Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) influences neurodevelopment. Thyroid homeostasis disruption is thought to be a possible underlying mechanism. However, current epidemiological evidence remains inconclusive. OBJECTIVES: This study aimed to explore the effects of prenatal PFAS exposure on the intelligence quotient (IQ) of school-aged children and assess the potential mediating role of fetal thyroid function. METHODS: The study included 327 7-year-old children from the Sheyang Mini Birth Cohort Study (SMBCS). Cord serum samples were analyzed for 12 PFAS concentrations and 5 thyroid hormone (TH) levels. IQ was assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models (GLM) and Bayesian Kernel Machine Regression (BKMR) were used to evaluate the individual and combined effects of prenatal PFAS exposure on IQ. Additionally, the impact on fetal thyroid function was examined using a GLM, and a mediation analysis was conducted to explore the potential mediating roles of this function. RESULTS: The molar sum concentration of perfluorinated carboxylic acids (ΣPFCA) in cord serum was significantly negatively associated with the performance IQ (PIQ) of 7-year-old children (ß = -6.21, 95 % confidence interval [CI]: -12.21, -0.21), with more pronounced associations observed among girls (ß = -9.57, 95 % CI: -18.33, -0.81) than in boys. Negative, albeit non-significant, cumulative effects were noted when considering PFAS mixture exposure. Prenatal exposure to perfluorooctanoic acid, perfluorononanoic acid, and perfluorooctanesulfonic acid was positively associated with the total thyroxine/triiodothyronine ratio. However, no evidence supported the mediating role of thyroid function in the link between PFAS exposure and IQ. CONCLUSIONS: Increased prenatal exposure to PFASs negatively affected the IQ of school-aged children, whereas fetal thyroid function did not serve as a mediator in this relationship.

Associations of cord serum polybrominated diphenyl ether (PBDE) mixture with birth outcomes and mediating role of thyroid function: Evidence from the Sheyang Mini Birth Cohort Study.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs), a series of worldwide applied flame retardants, may influence fetal growth and interfere with thyroid function. The study intended to explore the relationship between in-utero exposure to PBDE mixture and newborn anthropometric indexes and to further examine the potential mediating role of thyroid function. METHODS: Demographics and laboratory measures of 924 mother-infant pairs were obtained from the database of the Sheyang Mini Birth Cohort Study. We applied gas chromatography-mass spectrometry (GC-MS) and electrochemiluminescence immunoassay to measure nine PBDE congeners and seven thyroid function parameters in umbilical cord serum samples, respectively. We fitted generalized linear models and Bayesian kernel machine regression (BKMR) to evaluate associations of lipid-adjusted cord serum PBDEs, as individuals and as a mixture, with newborn anthropometric and cord serum thyroid function parameters. We applied causal mediation analysis to test our hypothesis that thyroid function parameters act as a mediator between PBDEs and birth outcomes. RESULTS: The molarity of cord serum ∑9PBDE had a median value of 31.23 nmol/g lipid (IQR 19.14 nmol/g lipid, 54.77 nmol/g lipid). BDE-209 was the most dominant congener. Birth length was positively associated with both single exposure to BDE-28 and cumulative exposure to PBDEs. Correspondingly, ponderal index (PI) was negatively associated with BDE-28 and the total effects of PBDE mixture. Free triiodothyronine had a negative trend with BDE-209 and PBDE mixture. In the sex-stratified analysis, BDE-153 concentrations were positively correlated with PI among males (ß = 0.03; 95%CI: 0.01, 0.05; P = 0.01) but not among females. Cord serum thyrotropin mediated 14.92% of the estimated effect of BDE-153 on PI. CONCLUSIONS: In-utero mixture exposure to PBDEs was associated with birth outcomes and thyroid function. Thyroid function might act as a mediator in the process in which PBDEs impact the growth of the fetus.

Occurrence and Exposure Assessment of Nickel in Zhejiang Province, China.

