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.

Environmental polycyclic aromatic hydrocarbon exposure in relation to metabolic syndrome in US adults.

The present study examined the associations of polycyclic aromatic hydrocarbon (PAH) exposure with metabolic syndrome (MetS) and its components. Data were from 5181 US adults recruited in the National Health and Nutrition Examine Survey 2001-2012. Environmental PAH exposure was estimated as concentrations of urinary PAH metabolites. Weighted quantile sum (WQS) regression and modified Poisson regression were separately conducted to estimate the associations of mixed and single PAH metabolites with MetS and its components. WQS regression analyses showed that participants with higher mixed PAH exposure had increased prevalence of MetS (prevalence ratio, 1.12; 95 % confidence interval, 1.06, 1.19), elevated waist circumference (1.07; 1.02, 1.12), elevated fasting blood glucose (1.07; 1.00, 1.14), elevated triglycerides (1.19; 1.09, 1.30), and reduced high-density lipoprotein cholesterol (1.11; 1.03, 1.20). In the models for single PAH metabolites, higher levels of 1-hydroxynaphthalene (1.15; 1.00, 1.32), 2-hydroxynaphthalene (1.20; 1.05, 1.38), 1-hydroxyphenanthrene (1.18; 1.04, 1.34), 2-hydroxyphenanthrene (1.38; 1.22, 1.57), and 1-pyrene (1.19; 1.05, 1.34) were respectively associated with increased prevalence of MetS (highest tertile vs lowest tertile). In addition, linear trends were noted for the associations of these PAH metabolites with MetS (all P for linear association ≤0.047). Smokers, drinkers, and participants with poor diet quality showed stronger associations between certain PAH metabolite with MetS. The findings suggest that the prevalence of MetS and its components increases when PAH exposure is at a high level, and that lifestyle factors, such as cigarette smoking, alcohol consumption, and diet quality, could modify the positive associations of certain PAH exposure with MetS.

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.

Associations of benzotriazoles and benzothiazoles with estrogens and androgens among pregnant women: A cohort study with repeated measurements.

People are extensively exposed to benzotriazoles (BTRs) and benzothiazoles (BTHs) derivatives, which are environmental pollutants that may possess endocrine-disrupting potential; however, no epidemiological evidence is available on the associations of BTRs and BTHs with estrogens and androgens. This study aimed at investigating the associations of BTRs and BTHs with estrogens and androgens among pregnant women. Based on a prospective cohort study, we included 459 pregnant women who donated a complete serial of urine samples at each trimester and had repeated measurements of four BTRs, four BTHs, three estrogens (estrone, 17ß-estradiol, and estrio), and two androgens (dehydroepiandrosterone and testosterone) in the urine samples. Associations of repeatedly measured BTRs and BTHs with maternal urinary estrogens and androgens were analyzed, and the cross-sectional associations were also analyzed. Tolyltriazole (TTR) (≥59.3%) and benzothiazole (BTH) (≥93.5%) had the highest detection rate among the BTRs and BTHs, respectively. Repeated measurement analysis and cross-sectional analysis consistently found the target BTRs and BTHs were positively associated with 17ß-estradiol, estriol, and testosterone, while the trend of the associations with estrone and dehydroepiandrosterone was inconsistent. Among the positive associations with 17ß-estradiol, estriol, and testosterone, the percent of change in estriol associated with TTR was the most prominent [28.5% (95% confidential interval: 24.2%, 32.9%) for each doubling in TTR]. The significant associations with estrone, estriol, testosterone, and dehydroepiandrosterone were stronger among pregnant women who gave birth to a boy than those who gave birth to a girl. These findings add epidemiological evidence on the endocrine-disrupting potential of BTRs and BTHs and highlight the importance of focusing on the health outcomes of BTRs and BTHs related to disturbed estrogens and androgens. Future studies are needed to validate these findings and explore the underlying mechanisms.

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.

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.

Preconceptional and the first trimester exposure to PM2.5 and offspring neurodevelopment at 24 months of age: Examining mediation by maternal thyroid hormones in a birth cohort study.

Prenatal fine particulate matter (PM2.5) exposure has been associated with impaired offspring neurodevelopment; however, the association of PM2.5 exposure during preconception with offspring's neurodevelopment and factors responsible for this association are still unclear. This study estimated the associations of PM2.5 exposure during preconception and the first trimester with offspring neurodevelopment and evaluated whether maternal thyroid hormones mediate these associations. We recruited 1329 mother-child pairs between 2013 and 2015 in Wuhan, China. PM2.5 exposure levels of each woman during the 3 months preconception and the first trimester were estimated using land-use regression models. Offspring neurodevelopment characterized by mental developmental index (MDI) and psychomotor developmental index (PDI) were measured at 24 months of age. Maternal serum levels of free thyroxine (FT3), free triiodothyronine (FT4), and thyroid-stimulating hormone (TSH) during early pregnancy were measured of a subset of the 1329 women (551 women). Generalized estimation equation and general linear regression models were used to estimate the associations between maternal PM2.5 exposure, thyroid hormones, and offspring neurodevelopment. After adjusting for potential confounders, we found that either among all participants or the subset, PM2.5 exposure during preconception and the first trimester was negatively associated with offspring PDI. Double increment in the first trimester PM2.5 exposure was significantly associated with 3.43 and 6.48 points decrease in offspring MDI. In the subset, each doubling of PM2.5 exposure during preconception and the first trimester was significantly associated with 7.93 and 8.02 points decrease in maternal FT4 level, respectively. Increased maternal FT4, in turn, was associated with increased PDI (ß = 16.69, 95% CI: 5.39, 27.99). About 7.7% (95% CI: 2.0%-19.4%) and 8.6% (95% CI: 3.0%, 22.1%) of the effect of PM2.5 exposure during preconception on offspring PDI was mediated through maternal FT4 and the FT4/FT3 ratio, respectively.

