Urinary biomarkers of exposure to organophosphate, pyrethroid, neonicotinoid insecticides and oxidative stress: A repeated measurement analysis among pregnant women.

Exposure to insecticides may be associated with increased oxidative stress (OS), but few studies have assessed the associations of OS biomarkers (OSBs) with exposure to multiple insecticides and their mixture, especially in pregnant women who are a vulnerable population. In the present study, 1,094 Chinese pregnant women were recruited and a total of 3,282 urine samples were collected at their three trimesters to measure eight metabolites of organophosphates, three metabolites of pyrethroids, nine typical neonicotinoids/their metabolites, and three OSBs of DNA damage (8-OHdG), RNA damage (8-OHG), and lipid peroxidation (HNE-MA). Among the twenty target insecticide metabolites, sixteen of them were frequently detected; thirteen of them were detected in over 86% of all the urine samples except for imidacloprid (IMI, detection frequency: 72.9%), desnitro-imidacloprid (DN-IMI, 70.0%), and clothianidin (CLO, 79.6%). The reproducibility of their concentrations across the three trimesters was poor to fair (intraclass correlation coefficients <0.50). Multiparity and warm season were related to higher urinary levels of some insecticide metabolites, while higher education level and inadequate weight gain during pregnancy were significantly associated with lower concentrations of certain insecticide metabolites. Linear mixed model analyses suggested that almost all the frequently detected insecticide metabolites [other than 3-phenoxybenzoic acid (3-PBA)] were significantly associated with elevated levels of the three OSBs (8-OHdG, 8-OHG, and HNE-MA), where the percent change (Δ%) ranged 8.10-36.0% for 8-OHdG, 8.49-34.7% for 8-OHG, and 5.92-182% for HNE-MA, respectively, with each interquartile ratio (IQR)-fold increase in the concentrations of the individual exposure biomarkers. Weighted quantile sum models demonstrated that the insecticide metabolite mixture was positively associated with the three OSBs. Overall, urinary desmethyl-clothianidin (DM-CLO) and 3,5,6-trichloro-2-pyridinol (TCPy) were the top insecticide exposure biomarkers contributing to the association with 8-OHdG and 8-OHG levels, while PNP contributed the most to the association with HNE-MA levels. These findings suggested that gestational exposure to organophosphates, pyrethroids, neonicotinoids, their transformation products, and their mixture may increase oxidative damage to lipids, RNA, and DNA during pregnancy.

Associations of Trimester-Specific Exposure to Perchlorate, Thiocyanate, and Nitrate with Childhood Neurodevelopment: A Birth Cohort Study in China.

Studies about the impacts of maternal exposure to perchlorate, thiocyanate, and nitrate on offspring neurodevelopment are scarce. Based on a birth cohort in China, 1,028 mothers provided urine samples at three trimesters for determination of the three target analytes, and their offspring neurodevelopment was evaluated at 2 years old. Associations of maternal exposure to the three chemicals with offspring neurodevelopment were estimated using three statistical methods. Trimester-specific analyses using generalized estimating equation models showed that double increment of thiocyanate and nitrate during the first trimester was associated with 1.56 (95% CI: -2.82, -0.30) and 1.22 (-2.40, -0.03) point decreases in the offspring mental development index (MDI), respectively. Weighted quantile sum (WQS) regression analyses showed that the mixture exposure at the first and second trimesters was negatively associated with the offspring MDI (ß = -2.39, 95% CI: -3.85, -0.93; ß = -1.75, 95% CI: -3.04, -0.47, respectively) and thiocyanate contributed the most to the association (65.0 and 91.6%, respectively). Bayesian kernel machine regression analyses suggested an inverted U-shape relationship of maternal urinary thiocyanate with the offspring MDI. These findings suggested that prenatal exposure to the three chemicals (at current levels), especially thiocyanate and nitrate, may impair neurodevelopment. Early pregnancy seems to be the sensitive window.

Association of Prenatal Exposure to Organophosphate, Pyrethroid, and Neonicotinoid Insecticides with Child Neurodevelopment at 2 Years of Age: A Prospective Cohort Study.