Nickel (Ni) is a silver-white metal with high antioxidative properties, often existing in a bivalent form in the environment. Despite being the fifth most abundant metal on Earth, anthropogenic activities, including industrial processes, have elevated Ni levels in environmental media. This study investigated Ni contamination in various food groups in Zhejiang Province, China, mainly focusing on Ni levels in beans, vegetables, aquatic foods, meat products, cereal products, and fruits. A total of 2628 samples were collected and analyzed. Beans exhibited the highest Ni content in all samples. The overall detection rate of Ni was 86.5%, with variation among food categories. For plant-origin foods, legumes had the highest Ni concentration while for animal-origin foods, shellfish showed the highest median Ni concentration. The results indicate generally acceptable Ni exposure levels among Zhejiang residents, except for children aged 0-6. Beans were identified as the primary contributor to high Ni exposure risk. The paper suggests monitoring Ni contamination in food, especially for vulnerable populations, and provides insights into exposure risks in different age groups.

Occurrence and Health Risks of Organic Micropollutants in Tap Water in Dalian.

Organic micropollutants (OMPs) in tap water may pose risks to human health. Previous studies on the potential health risks of OMPs in tap water may have underestimated the potential health risks of OMPs due to their limited coverage in target pollutants and incomplete toxicity data. In this study, tap water samples were collected in 37 sampling sites in Dalian, China. More than 1,200 target pollutants were screened by combining screening analysis and target analysis. A total of 93 OMPs were detected, with concentration summation ranging from 157 to 1.7 × 104 ng/L among different sampling sites. A total of 17 OMPs (12 agrochemicals, 3 pharmaceuticals and personal care products, and 2 other compounds) were detected in over 80% of the sampling sites. Especially, imidacloprid, tebuconazole, and atrazine-desethyl were found in all the sampling sites. Computational toxicology models were adopted to predict the missing toxicity threshold values of the identified chemicals. Noncarcinogenic risks were estimated to be negligible among all the sampling sites, while carcinogenic risks at six sites were above 10-6 but below 10-4, indicating non-negligible risks. Griseofulvin contributed the most to the carcinogenic risk. This study offers valuable insights that can guide future initiatives to safeguard tap water safety.

Cadmium Exposure in Aquatic Products and Health Risk Classification Assessment in Residents of Zhejiang, China.

Cadmium (Cd) pollution of food safety is a prominent food safety concern worldwide. The concentration of Cd in six aquatic food categories collected from 2018 to 2022 was analyzed using inductively coupled plasma mass spectrometry, and the Cd exposure levels were calculated by combining the Cd concentration and food consumption data of 18913 urban and rural residents in Zhejiang Province in 2015-2016. The mean Cd concentration was 0.699 mg/kg and the mean Cd exposure of aquatic foods was 0.00951 mg/kg BW/month for the general population. Marine crustaceans were the largest Cd contributor, corresponding to 82.7%. The regional distribution results showed that the average Cd exposure levels of 11 cities did not exceed the provisional tolerable monthly intake (PTMI). According to the subgroups, the Cd mean exposure level of 2-3-year-old children was significantly higher than that of the other age groups but did not exceed the PTMI. Health risk classification assessment demonstrated that the final risk score was six, and the health risk level of Cd exposure in aquatic products in the Zhejiang population was medium. These results demonstrated that the risk of Cd exposure in certain food types or age groups should be given more concern.

Multiple mediation effects on association between prenatal triclosan exposure and birth outcomes.

