preliminary evidence that plasma TFA concentrations are associated with increased blood pressure and the risk of hypertension in US adults. This study also suggests that linolelaidic acid might exhibit more deleterious effects on hypertension than other TFAs. Further studies should be conducted to validate these results.

Temporal trend in mortality due to congenital heart disease in China from 2008 to 2021.

BACKGROUND: Congenital heart disease (CHD) is a leading cause of birth defect-related mortality. However, more recent CHD mortality data for China are lacking. Additionally, limited studies have evaluated sex, rural-urban, and region-specific disparities of CHD mortality in China. METHODS: We designed a population-based study using data from the Dataset of National Mortality Surveillance in China between 2008 and 2021. We calculated age-adjusted CHD mortality using the sixth census data of China in 2010 as the standard population. We assessed the temporal trends in CHD mortality by age, sex, area, and region from 2008 to 2021 using the joinpoint regression model. RESULTS: From 2008 to 2021, 33,534 deaths were attributed to CHD. The period witnessed a two-fold decrease in the age-adjusted CHD mortality from 1.61 to 0.76 per 100,000 persons (average annual percent change [AAPC] = -5.90%). Females tended to have lower age-adjusted CHD mortality than males, but with a similar decline rate from 2008 to 2021 (females: AAPC = -6.15%; males: AAPC = -5.84%). Similar AAPC values were observed among people living in urban (AAPC = -6.64%) and rural (AAPC = -6.12%) areas. Eastern regions experienced a more pronounced decrease in the age-adjusted CHD mortality (AAPC = -7.86%) than central (AAPC = -5.83%) and western regions (AAPC = -3.71%) between 2008 and 2021. Approximately half of the deaths (46.19%) due to CHD occurred during infancy. The CHD mortality rates in 2021 were lower than those in 2008 for people aged 0-39 years, with the largest decrease observed among children aged 1-4 years (AAPC = -8.26%), followed by infants (AAPC = -7.01%). CONCLUSIONS: CHD mortality in China has dramatically decreased from 2008 to 2021. The slower decrease in CHD mortality in the central and western regions than in the eastern regions suggested that public health policymakers should pay more attention to health resources and health education for central and western regions.

Temporal Trend in Suicide Mortality for Chinese Adolescents, 2008 to 2021.

This study aims to evaluate the temporal trend in suicide mortality for Chinese adolescents aged 10 to 19 years from 2008 to 2021.

Impact of Newborn Screening Programme for Congenital Heart Disease in Shanghai: a five-year observational study in 801,831 newborns.

Background: Newborn Screening Programme for Congenital Heart Disease (CHD) in Shanghai has been in operation for over 5 years, and its feasibility and effectiveness still lack a systematic and comprehensive evaluation. This study aimed to detail the implementation of the programme and evaluate its results, benefits, and reliability in clinical practice. Methods: This study was an observational study involving all newborns received CHD screening in Shanghai from 2017 to 2021. Pulse oximetry (POX) plus cardiac murmur auscultation (namely the dual-index method) was used for CHD screening in newborns aged 6-72 h. Newborns who screened positive was recommended for echocardiography, and those diagnosed with CHD would be planned for further evaluation and intervention. Data were aggregated by birth year and district of birth. Results of neonatal CHD screening, diagnosis and treatment, and temporal trends of infant mortality rate (IMR) and the proportion of under-five mortality (U5M) attributed to CHD were analysed. A retrospective cohort study was also conducted to assess the reliability of the dual-index method in clinical practice. Findings: In total, 801,831 (99.48%) newborns were screened for CHD, 16,489 (2.06%) were screened positive, and 3541 (21.47%) of the screened-positive newborns were identified with CHD. Seven hundred and fifty-two patients with CHD received surgical or interventional treatment with a successful rate of 94.81%. The period from 2015 to 2021 witnessed an approximately twofold decrease in IMR from 4.58‰ to 2.30‰, and a downtrend in the proportion of U5M attributed to CHD from 25.93% to 16.61%. High sensitivity and specificity of the dual-index method in clinical practice were observed for both critical (100.00% and 97.72%) and major CHD (98.47% and 97.76%). Interpretation: Newborn screening programme for CHD has been well implemented in Shanghai, and this programme is a successful public health intervention to reduce infant death. Our study provides encouraging evidence and experience for implementing newborn screening programme for CHD nationwide in China. Funding: This study was supported by the National Key Research and Development Programme of China (2021YFC2701004 and 2016YFC1000506), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-002), and Three-Year Planning for Strengthening the Construction of Public Health System in Shanghai (No. GWIV-24).