BACKGROUND: Widespread insecticide exposure might be a risk factor for neurodevelopment of our children, but few studies examined the mixture effect of maternal coexposure to organophosphate insecticides (OPPs), pyrethroids (PYRs), and neonicotinoid insecticides (NNIs) during pregnancy on child neurodevelopment, and critical windows of exposure are unknown. OBJECTIVES: We aimed to evaluate the association of prenatal exposure to multiple insecticides with children's neurodevelopment and to identify critical windows of the exposure. METHODS: Pregnant women were recruited into a prospective birth cohort study in Wuhan, China, from 2014-2017. Eight metabolites of OPPs (mOPPs), three metabolites of PYRs (mPYRs), and nine metabolites of NNIs (mNNIs) were measured in 3,123 urine samples collected at their first, second, and third trimesters. Children's neurodevelopment [mental development index (MDI) and psychomotor development index (PDI)] was assessed using the Bayley Scales of Infant Development at 2 years of age (N=1,041). Multivariate linear regression models, generalized estimating equation models, and weighted quantile sum (WQS) regression were used to estimate the association between the insecticide metabolites and Bayley scores. Potential sex-specific associations were also examined. RESULTS: Single chemical analysis suggested higher urinary concentrations of some insecticide metabolites at the first trimester were significantly associated with lower MDI and PDI scores, and the associations were more prominent among boys. Each 1-unit increase in ln-transformed urinary concentrations of two mOPPs, 3,5,6-trichloro-2-pyridinol and 4-nitrophenol, was associated with a decrease of 3.16 points [95% confidence interval (CI): -5.59, -0.74] and 3.06 points (95% CI: -5.45, -0.68) respectively in boys' MDI scores. Each 1-unit increase in that of trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (trans-DCCA; an mPYR) was significantly associated with a decrease of 2.24 points (95% CI: -3.89, -0.58) in boys' MDI scores and 1.90 points (95% CI: -3.16, -0.64) in boys' PDI scores, respectively. Significantly positive associations of maternal urinary biomarker concentrations [e.g., dimethyl phosphate (a nonspecific mOPP) and desmethyl-clothianidin (a relatively specific mNNI)] with child neurodevelopment were also observed. Using repeated holdout validation, a 1-quartile increase in the WQS index of the insecticide mixture (in the negative direction) at the first trimester was significantly associated with a decrease of 3.02 points (95% CI: -5.47, -0.57) in MDI scores among the boys, and trans-DCCA contributed the most to the association (18%). CONCLUSIONS: Prenatal exposure to higher levels of certain insecticides and their mixture were associated with lower Bayley scores in children, particularly in boys. Early pregnancy may be a sensitive window for such an effect. Future studies are needed to confirm our findings. https://doi.org/10.1289/EHP12097.

Exposure to multiple neonicotinoid insecticides, oxidative stress, and gestational diabetes mellitus: Association and potential mediation analyses.

As the most extensively used insecticides worldwide, neonicotinoid insecticides (NNIs) have received a growing global concern over their adverse health effects. This study aimed to assess the associations of urinary concentrations of NNIs in early pregnancy with gestational diabetes mellitus (GDM) and the mediation roles of oxidative DNA damage, RNA damage, and lipid peroxidation in the associations. With a prospective nested case-control study, 519 GDM cases and 519 controls were matched on the infant's sex and maternal age. Urinary biomarkers of NNIs exposure and oxidative stress were measured in early pregnancy. We estimated the associations of single and the mixture of NNIs and their metabolites with GDM by conditional logistic regression and quantile g-computation models, respectively. The mediating roles of oxidative stress were evaluated by the structural equation model. The odds of GDM significantly increased by 15 %, 18 %, 26 %, 42 %, 49 %, and 13 % in each unit increment of ln-transformed concentrations of urinary imidacloprid (IMI), imidacloprid-olefin (IMI-olefin), desnitro-imidacloprid (DN-IMI), thiamethoxam (THM), clothianidin, and desmethyl-clothianidin, respectively. Exposure to the mixture of NNIs was associated with increased odds of GDM (adjusted OR: 1.76; 95 %CI: 1.45, 2.13). Advanced maternal age enhanced the associations of 5-hydroxy-IMI, DN-IMI, and IMI-olefin with GDM (P < 0.05), and being overweight/obese before pregnancy strengthened the effects of IMI, IMI-olefin, and THM on GDM (P < 0.05). In the association of NNIs exposure and GDM, the proportions mediated by oxidative DNA damage, RNA damage, and overall oxidative stress were 9.8 %, 11.8 %, and 14.5 %, respectively (P < 0.05). Exposure to individual NNIs and a mixture of NNIs were associated with GDM, and maternal age and pre-pregnancy BMI may modify the association. The possible mechanism underlying the association between NNIs and GDM may involve oxidative damage to nucleic acids.

Urinary metabolites of multiple volatile organic compounds, oxidative stress biomarkers, and gestational diabetes mellitus: Association analyses.