BACKGROUND: Triclosan is a broad-spectrum antimicrobial, and was thought to affect intrauterine development, but the mechanism remains unclear. OBJECTIVE: To explore the association between prenatal triclosan exposure and birth outcomes. METHODS: Based on 726 mother-child pairs from the Sheyang Mini Birth Cohort Study (SMBCS), we used the available (published) data of triclosan in maternal urines, the hormones including thyroid-related hormones, gonadal hormones in cord blood, and adipokines, trimethylamine-N-oxide (TMAO) and its precursors in cord blood to explore possible health effects of triclosan on birth outcomes through assessing different hormones and parameters, using Bayesian mediation analysis. RESULTS: Maternal triclosan exposure was associated with ponderal index (ß = 0.317) and head circumference (ß = -0.172) in generalized linear models. In Bayesian mediation analysis of PI model, estradiol (ß = 0.806) and trimethylamine (TMA, ß = 0.164) showed positive mediation effects, while total thyroxine (TT4, ß = -0.302), leptin (ß = -2.023) and TMAO (ß = -0.110) showed negative mediation effects. As for model of head circumference, positive mediation effects were observed in free thyroxine (FT4, ß = 0.493), TMA (ß = 0.178), and TMAO (ß = 0.683), negative mediation effects were observed in TT4 (ß = -0.231), testosterone (ß = -0.331), estradiol (ß = -1.153), leptin (ß = -2.361), choline (ß = -0.169), betaine (ß = -0.104), acetyl-L-carnitine (ß = -0.773). CONCLUSION: The results indicated triclosan can affect intrauterine growth by interfering thyroid-related hormones, gonadal hormones, adipokines, TMAO and its precursors.

Integrated estrogenic effects and semi-volatile organic pollutants profile in secondary and tertiary wastewater treatment effluents in North China.

Endocrine-disrupting effects on aquatic organisms caused by wastewater discharging have raised extensive concerns. However, the efficiency of various wastewater treatment processes to remove estrogenic activity in effluents and the association with organic micropollutants was not well known. We evaluated the estrogenic activity using a well-characterized in vivo bioassay featuring the Chinese rare minnows (Gobiocypris rarus) and analyzed 886 semi-volatile organic compounds (SVOCs) in effluents from four secondary wastewater treatment plants (SWTP A-D) and a tertiary wastewater treatment plant (TTP E) that utilized various common treatment processes in northern China. The final effluents from SWTPs and TTP E all exhibited estrogenic effects, increasing male fish plasma vitellogenin (VTG) contents and estradiol/testosterone (E2/T) ratios. Key regulating genes in the male fish liver including vtg1, vtg3, era, erß, and cyp19a were upregulated. TTP E demonstrated high performance in reducing estrogenic activity in the effluents, with a reduction of 64% in integrative biomarkers of estrogenic response (IBR). UV disinfection at SWTPs removed IBR by 14%- 33%, while ozone disinfection at TTP E did not reduce IBR. Several SVOCs including alkanes, chlorobenzenes, and phthalates, detected at ng/L to µg/L level, significantly correlated with effluent estrogenic activity. Our findings suggest the necessity and the potential means to improve the efficiency of current wastewater treatment approaches to achieve better protection for aquatic organisms against the joint effects of mixtures of various categories of micropollutants in effluents.

Carbamate pesticides exposure and delayed physical development at the age of seven: Evidence from the SMBCS study.

BACKGROUND: Carbamate pesticides are widely used in agriculture and cause widespread human exposure. The health effect of carbamates on physical development remains unclear. The current study aimed to explore the carbamate's health effect on physical development. METHODS: Prenatal, 3-year-old, 7-year-old urinary carbofuranphenol concentration was measured by gas chromatography tandem mass spectrometry and adjusted by creatinine. Anthropometric indices were measured by standard method and z-score standardized. Generalized linear models (GLM) were using to assess associations between exposure measurements and anthropometric indices. The generalized estimate equation (GEE) was applied to analyze the association between multiperiod exposure and anthropometric indices, and time-interaction terms were used to exam health effect consistency of exposure in each period. Gender-stratified analysis were conducted according to results of gender-interaction terms to identify gender-specific effects. RESULTS: The gender-interaction term of prenatal exposure with height z-score was significant (ß = -0.057; 95% CI: -0.113, -0.001; p = 0.045). The 3-year-old carbofuranphenol level showed negative associations with weight z-score (ß = -0.019; 95% CI: -0.038, -0.000; p = 0.040), height z-score (ß = -0.015; 95% CI: -0.028, -0.001; p = 0.026), chest circumference (ß = -0.086; 95% CI: -0.171, -0.001; p = 0.046), and waist circumference (ß = -0.128; 95% CI: -0.230, -0.026; p = 0.014). No statistically significant trend was found for prenatal and 7-year-old carbofuranphenol levels. In GEEs, carbofuranphenol level was negatively associated with weight z-score (ß = -0.103; 95% CI: -0.195, -0.011; p = 0.027), height z-score (ß = -0.087; 95% CI: -0.152, -0.022; p = 0.008), and chest circumference (ß = -0.472; 95% CI: -0.918, -0.026; p = 0.037). Boy's height z-score was inversely associated with carbamate exposure (ß = -0.140; 95% CI: -0.227, -0.053; p = 0.001). CONCLUSIONS: Prenatal and postnatal carbamate exposure may affect physical developmental process.