Fischer's base-triggered formal (3+2) cycloadditions with 3-isothiocyanato oxindoles as acceptor-donor synthons.

Herein, previously unreported Fischer's base reactants serving as useful 2C building blocks in (3+2) cycloaddition reactions to build a library of bispiro[Fischer's base-oxindole] hybrids are described. These structurally intriguing products containing three adjacent quaternary stereocentres were smoothly afforded in up to 82% yield and >20 : 1 dr under catalyst-free conditions. Notably, the present protocol firstly employs 3-isothiocyanato oxindole serving as an acceptor and then as a donor in the formal (3+2) cycloadditions, allowing practical, straightforward access to structurally diverse cycloadducts. This work expands the applicability scope of 3-isothiocyanato oxindoles, which have been limited to behaving as donor/acceptor-based synthons in cycloadditions in previous work.

Enantioselective Synthesis of Bispiro[indanedione-oxindole-cyclopropane]s through Organocatalytic [2+1] Cycloaddition.

A series of compounds featuring a novel bispiro[indanedione-oxindole-cyclopropane] moiety have been synthesized through a squaramide-catalyzed [2+1] cycloaddition reaction. The tandem Michael-alkylation reaction of 2-arylidene-1,3-indanediones with 3-bromooxindoles furnished the cycloadducts in high yields with excellent diastereo- and enantioselectivities. The ammonium ylide in the catalytic process, as a key intermediate, was revealed by the high-resolution mass spectrometry study.

Synthesis and Activity Evaluation of Vinpocetine-Derived Indole Alkaloids.

This study focuses on the synthesis of novel vinpocetine derivatives (2-25) and their biological evaluation. The chemical structures of the synthesized compounds were fully characterized using techniques such as 1H NMR, 13C NMR, and HRMS. The inhibitory activity of the synthesized compounds on PDE1A was evaluated, and the results revealed that compounds 3, 4, 5, 12, 14, 21, and 25 exhibited superior inhibitory activity compared to vinpocetine. Compound 4, with a para-methylphenyl substitution, showed a 5-fold improvement in inhibitory activity with an IC50 value of 3.53 ± 0.25 µM. Additionally, compound 25, with 3-chlorothiazole substitution, displayed an 8-fold increase in inhibitory activity compared to vinpocetine (IC50 = 2.08 ± 0.16 µM). Molecular docking studies were conducted to understand the binding models of compounds 4 and 25 within the active site of PDE1A. The molecular docking study revealed additional binding interactions, such as π-π stacking and hydrogen bonding, contributing to the enhanced inhibitory activity and stability of the ligand-protein complexes. Overall, the synthesized vinpocetine derivatives demonstrated promising inhibitory activity on PDE1A, and the molecular docking studies provided insights into their binding modes, supporting further development of these compounds as potential candidates for drug research and development.

Associations of single and multiple perfluoroalkyl substances exposure with folate among adolescents in NHANES 2007-2010.

BACKGROUND: The accumulation of perfluoroalkyl substances (PFAS) in human body has raised concerns about the potential health impacts on children and adolescents. However, no study has evaluated the associations of PFAS exposure with folate concentrations among adolescents. METHODS: In the present study, we mainly used three statistical approaches, namely multiple linear regression, Bayesian Kernel Machine Regression (BKMR), and quantile-based g-computation (Q-gcomp) models, to evaluate associations of individual PFAS and their mixtures with serum and red blood cell (RBC) folate concentrations in a sample of 721 adolescents from the NHANES 2007-2010. RESULTS: In multiple linear regression models, for per unit increase in ln-transformed perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) concentrations, RBC folate concentrations decreased by 72.4 (95% confidence interval (CI): -112.7, -32.2), 58.3 (95% CI: -115.0, -1.6), 60.7 (95% CI: -107.5, -13.8), and 76.5 (95% CI: -119.0, -33.9) nmol/L, respectively. A similar significant inverse association was also observed between ln-transformed PFDA and serum folate. BKMR models further confirmed inverse associations of serum PFOS and PFDA with RBC folate, and serum PFDA with serum folate. However, the inverse associations of PFOA and PFNA with RBC folate shown in multiple linear regression model were not observed or less evident in BKMR analyses. We observed interactions of PFOA with PFOS, PFNA, and PFDA on RBC folate in BKMR models, with the negative slopes for PFOS, PFNA, and PFDA increased when PFOA concentration increased from the 10th percentile to the 90th percentile. Both BKMR and Q-gcomp models suggested that the mixtures of five PFAS showed inverse overall associations with RBC folate concentration. CONCLUSIONS: The present study revealed that adolescent exposure to PFAS might affect serum and RBC folate concentrations.