Volatile organic compounds are ubiquitous in the environment, which may cause various adverse health effects. The objectives of this study were to investigate associations of single and mixture of urinary metabolites of volatile organic compounds (mVOCs) with gestational diabetes mellitus (GDM) risk, and examine the possible role of oxidative stress in the associations. This nested case-control study included 454 GDM cases and 454 healthy controls matched by maternal age and infant sex. Urinary concentrations of twenty-one mVOCs and three oxidative stress biomarkers (including 8-OHdG, 8-OHG, and HNEMA), in early pregnancy were measured. Analyses using logistic regression model showed that an interquartile range increase in urinary concentrations of six individual mVOCs (ATCA, BPMA, CEMA, 3HPMA, MU, and TGA) were significantly associated with increased odds of GDM by 19-27%. Weighted quantile sum regression analyses showed that in each quartile increment of the mixture of mVOCs, the odds of GDM increased by 39% (95% CI: 16%, 67%), with 2-aminothiazoline-4-carboxylic acid weighted the most in the associations (weight: 25%). Furthermore, significant associations of the oxidative stress biomarkers with both GDM and certain mVOCs were observed. These results suggested that certain urinary mVOCs (correspondingly, the parent VOCs such as 1-bromopropane, cyanide, and benzene should be concerned as priority ones for regulation and policy making) in early pregnancy were significantly associated with elevated GDM incidence, and the associations were potentially related with oxidative stress biomarkers.

Urinary metabolites of multiple volatile organic compounds among pregnant women across pregnancy: Variability, exposure characteristics, and associations with selected oxidative stress biomarkers.

Volatile organic compounds (VOCs) are a group of pollutants pervasive in daily life with identified adverse health effects. However, no study has investigated the variability in VOC metabolites during pregnancy and their relationships with oxidative stress biomarkers in pregnant women. In the present study, the variability of 21 selected VOC metabolites was examined and their relationships with three selected oxidative stress biomarkers measured in spot urine samples at three trimesters of 1094 pregnant women were analyzed. Nineteen VOC metabolites were ubiquitous in the urine samples with detection rates ranging from 75.9% to 100%. Monohydroxybutenyl mercapturic acid (MHBMA) and s-phenyl mercapturic acid (PMA) had detection rates lower than 1.00%. Intraclass correlation coefficients (ICCs) of the detected analytes at three trimesters ranged 0.07-0.24, and the concentrations were highest in the first trimester. Higher concentrations of some VOC metabolites were related with participant characteristics including higher pre-pregnancy body mass index (BMI), lower education level, unemployment during pregnancy, multiparity, and sampling season of summer or winter. In repeated cross-sectional analyses, interquartile range (IQR) increases in the 19 detected VOC metabolites were positively related with 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), and 4-hydroxy nonenal mercapturic acid (HNEMA) with the estimates ranging from 9.00% to 204%. The mixture effect of the VOC metabolites on the oxidative stress biomarkers was further assessed using weighted quantile sum regression (WQS) models and the results showed that the WQS index of VOC metabolite mixture was significantly associated with 8-OHdG (ß: 0.37, 0,32, and 0.39 at the 1st, 2nd, and 3rd trimester, respectively), 8-OHG (0.38, 0.32, and 0.39) and HNEMA (1.21, 1.08, and 1.10). Glycidamide mercapturic acid (GAMA), and trans,trans-muconic acid (MU) were the strongest contributors of the mixture effect on 8-OHdG, 8-OHG, and HNEMA, respectively. Overall, urinary concentrations of the VOC metabolites during pregnancy were strongly associated with the oxidative stress biomarkers.

Variability, determinants, and associations with oxidative stress biomarkers of pentachlorophenol among Chinese pregnant women: A longitudinal study.