Umbilical cord serum PBDE concentrations and child adiposity measures at 7 years.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) exist extensively in the environment. Toxicological studies suggested PBDEs may interfere with adipogenic pathways. However, few human evidence addressed PBDE exposures in utero related to childhood adiposity. OBJECTIVE: We assessed associations between PBDEs concentrations in cord serum and childhood adiposity measures at 7 years. METHODS: Among 318 mother-child pairs from Sheyang Mini Birth Cohort Study (SMBCS) in China, nine PBDE congener concentrations were quantified in umbilical cord serum using gas chromatography-negative chemical ionization mass spectrometry (GC-NCI-MS). Anthropometric indicators of children aged 7 years were measured, including weight, height and waist circumference. Age and sex-specific body mass index (BMI) z scores were calculated based on World Health Organization (WHO)'s child growth standards. Multivariate linear and logistic regression models adjusted for putative confounders were performed to examine associations between PBDE congeners and adiposity parameters. RESULTS: BDE-209 was the most abundant congener of PBDEs with a median value of 19.5 ng/g lipid. The geometric mean values of nine PBDE congeners ranged from below limit of detection (LOD) to 18.1 ng/g lipid, and the detection rates were 46.5%~96.5%. Cord serum BDE-153 and BDE-154 concentrations were associated with lower childhood BMI z score (regression coefficient, ß=-0.15, 95% confidence interval: -0.29, -0.02; p=0.02; ß=-0.23, 95%CI: -0.43, -0.03; p=0.03, respectively) and lower waist circumference (ß=-0.75 cm, 95%CI: -1.43, -0.06; p=0.03; ß=-1.22 cm, 95%CI: -2.23, -0.21; p=0.02, respectively), after controlling for potential confounders. Moreover, prenatal BDE-154 exposure was related to a decreased obesity risk of children aged 7 years (odds ratio, OR=0.46, 95%CI: 0.22, 0.94; p=0.03). These effects were only observed among boys in sex-straitified analyses. CONCLUSIONS: Cord serum BDE-153 and BDE-154 concentrations were related to reduced adiposity measures at 7 years of age. Further evidence regarding the impacts of prenatal PBDE exposures on childhood development is warranted.

Prenatal exposure to mixture of heavy metals, pesticides and phenols and IQ in children at 7 years of age: The SMBCS study.