Catalytic asymmetric Michael/cyclization reaction of 3-isothiocyanato thiobutyrolactone: an approach to the construction of a library of bispiro[pyrazolone-thiobutyrolactone] skeletons.

Here, we demonstrate the first example of 3-isothiocyanato thiobutyrolactone serving as a useful building block in the Michael/cyclization reaction with alkylidene pyrazolones for the enantioselective construction of optically active structural bispiro[pyrazolone-thiobutyrolactone] skeletons containing three contiguous stereocenters with two spiroquaternary stereocenters. These products were smoothly afforded in up to 90% yield, >20 : 1 dr and >99% ee with chiral squaramide as the catalyst under mild conditions. Notably, this is also the first example of the merger of a spirocyclic pyrazolone scaffold with a spirocyclic thiobutyrolactone scaffold, potentially useful in medicinal chemistry.

Maternal serum 25-hydroxyvitamin D levels and infant atopic dermatitis: A prospective cohort study.

BACKGROUND: Maternal vitamin D status during pregnancy has been linked with the risk of atopic dermatitis (AD) in children, while the results were inconsistent. The objective of this study was to assess the potential association. METHODS: Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in pregnant women from the birth cohort MKFOAD. Infant AD was diagnosed according to Williams' criteria. Multivariate logistic regression model was used to examine the association of maternal serum 25(OH)D levels in the first, second, and third trimester of gestation with the risk of infant AD at first year of age. RESULTS: In total, 121 (26.5%) of 456 infants developed AD prior to 1 year of age. In general, higher maternal serum 25(OH)D levels throughout pregnancy were associated with increased risks of AD in infants prior to 1 year of age in multivariate logistic regression models, with borderline statistical significance in the first (per ln unit increase: adjusted OR = 1.93, 95% CI: 0.96, 3.88) and second (per ln unit increase: adjusted OR = 1.72, 95% CI: 0.93, 3.19) trimester. Multivariate logistic regression models using categorical variables of maternal 25(OH)D levels by tertiles showed similar results: Infants born to mothers with serum 25(OH)D levels in the highest tertile had higher risk of AD than those with 25(OH)D in the lowest tertile. CONCLUSIONS: The present study found some evidence supporting that higher maternal 25(OH)D levels during pregnancy increased the risk of infant AD. However, the clinical implication of the findings should be limited for those with blood levels over the recommendations.

Synthesis of methanesulfone-containing tetrasubstituted carbon stereocenters.

A methanesulfonylation reaction for the synthesis of sulfone-containing tetrasubstituted carbon stereocenters is described for the first time by simple treatment of indanedione-chromanone synthons with Et3N and easily accessible MsCl without any use of organometallic chemistry. This technology gave the corresponding valuable chromone-based 2-methanesulfonylated 1,3-indanediones in good yields (up to 89% yield) under mild conditions. The present work provides an attractive strategy for the construction of biologically interesting sulfone-containing tetrasubstituted carbon stereocenters, which might be valuable in medicinal chemistry.

Prenatal exposure to perfluoroalkyl substances and cord plasma lipid concentrations.

The effect of prenatal exposure to perfluoroalkyl substances (PFAS) on lipid concentrations in newborns is unknown. Using data from the Shanghai-Minhang Birth Cohort Study, we prospectively assessed the health effects of prenatal exposure to individual and multiple PFAS on cord lipid concentrations. Maternal plasma samples collected at 12-16 weeks of gestation were analyzed for eleven PFAS, and cord blood samples were analyzed for lipids: total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). We used multiple linear regression models to evaluate the associations of each individual PFAS with each lipid parameter, and used Bayesian Kernel Machine Regression (BKMR) models to assess the overall and single-exposure effects of eight PFAS with the detection rate above 80% on cord lipid concentrations. In multiple linear regression models, for each unit increase in ln-transformed maternal concentrations of perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUdA), and perfluorotridecanoic acid (PFTrDA), ln-transformed TC concentration decreased by 0.15 mg/dL (95% confidence interval (CI): -0.25, -0.05), 0.12 mg/dL (95% CI: -0.19, -0.05), 0.12 mg/dL (95% CI: -0.19, -0.05), and 0.05 mg/dL (95% CI: -0.09, -0.01), respectively, and ln-transformed HDL-C concentration decreased by 0.17 mg/dL (95% CI: -0.29, -0.05), 0.12 mg/dL (95% CI: -0.20, -0.03), 0.12 mg/dL (95% CI: -0.20, -0.03), and 0.06 mg/dL (95% CI: -0.11, -0.00), respectively. Statistically significant inverse associations were also observed between ln-transformed concentrations of PFDA, PFUdA, or PFTrDA and ln-transformed cord concentrations of TG and LDL-C. In BKMR models, the mixture of eight PFAS showed suggestively inverse association with all ln-transformed lipid concentrations, such that ln-transformed TC concentration of exposure to the 75th percentile of the mixture was 0.11 units (95% credible interval, -0.21, -0.01) lower than the 25th percentile exposure. Our findings indicated that prenatal exposure to PFAS may disrupt lipid metabolism in newborns.