Pentachlorophenol (PCP) is ubiquitous and moderately persistent in the environment, and it is an identified human carcinogen. Previous animal experiments indicate that toxic mechanisms of PCP include oxidative stress. However, no epidemiological study has reported the association between PCP exposure and oxidative stress; such association in pregnant women, a vulnerable population, is of particular interest. This study aimed to characterize PCP concentrations in 2304 urine samples from 768 pregnant women, explore its determinants, and evaluate the associations between PCP exposure and three oxidative stress biomarkers across three trimesters. The median concentrations of PCP (100% detected) in the first, second, and third trimester were 0.61, 0.59, and 0.48 ng/mL, respectively, with a significant decrease trend. The intraclass correlation coefficient of specific gravity (SG)-adjusted PCP was 0.26, indicating high variability for PCP across the three trimesters. PCP concentrations were significantly higher in older, pre-pregnancy overweight, multiparous, high-income, and employed women during pregnancy. Urinary PCP was markedly lower in samples collected during spring compared to other seasons. Linear mixed effect models for repeated measures revealed that ln-transformed SG-adjusted PCP was significantly associated with increased 8-hydroxy-2'-deoxyguanosine (8-OHdG; percent change [%Δ] caused by each interquartile range increase of PCP: 46.2, 95% confidence interval [CI]: 40.2, 52.5) and 8-hydroxyguanosine (8-OHG;%Δ [95% CI]: 44.8 [40.1, 49.8]), but the positive association with 4-hydroxy2-nonenal-mercapturic acid (HNE-MA) was not significant. PCP was also positively associated with increased 8-OHdG and 8-OHG in each trimester using general linear models, and its associations with HNE-MA were only significant at T1 (%Δ [95% CI]: 19.1 [1.05, 40.3]) and T2 (%Δ [95% CI]: 12.6 [0.32, 26.3]). Our findings provide valuable information about PCP exposure characteristics during pregnancy and the potential effects of PCP exposure on oxidative stress in pregnant women.

Comprehensive analysis of FRAS1/FREM family as potential biomarkers and therapeutic targets in renal clear cell carcinoma.

Background: FRAS1 (Fraser syndrome protein 1), together with FREM1 (the Fras1-related extracellular matrix proteins 1) and FREM2, belonging to the FRAS1/FREM extracellular matrix protein family, are considered to play essential roles in renal organogenesis and cancer progression. However, their roles in kidney renal clear cell carcinoma (KIRC) remain to be elucidated. Methods: FRAS1/FREM RNA expression analysis was performed using TCGA/GTEx databases, and valided using GEO databases and real-time PCR. Protein expression was peformed using CPTAC databases. Herein, we employed an array of bioinformatics methods and online databases to explore the potential oncogenic roles of FRAS1/FREM in KIRC. Results: We found that FRAS1, FREM1 and FREM2 genes and proteins expression levels were significantly decreased in KIRC tissues than in normal tissues. Decreased FRAS1/FREM expression levels were significantly associated with advanced clinicopathological parameters (pathological stage, grade and tumor metastasis status). Notably, the patients with decreased FRAS1/FREM2 expression showed a high propensity for metastasis and poor prognosis. FRAS1/FREM were correlated with various immune infiltrating cells, especially CD4+ T cells and its corresponding subsets (Th1, Th2, Tfh and Tregs). FRAS1 and FREM2 had association with DNA methylation and their single CpG methylation levels were associated with prognosis. Moreover, FRAS1/FREM might exert antitumor effects by functioning in key oncogenic signalling pathways and metabolic pathways. Drug sensitivity analysis indicated that high FRAS1 and FREM2 expression can be a reliable predictor of targeted therapeutic drug response, highlighting the potential as anticancer drug targets. Conclusion: Together, our results indicated that FRAS1/FREM family members could be potential therapeutic targets and valuable prognostic biomarkers of KIRC.

Corrigendum: Efficacy and Safety of Shenqu Xiaoshi Oral Liquid Compared With Domperidone Syrup in Children With Functional Dyspepsia.

[This corrects the article DOI: 10.3389/fphar.2022.831912.].

Urinary 2,4-dichlorophenoxyacetic acid in Chinese pregnant women at three trimesters: Variability, exposure characteristics, and association with oxidative stress biomarkers.

Widespread exposure to herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) could have potential adverse health effects on pregnant women. However, related data are scarce. This study aimed to characterize 2,4-D exposure among three trimesters of pregnancy and to explore the relationship of 2,4-D with oxidative stress biomarkers [i.e., 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-hydroxy guanosine (8-OHG), and 4-hydroxy nonenal mercapturic acid (HNEMA)] in urine. The present study analyzed 3675 urine samples of 1225 women (across the three trimesters of pregnancy) in Wuhan, central China. 2,4-D was detectable in 97.4% of the urine samples. The median unadjusted concentration of 2,4-D was 0.12 ng/mL, and the corresponding concentration adjusted by urinary specific gravity (SG-adjusted) was 0.13 ng/mL. The intraclass correlation coefficient of 2,4-D (SG-adjusted concentrations) was 0.07 across the three trimesters. Significantly higher urinary levels of 2,4-D were found in samples from younger pregnant women/samples collected during winter. In addition, significantly positive association between urinary concentrations of oxidative stress biomarkers and 2,4-D were found in repeated analysis; an interquartile range increase in 2,4-D was significantly (p < 0.001) associated with a 20.8% increase in 8-OHG, a 26.7% increase in 8-OHdG, and a 30.7% increase in HNEMA, respectively. Such associations were also found in trimester-specific analyses. This is the first time to quantify the urinary 2,4-D of pregnant women in China, and this study found significantly positive associations of 2,4-D with oxidative stress biomarkers. Further studies are needed to verify such associations and explore other potential adverse effects of 2,4-D exposure.