OBJECTIVE: Prenatal exposure to heavy metals, pesticides and phenols has been suggested to interfere with neurodevelopment, but the neurotoxicity of their mixtures is still unclear. We aimed to elucidate the associations of maternal urinary concentrations of selected chemical mixtures with intelligence quotient (IQ) in children. METHODS: Maternal urinary concentrations of selected heavy metals, pesticide metabolites, and phenols were quantified in pregnant women who participated in the Sheyang Mini Birth Cohort Study (SMBCS) from June 2009 to January 2010. At age 7 years, child's IQ score was assessed using the Chinese version of Wechsler Intelligence Scale for Children (C-WISC) by trained pediatricians. Generalized linear regression models (GLM), Bayesian kernel machine regression (BKMR) models and elastic net regression (ENR) models were used to assess the associations of urinary concentrations individual chemicals and their mixtures with IQ scores of the 7-year-old children. RESULTS: Of 326 mother-child pairs, single-chemical models indicated that prenatal urinary concentrations of lead (Pb) and bisphenol A (BPA) were significantly negatively associated with full intelligence quotient (FIQ) among children aged 7 years [ß = -2.31, 95% confidence interval (CI): -4.13, -0.48; p = 0.013, sex interaction p-value = 0.076; ß = -1.18, 95% CI: -2.21, -0.15; p = 0.025; sex interaction p-value = 0.296, for Pb and BPA, respectively]. Stratified analysis by sex indicated that the associations were only statistically significant in boys. In multi-chemical BKMR and ENR models, statistically significant inverse association was found between prenatal urinary Pb level and boy's FIQ scores at 7 years. Furthermore, BKMR analysis indicated that the overall mixture was associated with decreases in boy's IQ when all the chemicals' concentrations were at their 75th percentiles or higher, compared to at their 50th percentiles. ENR models revealed that maternal urinary Pb levels were statistically significantly associated with lower FIQ scores (ß = -2.20, 95% CI: -4.20, -0.20; p = 0.031). CONCLUSIONS: Prenatal exposure to selected chemical mixtures may affect intellectual performance at 7 years of age, particularly in boys. Pb and BPA were suspected as primary chemicals associated with child neurodevelopment.

Sex-Specific Differences in Cognitive Abilities Associated with Childhood Cadmium and Manganese Exposures in School-Age Children: a Prospective Cohort Study.

To examine sex-specific associations of neonatal and childhood exposure to eight trace elements with cognitive abilities of school-age children. The association between exposure and effects was assessed among 296 school-age children from a population-based birth cohort study, who had manganese (Mn), cadmium (Cd), and lead (Pb) exposure measured in cord blood and chromium (Cr), manganese, cobalt (Co), copper (Cu), arsenic (As), selenium (Se), cadmium, and lead exposure quantified in spot urine. Cognitive abilities were assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models were performed to analyze associations of intelligence quotient (IQ) with trace element concentrations in cord blood and urinary trace element levels. General linear models were used to evaluate association between exposure fluctuation and children's IQ. Urinary Cd concentrations were negatively associated with full-scale IQ (ß = - 3.469, 95% confidence interval (CI) - 6.291, - 0.647; p = 0.016) and performance IQ (ß = - 4.012, 95% CI - 7.088, - 0.936; p = 0.011) in girls; however, neonatal Cd exposure expressed as Cd concentrations in cord blood was in inverse associations with verbal IQ (ß = - 2.590, 95% CI - 4.570, - 0.609; p = 0.010) only in boys. Positive association between urinary Mn concentrations and performance IQ (ß = 1.305, 95% CI 0.035, 2.575; p = 0.044) of children was observed, especially in girls. In addition, inverse association of urinary Cu concentrations with verbal IQ (ß = - 2.200, 95% CI - 4.360, - 0.039; p = 0.046) was only found in boys. Childhood Cd exposure may adversely affect cognitive abilities, while Mn exposure may beneficially modify cognitive abilities of school-age children, particularly in girls.

H-DenseUNet: Hybrid Densely Connected UNet for Liver and Tumor Segmentation From CT Volumes.

Liver cancer is one of the leading causes of cancer death. To assist doctors in hepatocellular carcinoma diagnosis and treatment planning, an accurate and automatic liver and tumor segmentation method is highly demanded in the clinical practice. Recently, fully convolutional neural networks (FCNs), including 2-D and 3-D FCNs, serve as the backbone in many volumetric image segmentation. However, 2-D convolutions cannot fully leverage the spatial information along the third dimension while 3-D convolutions suffer from high computational cost and GPU memory consumption. To address these issues, we propose a novel hybrid densely connected UNet (H-DenseUNet), which consists of a 2-D DenseUNet for efficiently extracting intra-slice features and a 3-D counterpart for hierarchically aggregating volumetric contexts under the spirit of the auto-context algorithm for liver and tumor segmentation. We formulate the learning process of the H-DenseUNet in an end-to-end manner, where the intra-slice representations and inter-slice features can be jointly optimized through a hybrid feature fusion layer. We extensively evaluated our method on the data set of the MICCAI 2017 Liver Tumor Segmentation Challenge and 3DIRCADb data set. Our method outperformed other state-of-the-arts on the segmentation results of tumors and achieved very competitive performance for liver segmentation even with a single model.

Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

Maternal polycystic ovary syndrome (PCOS), a condition associated with hyperandrogenism, is suggested to increase anxiety-like behavior in the offspring. Because PCOS is closely linked to obesity, we investigated the impact of an adverse hormonal or metabolic maternal environment and offspring obesity on anxiety in the offspring. The obese PCOS phenotype was induced by chronic high-fat-high-sucrose (HFHS) consumption together with prenatal dihydrotestosterone exposure in mouse dams. Anxiety-like behavior was assessed in adult offspring with the elevated-plus maze and open-field tests. The influence of maternal androgens and maternal and offspring diet on genes implicated in anxiety were analyzed in the amygdala and hypothalamus with real-time PCR ( n = 47). Independent of diet, female offspring exposed to maternal androgens were more anxious and displayed up-regulation of adrenoceptor α 1B in the amygdala and up-regulation of hypothalamic corticotropin-releasing hormone ( Crh). By contrast, male offspring exposed to a HFHS maternal diet had increased anxiety-like behavior and showed up-regulation of epigenetic markers in the amygdala and up-regulation of hypothalamic Crh. Overall, there were substantial sex differences in gene expression in the brain. These findings provide novel insight into how maternal androgens and obesity exert sex-specific effects on behavior and gene expression in the offspring of a PCOS mouse model.-Manti, M., Fornes, R., Qi, X., Folmerz, E., Lindén Hirschberg, A., de Castro Barbosa, T., Maliqueo, M., Benrick, A., Stener-Victorin, E. Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

DCAN: Deep contour-aware networks for object instance segmentation from histology images.

In histopathological image analysis, the morphology of histological structures, such as glands and nuclei, has been routinely adopted by pathologists to assess the malignancy degree of adenocarcinomas. Accurate detection and segmentation of these objects of interest from histology images is an essential prerequisite to obtain reliable morphological statistics for quantitative diagnosis. While manual annotation is error-prone, time-consuming and operator-dependant, automated detection and segmentation of objects of interest from histology images can be very challenging due to the large appearance variation, existence of strong mimics, and serious degeneration of histological structures. In order to meet these challenges, we propose a novel deep contour-aware network (DCAN) under a unified multi-task learning framework for more accurate detection and segmentation. In the proposed network, multi-level contextual features are explored based on an end-to-end fully convolutional network (FCN) to deal with the large appearance variation. We further propose to employ an auxiliary supervision mechanism to overcome the problem of vanishing gradients when training such a deep network. More importantly, our network can not only output accurate probability maps of histological objects, but also depict clear contours simultaneously for separating clustered object instances, which further boosts the segmentation performance. Our method ranked the first in two histological object segmentation challenges, including 2015 MICCAI Gland Segmentation Challenge and 2015 MICCAI Nuclei Segmentation Challenge. Extensive experiments on these two challenging datasets demonstrate the superior performance of our method, surpassing all the other methods by a significant margin.

Gland segmentation in colon histology images: The glas challenge contest.

Colorectal adenocarcinoma originating in intestinal glandular structures is the most common form of colon cancer. In clinical practice, the morphology of intestinal glands, including architectural appearance and glandular formation, is used by pathologists to inform prognosis and plan the treatment of individual patients. However, achieving good inter-observer as well as intra-observer reproducibility of cancer grading is still a major challenge in modern pathology. An automated approach which quantifies the morphology of glands is a solution to the problem. This paper provides an overview to the Gland Segmentation in Colon Histology Images Challenge Contest (GlaS) held at MICCAI'2015. Details of the challenge, including organization, dataset and evaluation criteria, are presented, along with the method descriptions and evaluation results from the top performing methods.

Adverse associations between maternal and neonatal cadmium exposure and birth outcomes.

