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Disinfection byproducts (DBPs) are a class of ubiquitous chemicals in drinking water and inevitably result in widespread human exposures. Potentially adverse health effects of DBP exposures, including reproductive and developmental outcomes, have been increasing public concerns. Several reviews have focused on the adverse pregnancy outcomes of DBPs. This review summarized current evidence on male reproduction health upon exposure to DBPs from toxicological and epidemiological literature. Based on existing experimental studies, there are sufficient evidence showing that haloacetic acids (HAAs) are male reproductive toxicants, including reduced epididymal weight, decreased semen parameters and sperm protein 22, and declined testosterone levels. However, epidemiological evidence remains insufficient to support a link of DBP exposures with adverse male reproductive outcomes, despite that blood and urinary DBP biomarkers are associated with decreased semen quality. Eight potential mechanisms, including germ/somatic cell dysfunction, oxidative stress, genotoxicity, inflammation, endocrine hormones, folate metabolism, epigenetic alterations, and gut microbiota, are likely involved in male reproductive toxicity of DBPs. We also identified knowledge gaps in toxicological and epidemiological studies to enhance future needs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Maternal exposure to regulated disinfection by-products (DBPs) during pregnancy has been linked with adverse birth outcomes. However, no human studies have focused on drinking water nitrosamines, a group of emerging unregulated nitrogenous DBPs that exhibits genotoxicity and developmental toxicity in experimental studies. This cohort study included 2457 mother-infant pairs from a single drinking water supply system in central China, and maternal trimester-specific and entire pregnancy exposure of drinking water nitrosamines were evaluated. Multivariable linear and Poisson regression models were used to estimate the associations between maternal exposure to nitrosamines in drinking water and birth outcomes [birth weight (BW), low birth weight (LBW), small for gestational age (SGA) and preterm delivery (PTD)]. Elevated maternal N-nitrosodimethylamine (NDMA) exposure in the second trimester and N-nitrosopiperidine (NPIP) exposure during the entire pregnancy were associated with decreased BW (e.g., β = -88.6 g; 95% CI: -151.0, -26.1 for the highest vs. lowest tertile of NDMA; p for trend = 0.01) and increased risks of PTD [e.g., risk ratio (RR) = 2.16; 95% CI: 1.23, 3.79 for the highest vs. lowest tertile of NDMA; p for trend = 0.002]. Elevated maternal exposure of N-nitrosodiethylamine (NDEA) in the second trimester was associated with increased risk of SGA (RR = 1.80; 95% CI: 1.09, 2.98 for the highest vs. lowest tertile; p for trend = 0.01). Our study detected associations of maternal exposure to drinking water nitrosamines during pregnancy with decreased BW and increased risks of SGA and PTD. These findings are novel but require replication in other study populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Organochlorine pesticides (OCPs) are endocrine-disrupting chemicals and may alter male reproductive hormone concentrations., Objective: To explore the associations between multiple OCP exposures and serum testosterone concentrations among Chinese men., Methods: We investigated 421 men who provided serum samples from an infertility clinic in Wuhan, China. Each man completed a questionnaire concerning demographic characteristics and lifestyle habits. Serum concentrations of 18 OCPs and total testosterone were measured. Linear regression models were used to explore whether serum OCP levels were associated with altered testosterone concentrations, and potential effect modifications by age and body mass index (BMI) were also examined., Results: After adjusting for potential confounders, elevated dieldrin and p,p'-DDD levels had monotonically negative and positive exposure-response associations with testosterone concentrations, respectively (-30.98 ng/dL, 95% CI: -72.34, 10.37; P for trend = 0.12 and 41.31 ng/dL, 95% CI: -0.32, 82.93; P for trend = 0.06 for the highest vs. non-detectable exposure category, respectively). After stratification by age and BMI, dieldrin in relation to decreased testosterone concentrations was more pronounced among men aged <30 years old, and p,p'-DDD in relation to increased testosterone concentrations was stronger among men aged ≥30 years old and among men with a BMI <24 kg/m 2 , though the differences were not statistically significant., Conclusion: The study found evidence that serum dieldrin and p,p'-DDD concentrations might be associated with altered serum testosterone concentrations., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Prenatal exposure to metals has been linked with adverse pregnancy outcomes. Oxidative