Prenatal exposure to perfluoroalkyl substances and thyroid hormone concentrations in cord plasma in a Chinese birth cohort.

BACKGROUND: Evidence of associations between prenatal exposure to perfluoroalkyl substances (PFASs) and fetal thyroid hormones (THs) is controversial, and few studies have estimated the associations, while addressing the high correlations among multiple PFASs. We aimed to examine the associations between prenatal PFAS exposure and thyroid hormone concentrations in cord blood. METHODS: A total of 300 mother-infant pairs from the Shanghai-Minhang Birth Cohort Study were included. We measured the concentrations of eight PFASs in maternal plasma samples collected at 12-16 gestational weeks, as well as those of total thyroxine (T4), free T4 (FT4), total triiodothyronine (T3), free T3 (FT3), and thyroid stimulating hormone (TSH) in cord plasma. We estimated the associations between maternal PFAS concentrations and TH concentrations using linear regression and Bayesian kernel machine regression (BKMR) models. RESULTS: In BKMR models, higher PFAS mixture concentrations were associated with increased T3 concentrations, and there were suggestive associations with increased FT3 concentrations. For single-exposure effects in BKMR models, a change in PFDA, PFUdA, and PFOA concentrations from the 25th to 75th percentile was associated with a 0.04 (95%CrI: - 0.01, 0.09), 0.02 (95%CrI: - 0.03, 0.07), and 0.03 (95%CrI: - 0.001, 0.06) nmol/L increase in T3 concentrations, respectively. PFOA, PFNA, and PFDA were the predominant compounds in PFASs-FT3 associations, and the corresponding estimates were 0.11 (95% CrI: 0.02, 0.19), - 0.17 (95% CrI: - 0.28, - 0.07), and 0.12 (95% CrI: - 0.004, 0.24) pmol/L, respectively. A change in PFNA and PFOA concentrations from the 25th to 75th percentile was associated with a - 1.69 (95% CrI: - 2.98, - 0.41) µIU/mL decrease and a 1.51 (95% CrI: 0.48, 2.55) µIU/mL increase in TSH concentrations. The associations of PFOA and PFNA with T3/FT3 were more pronounced in boys, while those with TSH were more pronounced in girls. CONCLUSION: Our results suggest that prenatal exposure to multiple PFASs was associated with thyroid hormones in cord blood. However, individual PFAS had varied effects-differing in magnitude and direction-on fetal thyroid hormones.

Transition-metal-free cascade benzannulations for synthesizing 2-hydroxybenzophenones.

A set of cascade benzannulations of readily accessible chromone-3-carboxaldehydes and γ-nitroaldehydes for synthesizing biologically relevant 2-hydroxybenzophenones has been developed. The cascade was found to provide a transition-metal-free strategy for synthesizing 2-hydroxybenzophenones in acceptable yields (up to 57%).

Synthesis of Multifunctional α,α-Difluoroketones through Allylic Alkylation of Difluoroenoxysilanes with MBH Carbonates.

The first allylic alkylation of difluoroenoxysilanes with MBH carbonates catalyzed by triethylenediamine (DABCO) is developed, which allows rapid access to multifunctional α-gem-difluoroketones with up to 97% yields. Moreover, the gram-scale synthesis and the diversifying transformation of products to valuable gem-difluorinated molecules highlight the practicality of this methodology.

Prenatal bisphenol A exposure, fetal thyroid hormones and neurobehavioral development in children at 2 and 4 years: A prospective cohort study.