A nationwide study of occurrence and exposure assessment of neonicotinoid insecticides and their metabolites in drinking water of China.

Neonicotinoid insecticides (NNIs) are the most extensively used insecticides worldwide, threatening ecosystem and human health. However, nationwide studies of NNIs and their metabolites in drinking water are limited. In order to characterize the contamination status of NNIs in drinking water throughout China, we collected 884 drinking water samples including 789 tap water and 95 groundwater samples from 32 provinces (covering seven regions of mainland China: south, central, east, north, northeast, northwest, and southwest) and Hong Kong. Ten NNIs and six of their main metabolites were determined in the water samples. The relative potency factor method was used to assess the cumulative concentrations of NNIs and their metabolites (imidacloprid-equivalent total NNIs, IMIeq) based on the chronic reference doses (cRfDs) of the NNIs or the toxic effects of the mataboilites. The IMIeq varied among the studied regions, with a median concentration of 24.5 ng/L and a maximum concentration of 8,622 ng/L. The predominant NNIs in drinking water were acetamiprid (ACE) and imidacloprid (IMI). Compared with tap water derived from groundwater, much higher concentrations of IMIeq and NNIs were found in tap water derived from surface water. Different concentrations and patterns of NNIs in drinking water were observed in different regions, provinces, and capital cities, mainly due to regional and provincial differences in crop types and volumes of pesticide usage. The concentrations of NNIs in the drinking water of provincial capitals and small/medium cities were higher than the concentrations in rural areas. The estimated daily intake (EDI) of IMIeq was at least two orders of magnitude lower than the cRfD of IMI, while the NNIs in 16 drinking water samples exceeded the acceptable value (100 ng/L) recommended by the European Union. This study provided a nationwide profile of the occurrence of NNIs and their metabolites in the drinking water of China and the associated potential cumulative human health risks, taking into account of the toxicity differences between NNIs and their metabolites.

Assessment of imidacloprid related exposure using imidacloprid-olefin and desnitro-imidacloprid: Neonicotinoid insecticides in human urine in Wuhan, China.

While neonicotinoid insecticides (NNIs) have been widely used worldwide, limited studies have measured specific metabolites of imidacloprid (IMI, the most commonly used NNI) in human urine. To better understand human exposure to NNIs, 10 parent compounds, and 6 of their metabolites were analyzed in 408 urine samples collected from 129 healthy adults in Wuhan, Central China, during autumn and winter of 2018. These specimens included repeated urine samples taken in 3 d from 75 volunteers. The urinary concentrations of desnitro-imidacloprid (DN-IMI), imidacloprid-olefin (IMI-olefin), and desmethyl-acetamiprid (DM-ACE) were higher (4-40 times) than those of their parent compounds (IMI and acetamiprid, ACE). DN-IMI and IMI-olefin accounted for 92% of the urinary Σ3IMI (the sum of IMI and its specific metabolites measured). Positive correlations (r) were observed between DN-IMI and IMI (0.50), IMI-olefin and IMI (0.75), and DM-ACE and ACE (0.53). Good to excellent inter-day reliabilities (unadjusted intraclass correlation coefficients) were observed for IMI-olefin (0.61) and DM-ACE (0.81), while moderate inter-day reliability was observed for DN-IMI (0.43). The urinary NNI concentrations were significantly higher in autumn than in winter, and higher in urban areas than in rural areas, while no significant gender or age-related differences were observed. To our knowledge, this is the first report on DN-IMI and IMI-olefin in human urine.

A nationwide study of the occurrence and distribution of atrazine and its degradates in tap water and groundwater in China: Assessment of human exposure potential.

Despite frequent detection of atrazine (ATZ) and its degradates (including hydroxyatrazine, ATZ-OH; deethylatrazine, DEA; deisopropylatrazine, DIA; and deethyldeisopropylatrazine, DACT) in a variety of water bodies, documentation of their occurrence and distribution in tap water in China is still scarce. A nationwide survey about ATZ and its degradates (ATZs) in tap water from 31 provinces in 7 regions of mainland China and Hong Kong was conducted during June 2019. At least one of the analytes was found in all the water samples (n = 884). The median sum concentrations of ATZs (ΣATZs) was 21.0 ng/L (range: 0.02 ng/L-3.04 µg/L). The predominant compounds of ATZs in tap water were ATZ and DEA, with a detection frequency of 99.5% and 98.0%, respectively, followed by ATZ-OH (87.3%), DACT (84.0%), and DIA (78.1%). Significant regional variations (p < 0.05) were found in the concentrations of ATZs in tap water, and the highest concentration of ΣATZs (median: 254 ng/L, range: 0.44 ng/L-3.04 µg/L) was found in Northeastern China, followed by Eastern (37.2 ng/L, 0.02-706 ng/L), Northern (30.2 ng/L, 0.04-317 ng/L), Central (29.3 ng/L, 0.04-256 ng/L), Southern (25.0 ng/L, 0.04-297 ng/L), Southwestern (17.2 ng/L, 0.02-388 ng/L), and Northwestern China (3.22 ng/L, 0.06-214 ng/L). The level of ΣATZs in groundwater from rural area of China was about 1/3 of that found in tap water. ATZs cannot be removed by boiling tap water. The highest estimated daily intake of ΣATZs (248 ng/kg-body weight/day) was found in the infant population of Changchun, Jilin, Northeastern China.