Urinary paraben derivatives in pregnant women at three trimesters: Variability, predictors, and association with oxidative stress biomarkers.

Exposure to parabens has been shown to increase oxidative stress, which has a vital impact on the development of numerous diseases. However, few studies reported the effects of the paraben derivatives on oxidative stress, particularly among pregnant women. This study, using repeated measurements, aimed to understand the exposure profiles of urinary paraben derivative concentrations and their relationships with oxidative stress biomarkers (OSBs). A total of 861 pregnant women, who provided spot urine samples at three trimesters, were included, and 2583 urine samples were used to measure four paraben derivatives [p-hydroxybenzoic acid (p-HB), 3,4-dihydroxybenzoic acid (3,4-DHB), methyl protocatechuate, and ethyl protocatechuate], four parabens (methyl, ethyl, propyl, and butyl), and three OSBs [8-hydroxy-2'-deoxyguanosine (for DNA), 8-hydroxyguanosine (for RNA), and 4-hydroxy nonenal mercapturic acid (for lipid)]. Pregnant women were extensively exposed to parabens and paraben derivatives with detection frequencies (DFs) of 86.1%-100%, except for butylparaben with a DF of 14.9%. p-HB and 3,4-DHB had relatively high urinary concentrations (specific gravity-adjusted median values: 1394 and 74.5 ng/mL, respectively). Low reproducibility in paraben derivatives was found across the three trimesters. Sampling season, pre-pregnancy body mass index, and infant sex were predictors of some paraben derivatives/parabens. Linear mixed model analyses showed that all target compounds (if DF > 50%) were associated with increases in all the selected OSBs, where the percent change in OSBs with an interquartile range increase in paraben concentration ranged from 9.85% to 24.7%, while those in paraben derivative concentration ranged from 13.8% to 72.1%. Weighted quantile sum model showed that joint exposure was significantly associated with increased OSBs, and paraben derivatives were stronger contributors to OSBs compared with parabens. Overall, urinary paraben derivatives were associated with increased oxidative stress of nucleic acids and lipid in pregnant women.

Pentachlorophenol exposure in early pregnancy and gestational diabetes mellitus: A nested case-control study.

Pentachlorophenol (PCP) is an endocrine-disrupting chemical that is ubiquitously found in the environment. Few studies have reported PCP exposure in pregnant women and its association with gestational diabetes mellitus (GDM). This nested case-control study aimed to determine the concentration of urinary PCP in early pregnancy and explore the association between PCP exposure and GDM risk. This study included 293 GDM cases and 586 non-GDM controls matched by fetal sex and maternal age from a birth cohort in Wuhan, China. PCP concentrations in spot urine samples collected between 8 and 16 weeks of gestation were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Conditional logistic regression was used to assess the association between PCP exposure and the odds ratio of GDM. The median concentrations of specific gravity-adjusted PCP in controls and cases were 0.70 and 0.80 ng/mL, respectively, with no significant differences (P > 0.05). The multivariate-adjusted odds ratios (ORs) (95% confidence intervals) for GDM across quartiles of urinary PCP were 1 (reference), 1.63 (1.06-2.50), 1.70 (1.11-2.61), and 1.35 (0.87-2.08), respectively, showing a potential "inverted-U" shaped association. In addition, PCP levels and maternal age or fetal sex had significant interactions with GDM risk (both P for interaction < 0.05). Among older women and those carrying female fetuses, the ORs of GDM risk were higher. This study suggests that pregnant women in central China are widely exposed to PCP, and this is the first time to report that PCP exposure may increase the risk of GDM (with potential effect modifications by maternal age and fetal sex). The association observed is in agreement with PCP's "inverted-U" anti-estrogenic effect in vivo; thus, such an effect in humans at environmentally relevant doses should be studied further.

Improvement of the Accuracy in the Identification of Coronary Artery Disease Combining Heart Sound Features.