Effects of low-level cadmium (Cd) exposure during early life on fetal growth remain unclear. Our aim was to evaluate whether Cd exposure in maternal urine and umbilical cord blood was associated with birth size parameters. A birth cohort study including 1073 mother-newborn pairs was conducted from 2009 to 2010 in an agricultural population in China. Cd concentrations were analyzed in both cord blood and maternal urine. Generalized linear models were performed to determine associations between maternal and neonatal exposure to Cd and birth indicators, including birth weight, length, head circumference and ponderal index. The median (25th to 75th percentile) value of Cd concentration in maternal urine and umbilical cord blood was 0.19 (0.08, 1.00) µg/L and 0.40 (

Adverse Associations of both Prenatal and Postnatal Exposure to Organophosphorous Pesticides with Infant Neurodevelopment in an Agricultural Area of Jiangsu Province, China.

BACKGROUND: Prenatal exposure to organophosphorous (OP) pesticides has been found to be associated with adverse effects on child neurodevelopment, but evidence on potential effects induced by both prenatal and postnatal OP exposure in infants is limited. OBJECTIVES: Our aim was to investigate the associations of both prenatal and postnatal OP exposure with birth outcomes and infant neurodevelopment. METHODS: Exposure to OP in 310 mother-infant pairs was assessed by measuring dimethylphosphate (DM), diethylphosphate (DE), and total dialkylphosphate (DAP) metabolites in urines from pregnant women and their children at 2 years of age. The Gesell Developmental Schedules was administered to examine neurodevelopment of 2-year-old children. RESULTS: Based on the Gesell Developmental Schedules, the proportions of children with developmental delays were < 6%. Adverse associations between head circumference at birth and prenatal OP exposure were demonstrated. Both prenatal and postnatal OP exposure was significantly associated with increased risk of being developmentally delayed. Specifically, odds ratio (OR) value for prenatal DEs was 9.75 (95% CI: 1.28, 73.98, p = 0.028) in the adaptive area, whereas in the social area, OR values for postnatal DEs and DAPs were 9.56 (95% CI: 1.59, 57.57, p = 0.014) and 12.00 (95% CI: 1.23, 117.37, p = 0.033), respectively. Adverse associations were observed only in boys, not in girls. CONCLUSIONS: Both prenatal and postnatal OP exposure may adversely affect the neurodevelopment of infants living in the agricultural area. The present study adds to the accumulating evidence on associations of prenatal and postnatal OP exposure with infant neurodevelopment. CITATION: Liu P, Wu C, Chang X, Qi X, Zheng M, Zhou Z. 2016. Adverse associations of both prenatal and postnatal exposure to organophosphorous pesticides with infant neurodevelopment in an agricultural area of Jiangsu Province, China. Environ Health Perspect 124:1637-1643; http://dx.doi.org/10.1289/EHP196.

3D-QSAR and docking studies of flavonoids as potent Escherichia coli inhibitors.

Flavonoids are potential antibacterial agents. However, key substituents and mechanism for their antibacterial activity have not been fully investigated. The quantitative structure-activity relationship (QSAR) and molecular docking of flavonoids relating to potent anti-Escherichia coli agents were investigated. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed by using the pIC50 values of flavonoids. The cross-validated coefficient (q(2)) values for CoMFA (0.743) and for CoMSIA (0.708) were achieved, illustrating high predictive capabilities. Selected descriptors for the CoMFA model were ClogP (logarithm of the octanol/water partition coefficient), steric and electrostatic fields, while, ClogP, electrostatic and hydrogen bond donor fields were used for the CoMSIA model. Molecular docking results confirmed that half of the tested flavonoids inhibited DNA gyrase B (GyrB) by interacting with adenosine-triphosphate (ATP) pocket in a same orientation. Polymethoxyl flavones, flavonoid glycosides, isoflavonoids changed their orientation, resulting in a decrease of inhibitory activity. Moreover, docking results showed that 3-hydroxyl, 5-hydroxyl, 7-hydroxyl and 4-carbonyl groups were found to be crucial active substituents of flavonoids by interacting with key residues of GyrB, which were in agreement with the QSAR study results. These results provide valuable information for structure requirements of flavonoids as antibacterial agents.