Findings about the association between prenatal Bisphenol A (BPA) exposure and neurobehavioral development in children are still inconsistent. In addition, whether fetal thyroid hormones (THs) mediate the reported association remains unclear. The present study aimed to examine the association between prenatal BPA exposure and risks of child behavioral problems at 2 and 4 years of age and whether the association could be explained by alteration of fetal THs as measured in cord plasma. Using the Shanghai-Minhang Birth Cohort Study (S-MBCS), BPA concentration was measured in maternal urine samples collected at 12-16 weeks of gestation. Children's neurobehavioral development was assessed using the Child Behavior Checklist/1.5-5 (CBCL), at 2 and 4 years of age. Using generalized estimating equation (GEE) models, 745 mother-pairs were included to examine associations of BPA with CBCL scores, Using multiple linear regression models, 348 mother-pairs were included to evaluate the association between maternal BPA and THs in cord plasma. A mediation analysis was conducted to explore the potential mediating role of THs. After adjusting for potential confounders, prenatal BPA level was associated with increased risks of Emotionally Reactive problem, Anxious/Depressed problem, having Somatic Complaints, exhibiting Aggressive Behavior, and Internalizing and Externalizing Problems: compared to the lowest tertile, the risks in the highest tertile and middle tertile, ranged between 1.55-fold (95% CI: 1.09, 2.21) and 2.59-fold (95% CI: 1.52, 4.42). The association was more pronounced among boys. None of the associations reached statistical significance among girls. An inverse association between prenatal BPA and fetal TH level was also observed. However, the observed neurotoxic effects of prenatal BPA exposure did not appear to be mediated by THs levels. The current findings suggest that prenatal exposure to BPA may disrupt fetal THs levels and may induce long-lasting behavioral alterations, especially in boys.

HClO4 catalysed aldol-type reaction of fluorinated silyl enol ethers with acetals or ketals toward fluoroalkyl ethers.

A highly efficient metal-free aldol-type reaction of various acetals or ketals with fluorinated silyl enol ethers catalysed by less than 1 mol% HClO4 (70 wt%, aq.) is developed. This provides expedient access to a wide array of valuable fluoroalkyl ethers featuring a ketone carbonyl functionality in good to excellent yields (40 examples). Furthermore, the thus obtained adducts are readily elaborated into other fluorine-containing alkyl ethers with a rich structure.

Prenatal plasma concentrations of Perfluoroalkyl and polyfluoroalkyl substances and neuropsychological development in children at four years of age.

OBJECTIVE: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent pollutants and have endocrine disruptive and neurotoxic effects. The association between maternal PFAS concentrations and neuropsychological development in children is inconclusive. The present study aimed to examine the effect of maternal PFAS concentrations on neuropsychological development in 4-years-old children. METHODS: We used data from Shanghai-Minhang Birth Cohort, which recruited pregnant women at 12-16 gestational weeks. Among 981 women having PFAS measurement, 533 mother-child pairs were included in the study. A total of eight PFASs were measured, including perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUdA), perfluorododecanoic acid (PFDoA), and perfluorotridecanoic acid (PFTrDA). When infants turned 4 years old, mothers were asked to complete the Ages and Stages Questionnaires® (ASQ) to assess neuropsychological development of their children. Poisson regression model with robust variance estimates was used to examine the association between maternal PFAS concentrations and each developmental subscale of the ASQ. RESULTS: Prenatal plasma concentrations of most PFASs tended to be associated with increased risk of development problem in personal-social skills, including PFHxS, PFOS, PFOA, PFNA, PFDA, and PDUdA, and the associations for PFNA and PFDA were significant (per natural log unit increase: RRPFNA = 1.92, 95% CI: 1.21, 3.05; RR PFDA = 1.66, 95% CI: 1.17, 2.37). In stratified analyses by child' sex, the consistent pattern of higher risk of developmental problems in personal-social skills associated with most PFASs was mainly observed among girls (RRPFOS = 2.56, 95% CI: 1.20, 5.45; RRPFOA = 9.00, 95% CI: 3.82, 21.21; RRPFNA = 3.11, 95% CI: 1.36, 7.13; RRPFDA = 2.20, 95% CI: 1.21, 4.00; RRPFUdA = 2.44, 95% CI: 1.14, 5.20; RRPFDoA = 1.62, 95% CI: 1.04, 2.54). Boys with higher maternal PFOA concentrations had a decreased risk of developmental problems in gross motor skills (RR = 0.47, 95% CI: 0.25, 0.89). CONCLUSION: Prenatal plasma PFAS concentrations were associated with neuropsychological development in girls at 4 years of age, mainly in the subset of personal-social skills.

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.