Most researchers use features of diastolic murmurs to identify coronary artery disease. However, the diastolic murmurs of coronary artery disease are usually very weak and are easily contaminated by noise and valvular murmurs. Therefore, the diagnostic accuracy of coronary artery disease when only using diastolic murmurs is not well. An algorithm for improving the accuracy in the identification of coronary artery disease by combining the features of the first heart sound and diastolic murmurs was proposed. Firstly, a first heart sound feature extraction algorithm was used to identify coronary artery disease from noncoronary artery disease. Secondly, the Empirical Wavelet Transform algorithm was used to decompose the diastolic heart sound into three modes, and the spectral energy of each mode was calculated to distinguish coronary artery disease from noncoronary artery disease. Then, the features of the fist heart sound, the second diastolic spectral energy, and the parameter P3, which was used to discriminate the diastolic murmurs in coronary artery disease and in valvular disease, were combined together to improve the diagnostic accuracy of coronary artery disease. The comparison experiment results show that the accuracy of the proposed algorithm is superior to some state-of-the-art methods when they are used to diagnose coronary artery disease.

Efficacy and Safety of Shenqu Xiaoshi Oral Liquid Compared With Domperidone Syrup in Children With Functional Dyspepsia.

Background: Treatment of functional dyspepsia (FD) in children is generally symptomatic and unsatisfactory. Traditional Chinese medicines, such as Shenqu Xiaoshi Oral Liquid (SXOL), have been recommended to alleviate dyspeptic symptoms. However, evidence of their safety and efficacy remains limited to date. AIM: To assess whether 2 weeks of therapy with SXOL was non-inferior to domperidone syrup in children with FD. Methods: In this randomized, double-blind, double-simulated, non-inferiority, multi-center clinical trial, we recruited children (3-14 years) with FD according to the Rome IV criteria from 17 tertiary medical centers across China. Patients were randomly allocated (1:1) to receive SXOL or domperidone syrup for 2 weeks. We compared the participants' clinical scores from both groups based on the severity and frequency of dyspepsia symptoms according to Rome IV criteria (0, 1, 2, and 4 weeks after randomization). The primary endpoint was the total response rate, which was defined as the proportion of patients with a decrease of 30% or more in the FD symptoms clinical score from baseline, at the end of the 2-weeks treatment. A non-inferiority margin of -10% was set. Secondary endpoints and adverse events were assessed. This trial is registered with www.Chictr.org.cn, number ChiCTR1900022654. Results: Between February 2019 and March 2021, a total of 373 patients were assessed for eligibility, and 356 patients were enrolled and randomized. The clinical response rate at week two was similar for SXOL [118 (83.10%) of 142] and domperidone [128 (81.01%) of 158]; difference 2.09; 95% CI -6.74 to 10.71, thereby establishing non-inferiority. The total FD symptom scores were significantly improved in the two groups at 1-, 2-, and 4-weeks follow-up periods (p < 0.005). The decrease in symptom score compared with the baseline were similar between these two groups. Over the total study period, 10 patients experienced at least one treatment-related adverse event [six (3.37%)] in the SXOL group, four [(2.25%) in the domperidone group], although no serious adverse event was noted. Conclusion: Treatment with SXOL effectively improves dyspeptic symptoms and is well tolerated. In addition, it is not inferior to domperidone syrup and leads to sustained improvement in Chinese children with FD.

Fipronil and its metabolites in human seminal plasma from Shijiazhuang, north China.

Fipronil (FP) is an emerging insecticide which could induce reproductive toxicity in male rats at very low dosage, but the occurrence of FP and its transformation products (FPs) in human seminal plasma and their impacts on human semen quality have not been documented. In this study, FPs including FP, fipronil desulfinyl (FP-DES), fipronil sulfone (FP-SFO), fipronil amide (FP-AM), and fipronil sulfide (FP-SFI), were measured in seminal plasma samples (n = 200), which were collected from Shijiazhuang, north China. The cumulative concentration of FPs (ΣFPs), in the seminal plasma samples ranged from 0.003 to 0.180 ng/mL (median: 0.043 ng/mL). FP-SFO was the major target analyte (median: 0.040 ng/mL), accounting for approximately 42.3-100.0% of the ΣFPs. Significantly higher exposure levels of FPs were found in the overweight or obese group (≥25 kg/m2) vs. the normal BMI group (18.5-25 kg/m2) (ΣFPs: 0.047 vs. 0.033 ng/mL), never smoking group vs. current smoking group (ΣFPs: 0.057 vs. 0.037 ng/mL), and low sexual frequency group (<1 time/week) vs. high sexual frequency group (≥3 times/week) (ΣFPs: 0.048 vs. 0.030 ng/mL). No significant association between FPs and impaired semen quality parameter was found in this study. This is the first time to report FPs' occurrence in human seminal plasma and variations in their concentrations among people with different demographic and behavioral characteristics. Further studies on adverse effects of exposure to FPs on reproductive function are needed.