Feasibility of human hair follicle-derived mesenchymal stem cells/CultiSpher(®)-G constructs in regenerative medicine.

The use of human mesenchymal stem cells (hMSCs) in cell therapies has increased the demand for strategies that allow efficient cell scale-up. Preliminary data on the three-dimensional (3D) spinner culture describing the potential use of microcarriers for hMSCs culture scale-up have been reported. We exploited a rich source of autologous stem cells (human hair follicle) and demonstrated the robust in vitro long-term expansion of human hair follicle-derived mesenchymal stem cells (hHF-MSCs) by using CultiSpher(®)-G microcarriers. We analyzed the feasibility of 3D culture by using hHF-MSCs/CultiSpher(®)-G microcarrier constructs for its potential applicability in regenerative medicine by comparatively analyzing the performance of hHF-MSCs adhered to the CultiSpher(®)-G microspheres in 3D spinner culture and those grown on the gelatin-coated plastic dishes (2D culture), using various assays. We showed that the hHF-MSCs seeded at various densities quickly adhered to and proliferated well on the microspheres, thus generating at least hundreds of millions of hHF-MSCs on 1 g of CultiSpher(®)-G within 12 days. This resulted in a cumulative cell expansion of greater than 26-fold. Notably, the maximum and average proliferation rates in 3D culture were significantly greater than that of the 2D culture. However, the hHF-MSCs from both the cultures retained surface marker and nestin expression, proliferation capacity and differentiation potentials toward adipocytes, osteoblasts and smooth muscle cells and showed no significant differences as evidenced by Edu incorporation, cell cycle, colony formation, apoptosis, biochemical quantification and qPCR assays.

Large-scale expansion of Wharton's jelly-derived mesenchymal stem cells on gelatin microbeads, with retention of self-renewal and multipotency characteristics and the capacity for enhancing skin wound healing.

INTRODUCTION: Successful stem cell therapy relies on large-scale generation of stem cells and their maintenance in a proliferative multipotent state. This study aimed to establish a three-dimension culture system for large-scale generation of hWJ-MSC and investigated the self-renewal activity, genomic stability and multi-lineage differentiation potential of such hWJ-MSC in enhancing skin wound healing. METHODS: hWJ-MSC were seeded on gelatin microbeads and cultured in spinning bottles (3D). Cell proliferation, karyotype analysis, surface marker expression, multipotent differentiation (adipogenic, chondrogenic, and osteogenic potentials), and expression of core transcription factors (OCT4, SOX2, NANOG, and C-MYC), as well as their efficacy in accelerating skin wound healing, were investigated and compared with those of hWJ-MSC derived from plate cultres (2D), using in vivo and in vitro experiments. RESULTS: hWJ-MSC attached to and proliferated on gelatin microbeads in 3D cultures reaching a maximum of 1.1-1.30×10(7) cells on 0.5 g of microbeads by days 8-14; in contrast, hWJ-MSC derived from 2D cultures reached a maximum of 6.5 -11.5×10(5) cells per well in a 24-well plate by days 6-10. hWJ-MSC derived by 3D culture incorporated significantly more EdU (P<0.05) and had a significantly higher proliferation index (P<0.05) than those derived from 2D culture. Immunofluorescence staining, real-time PCR, flow cytometry analysis, and multipotency assays showed that hWJ-MSC derived from 3D culture retained MSC surface markers and multipotency potential similar to 2D culture-derived cells. 3D culture-derived hWJ-MSC also retained the expression of core transcription factors at levels comparable to their 2D culture counterparts. Direct injection of hWJ-MSC derived from 3D or 2D cultures into animals exhibited similar efficacy in enhancing skin wound healing. CONCLUSIONS: Thus, hWJ-MSC can be expanded markedly in gelatin microbeads, while retaining MSC surface marker expression, multipotent differential potential, and expression of core transcription factors. These cells also efficiently enhanced skin wound healing in vivo, in a manner comparable to that of hWJ-MSC obtained from 2D culture.