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Abstract Background Benzotriazoles (BTRs) and benzothiazoles (BTHs) are emerging contaminants with high production volume worldwide, which exhibit potential health risk to human. To date, little is known about the exposure of BTRs and BTHs (BTs) on human, especially in the context of pregnancy. Objectives We aimed to characterize the exposure profiles, temporal variability, and potential predictors of urinary BTs during pregnancy. Methods Between 2014 and 2015, we recruited 856 pregnant women in Wuhan who provided urine samples at three trimesters (13.1 ± 1.1, 23.7 ± 3.2, and 35.7 ± 3.4 gestational weeks). We measured the urinary concentrations of five BTRs (1‑H‑benzotriazole, 1‑hydroxy‑benzotriazole, xylyltriazole, tolyltriazole, 5‑chloro‑1‑H‑benzotriazole) and five BTHs (benzothiazole, 2‑hydroxy‑benzothiazole, 2‑methylthio‑benzothiazole, 2‑amino‑benzothiazole, 2‑thiocyanomethylthio‑benzothiazole) to characterize the exposure profiles of BTs. We calculated the intra-class correlation coefficients (ICCs) to assess the temporal variability and investigated potential predictors of urinary BTs by using the mixed models. Results Most of the targeted BTs were detected in over 50% of urine samples, except for 5‑chloro‑1‑H‑benzotriazole (9.3%) and 2‑thiocyanomethylthio-benzothiazole (1.4%). The predominant BTRs in urine was 1‑hydroxy‑benzotriazole [Geometric Mean (GM): 0.77 ng/mL]. Benzothiazole was the major derivative in urine samples with a GM concentration of 1.6 ng/mL. Correlations among BTHs (r = 0.04–0.39) were higher than that among BTRs (r = 0.02–0.14). The exposure pattern was constant at low level and co-exposure to all the targeted compounds was infrequent during pregnancy. Urinary concentrations of BTRs exhibited considerable within-subject variation (ICCs: 0.12–0.56) during pregnancy. Relatively high temporal reliability was observed for urinary concentrations of BTHs with ICCs ranging from 0.42 to 0.85. It was found that parity, household income, pregnancy occupational status, sampling season and menstrual cycle were associated with urinary concentrations of BTs in pregnant women (P < 0.05). Conclusions To the best of our knowledge, this is the first study to report the exposure profiles, variability and predictors of urinary BTs among pregnant women. Exposure assessment using multiple samples is essential in reducing measurement errors and identifying susceptible window of exposure in etiological studies. The potential predictors of urinary BTs raised concerns on tracing exposure routes and eliminating confounding variables in future studies. Highlights • Gestational exposure to BTs was investigated in 2568 urine samples collected from 856 pregnant women at three trimesters. • The exposure pattern was constant at low level and co-exposure to all the targeted compounds was infrequent. • Urinary BTRs exhibited substantial variation, while urinary BTHs were relatively stable during pregnancy. • Urinary BTs were associated with parity, household income, occupational status, sampling season and menstrual cycle. [ABSTRACT FROM AUTHOR]

• First study on maternal urinary levels of BTRs and BTHs and newborn mtDNAcn. • Exposure to BTRs and BTHs during first and third trimester were associated with newborn mtDNAcn alternation. • Sex-specific associations were observed between BTRs and BTHs exposure and newborn mtDNAcn. Mitochondria are sensitive to environmental toxicants due to the limited repair capacity. Exposure to benzotriazoles (BTRs) and benzothiazoles (BTHs) may contribute to adverse health outcomes through oxidative stress, which may interfere with mitochondrial function. However, the mitochondrial effects of exposure to BTs (BTRs and BTHs) have not yet been elucidated, particularly in human investigations. We examined the associations between trimester-specific urinary BTRs and BTHs concentrations and cord blood mitochondrial DNA copy number (mtDNAcn) in a prospective birth cohort. The present study included 742 mother-infant pairs who participated in a birth cohort between 2014 and 2015 in Wuhan and had data on urinary concentrations of BTRs and BTHs and mtDNAcn in cord blood. Concentrations of BTs were repeatedly measured in maternal urine samples at different trimesters using high performance liquid chromatography-tandem mass spectrometry. Relative mtDNAcn in umbilical cord blood was analyzed by quantitative real-time polymerase chain reaction. Generalized estimating equations were used to evaluate the associations between BTs exposure across gestation and mtDNAcn in cord blood. In the present study, we observed a positive association between urinary 2-methylthio-benzothiazole (2-MeS-BTH) concentrations in the first trimester and cord blood mtDNAcn, with marginal significance [percent changes (%Δ) = 3.97, 95% confidence interval (CI): −0.05, 8.16, p = 0.05], while urinary 2-amino-benzothiazole concentrations in the third trimester were significantly negatively associated with cord blood mtDNAcn (%Δ = −5.89, 95% CI: −10.32, −1.24). Similar patterns of associations were demonstrated between urinary 1-H-benzotriazole (1-H-BTR) and xylyltriazole concentrations in the third trimester and cord blood mtDNAcn (%Δ = −4.18 to −3.23). In sex-specific analysis, we identified that maternal urinary 1-H-BTR in the first trimester and 2-MeS-BTH in the third trimester were positively associated with cord blood mtDNAcn among male infants but not female (P for interaction = 0.05 for 1-H-BTR, P for interaction = 0.05 for 2-MeS-BTH, respectively). We found evidence that prenatal exposure to BTRs and BTHs were associated with cord blood mtDNAcn alternation, and these associations were modified by infant gender. Further investigations are needed to corroborate these findings. [ABSTRACT FROM AUTHOR]