Neonicotinoid insecticide metabolites in seminal plasma: Associations with semen quality.

Animal studies have revealed that exposure to neonicotinoid insecticides (NNIs) could compromise male reproductive function; however, related data on the occurrence of NNIs and their specific metabolites in human seminal plasma are scarce. To explore the potential effects of NNI exposure on male semen quality, we determined the concentrations of NNIs and some of their metabolites (collectively defined as mNNIs) in seminal plasma samples collected from men (n = 191) who visited a fertility clinic in Shijiazhuang, North China from 2018 to 2019. Associations between the mNNI concentrations and semen quality parameters were assessed using linear regression models, adjusting for important covariates. In the seminal plasma samples, desmethyl-acetamiprid (DM-ACE, detection frequency: 98.4%), imidacloprid-olefin (IMI-olefin, detection frequency: 86.5%), and desmethyl-clothianidin (DM-CLO, detection frequency: 70.8%) were frequently detected at median concentrations of 0.052, 0.003, and 0.007 ng/mL, respectively; meanwhile other compounds were detected at less than the method detection limits. In the single-mNNI models, the IMI-olefin concentration was associated with decreased progressive motility [IMI-olefin concentration: percent change (%Δ) = -17.0; 95% confidence interval (CI) = -30.3, -0.92; the highest tertile compared with the lowest tertile: %Δ = -21.1; 95% CI = -37.5, -0.23]. Similar results were found in the multiple-mNNIs models. No other inverse associations were found between the other mNNI concentrations and semen quality parameters. This is the first study to identify the occurrence of mNNIs in the seminal plasma and the potential associations of their concentrations with human semen quality parameters. These findings imply an inverse association between the IMI-olefin concentration and semen quality.

Exposure assessment of neonicotinoid insecticides and their metabolites in Chinese women during pregnancy: A longitudinal study.

Neonicotinoid insecticides (NNIs) are the most widely used insecticides globally and ubiquitous in the environment, which has led to widespread human exposure. However, studies on internal exposure levels of NNIs and their metabolites in pregnant women are scarce. In this study, we measured nine parent NNIs and ten main metabolites in 1224 urine samples donated by 408 pregnant women at three trimesters. In the urine samples, the unadjusted vs. specific gravity (SG) adjusted median concentrations and detection frequencies (DFs) of desmethyl-acetamiprid (DM-ACE; 1.01 vs. 1.08 ng/mL; DF: 99.7%), 5-hydroxy-imidacloprid (5-hydroxy-IMI; 0.54 vs. 0.56 ng/mL; 98.5%), imidacloprid-olefin (IMI-olefin; 0.41 vs. 0.44 ng/mL; 99.3%), and desnitro-imidacloprid (DN-IMI; 0.12 vs. 0.12 ng/mL; 90.4%) were higher than their corresponding parent NNIs, acetamiprid (ACE; <0.01 vs. <0.01 ng/mL; 26.4%) and imidacloprid (IMI; 0.04 vs. 0.04 ng/mL; 69.9%). The unadjusted and SG-adjusted median concentrations of clothianidin (CLO), thiamethoxam (THM), and desmethyl-clothianidin (DM-CLO) were 0.05 vs. 0.07, 0.05 vs. 0.06, and 0.04 vs. 0.05 ng/mL, with the DFs of 61.0%, 57.5%, and 75.7%, respectively. The cumulative exposure level, imidacloprid-equivalent total NNIs (IMIeq), was generated by the relative potency factor approach considering the toxic effects of NNIs and their metabolites. The unadjusted IMIeq varied from 0.17 ng/mL (SG-adjusted: 0.20) to 1969 ng/mL (SG-adjusted: 1817) with a median of 14.1 ng/mL (SG-adjusted: 14.1). A decreased trend was observed in urinary NNIs and their metabolites throughout the three trimesters. Maternal age, educational level, and household income were related to the concentrations of NNIs and their metabolites. DM-ACE, 5-hydroxy-IMI, and IMI-olefin were significantly lower in winter than in autumn; DN-IMI, THM, CLO, and DM-CLO were significantly higher in both summer and autumn than in winter. The maximum estimated daily intake of IMIeq [34.8 µg/kg-body weight (bw)/d] was lower than the chronic reference dose of IMI (57 µg/kg-bw/d) currently recommended by the United States Environmental Protection Agency. Human health risk of exposure to NNIs and their main metabolites warranted further studies.