• The associations of urinary BTs with the blood glucose levels were investigated. • Urinary levels of 2-OH-BTH were positively associated with 2-hour blood glucose. • Higher urinary levels of 2-OH-BTH were associated with increased risk of GDM. Benzotriazoles (BTRs) and benzothiazoles (BTHs) are emerging contaminants with potential insulin modulation activities. Pregnancy exposure to BTs (BTRs and BTHs) may be a risk factor for the development of gestational diabetes mellitus (GDM). However, epidemiological studies are limited. We prospectively investigated the associations of exposure to BTs at early pregnancy with the blood glucose levels and the risks of GDM. A prospective cohort of 1770 pregnant women who were free of diabetes at baseline was established between 2013 and 2015 in Wuhan, China. Urine samples collected at 13.1 ± 1.1 weeks of gestation were analyzed to estimate the exposure level of BTs. The diagnosis of GDM was based on a 75 g oral glucose tolerance test (OGTT) conducted at 26.4 ± 2.4 weeks of gestation. We examined the associations between urinary concentration of BTs and blood glucose levels by linear regression models. The associations of urinary BTs concentrations with the relative risk (RR) of GDM were evaluated by generalized estimating equations with Poisson regression. Effect modifications by fetus sex and pre-pregnancy body mass index (BMI) were further evaluated in the sensitivity analysis. Results: A total of 147 (8.31%) pregnant women were diagnosed with GDM. Median concentrations of urinary BTs did not differ significantly between pregnant women with and without GDM. It was found that urinary levels of benzothiazole and 2-hydroxy-benzothiazole (2-OH-BTH) were positively associated with 2-hour blood glucose (p for trend < 0.050). Comparing the high exposure group with the low exposure group of 2-OH-BTH, the adjusted RR of GDM was 1.79 (95% CI = 1.18 to 2.69, p for trend = 0.012). Sensitivity analysis indicated that the positive association of the urinary 2-OH-BTH level with the RR of GDM remained significant among pregnant women who had a male fetus (RR = 1.76, 95% CI = 1.02 to 3.03, p for trend = 0.041) and those with a normal pre-pregnancy BMI (RR = 1.85, 95% CI = 1.09 to 3.11, p for trend = 0.034). These findings suggested that higher urinary level of 2-OH-BTH in early pregnancy was associated with impaired glucose homeostasis and the increased risk of GDM. The results underscore the need of follow-up studies to validate the findings and elucidate the underlying biological mechanism. [ABSTRACT FROM AUTHOR]

Benzotriazole (BTR) and benzothiazole (BTH) derivatives are extensively applied in industrial processes and consumer products, and are thus frequently detected in the environmental matrices. Due to their potential estrogenic effects reported in animal studies, the assessment of human exposure to BTRs and BTHs is important. In this study, a method was developed and validated to determine six BTRs and five BTHs in human urine by using ultra-high performance liquid chromatography coupled with a triple quadrupole mass spectrometry (UHPLC-TQMS) in positive electrospray ionization mode. After de-conjugation by β -glucuronidase, urine samples were liquid-liquid extracted for the measurement of total concentrations of BTRs and BTHs. The linearity, detection limit, precision, recovery, accuracy and matrix effect were evaluated. The limits of detection were less than 0.5 ng/mL. The validated method demonstrated good precision (RSD% < 15%), linearity (R 2 > 0.99), recovery (>80%) and accuracy (80–100%). The method was successfully applied for the analysis of 22 human urine samples. Four out of eleven targeted compounds were detected in more than half of participants at ng/mL levels. [ABSTRACT FROM AUTHOR]