Selected transformation products of neonicotinoid insecticides (other than imidacloprid) in drinking water.

Several transformation products (or metabolites) of neonicotinoid insecticides (NNIs) have been detected in drinking water, such as desnitro-imidacloprid and imidacloprid-urea. However, data on the occurrences of the metabolites of NNIs (mNNIs) in drinking water are mainly limited to the imidacloprid metabolites. To identify whether the potential metabolites of other widely used NNIs (such as acetamiprid, clothianidin, and thiamethoxam) occur in drinking water and to characterize their distribution profiles, twelve selected (mainly urea and desnitro/decyano) metabolites of NNIs were measured in drinking water samples (n = 884, including n = 789 for tap water, and n = 95 for shallow groundwater) that were collected from 32 provinces in mainland China and Hong Kong. Nearly 90% of the drinking water samples contained the detected mNNI residues. Among the selected mNNIs, thiamethoxam-urea (THM-urea: 76%) and decyano-acetamiprid (decyano-ACE: 73%) were frequently detected (median: 0.94 and 0.25 ng/L, respectively), which were followed by clothianidin-urea (CLO-urea: 45%), desnitro-thiamethoxam (DN-THM: 38%), and other mNNIs (detected in less than 30% of the water samples). Surface-water-sourced tap water had an approximately 8-10 times higher median cumulative concentration (ng/L) of the selected mNNIs (ΣmNNIs: 3.88) than the deep groundwater-sourced tap water (0.53) and groundwater that was directly used as drinking water (0.38). Higher ratios of THM-urea accounted for ΣTHM in north and northwest China than in south China could be partly explained by the decreasing soil pH values from north to south in China. The higher ratios of decyano-ACE accounted for ΣACE in south China than in north and northwest China could be attributable to the lower soil pH levels, higher temperatures, and greater light intensities in south China. The THM-urea, decyano-ACE, and ΣmNNIs levels in cities were found to be significantly higher than those in nonurban areas. The THM-urea levels in seven drinking water samples from Guangxi and Henan Provinces exceeded the guideline limit (100 ng/L) of the European Union. This is the first study to identify THM-urea, decyano-ACE, CLO-urea, and DN-THM in drinking water. To better assess the mass loadings of NNIs in drinking water, mNNIs should be considered in further studies.

Urinary metabolites of multiple volatile organic compounds among general population in Wuhan, central China: Inter-day reproducibility, seasonal difference, and their associations with oxidative stress biomarkers.

General population are concurrently and extensively exposed to many volatile organic compounds (VOCs), including some Group 1 human carcinogens, such as 1,3-butadiene. However, only a few studies assessed internal exposure levels of VOCs; particularly, very limited studies have examined associations between the urinary concentrations of multiple VOC metabolites (mVOCs) and oxidative stress biomarkers (OSBs) among the general population. In this study, 21 mVOCs and three OSBs including 8-hydroxy-2'-deoxyguanosine (8-OHdG; for DNA), 8-hydroxyguanosine (8-OHG; for RNA), and 4-hydroxy nonenal mercapturic acid (HNEMA; for lipid) were measured in 406 urine samples collected from 128 healthy adults during autumn and winter of 2018 in Wuhan, central China, including repeated samples taken in 3 d from 75 volunteers. Inter-day reproducibility for most mVOCs was good to excellent; urinary concentrations of mVOCs in winter were generally higher than those in autumn. Risk assessment was conducted by calculating hazard quotients for the parent compounds, and the results suggested that acrolein, 1,3-butadiene, and cyanide should be considered as high-priority hazardous ones for management. After false-discovery adjustment, 16 of the studied mVOCs were positively associated with 8-OHdG and 8-OHG (ß values ranged from 0.04 to 0.48), and four mVOCs were positively associated with HNEMA (ß values ranged from 0.21 to 0.78). Weighted quantile sum regression analyses were used to assess associations of mVOC mixture and OSBs, and we found significantly positive associations between the mixture index and OSBs, among which the strongest mVOC contributors for the associations were 2-methylhippuric acid for both DNA (20%) and RNA (17%) oxidative damage, and trans,trans-muconic acid (50%) for lipid peroxidation. This study firstly reported good to excellent short-term reproducibility, seasonal difference in autumn and winter, and possible health risk in urinary concentrations of multiple mVOCs among the general population.