stress and epigenetic changes are potential mechanisms of action., Objectives: We aimed to examine the associations of individual and mixtures of metal exposures with oxidative stress and DNA methylation among pregnant women., Methods: We measured a panel of 16 metals and 3 oxidative stress biomarkers including 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) and 8-isoprostaglandin F2α (8-isoPGF2α) in urine from 113 pregnant women in a Chinese cohort. Biomarkers of global DNA methylation including Alu and long interspersed nucleotide element-1 (LINE-1) in cord blood were measured. Multivariable linear regression and Bayesian kernel machine regression (BKMR) models were separately applied to estimate the associations between individual and mixtures of metal exposures and biomarkers of oxidative stress and global DNA methylation., Results: In single-metal analyses, we observed positive associations between 11 metals [arsenic (As), cadmium (Cd), thallium (Tl), barium (Ba), nickel (Ni), vanadium (V), cobalt (Co), zinc (Zn), copper (Cu), selenium (Se) and molybdenum (Mo)] and at least one of oxidative stress biomarkers (all FDR-adjusted P-values < 0.05). In mixture analyses, we found positive overall associations of metal mixtures with 8-OHdG and 8-isoPGF2α, and Se was the most important predictor. There was no evidence on associations of urinary metals as individual chemicals and mixtures with Alu and LINE-1 methylation., Conclusion: Urinary metals as individual chemicals and mixtures were associated with increased oxidative stress, especially Se., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Studies indicate that phthalates can disrupt spermatogenesis and lead to the reduction of semen quality. However, the underlying mechanisms remain unclear. This study aimed to examine the associations of phthalate exposures as individual chemicals and mixtures with spermatogenesis-related miRNA106a. We detected eight phthalate metabolites in repeated urine samples and a single seminal plasma specimen among 111 men from an infertility clinic in Wuhan, China. Spermatogenesis-related miRNA106a was measured in seminal plasma. We used multivariable linear regression and Bayesian kernel machine regression (BKMR) models to separately evaluate the associations of phthalate metabolites as individual chemicals and mixtures with spermatogenesis-related miRNA106a. Elevated tertiles of urinary mono (2-ethylhexyl) phthalate (MEHP) was associated with decreased miRNA106a (-61.71%; 95%CI: 81.92, -18.93% for the highest vs. lowest tertile; P for trend = 0.01). Similarly, an inverse exposure-response relationship between seminal plasma MEHP concentrations and miRNA106a was also observed (-59.44%; 95%CI: 79.19, -20.95% for the highest vs. lowest tertile; P for trend = 0.01). The BKMR models showed that the mixtures of seminal plasma phthalate metabolites were associated with decreased miRNA106a when the chemical mixtures were ≥35th percentile compared to their medians. Nonlinear associations with miRNA106a were estimated for urinary and seminal plasma MEHP while fixing other phthalate metabolites at their medians. Our findings suggest that mixtures of phthalate metabolites in seminal plasma were negatively associated with spermatogenesis-related miRNA106a, and individual MEHP was the major contributor to the adverse effects., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Exposure to air pollution has been linked with altered immune function in adults, but little is known about its effects on early life. This study aimed to investigate the effects of exposure to air pollution during prenatal and postnatal windows on cell-mediated immune function in preschoolers., Methods: Pre-school aged children (2.9 ± 0.5 y old, n = 391) were recruited from a mother-child cohort study in Wuhan, China. We used a spatial-temporal land use regression (LUR) model to estimate exposures of particulate matter with aerodynamic diameters ≤2.5 μm (PM 2.5 ) and ≤10 μm (PM 10 ), and nitrogen dioxide (NO 2 ) during the specific trimesters of pregnancy and the first two postnatal years. We measured peripheral blood T lymphocyte subsets and plasma cytokines as indicators of cellular immune function. We used multiple informant models to examine the associations of prenatal and postnatal exposures to air pollution with cell-mediated immune function., Results: Prenatal exposures to PM 2.5 , PM 10 , and NO 2 during early pregnancy were negatively associated with %CD3 + and %CD3 + CD8 + cells, and during late pregnancy were positively associated with %CD3 + cells. Postnatal exposures to these air pollutants during 1-y or 2-y childhood were positively associated with IL-4, IL-5, IL-6, and TNF-α. We also observed that the associations of prenatal or postnatal air pollution exposures with cellular immune responses varied by child's sex., Conclusions: Our results suggest that exposure to air pollution during different critical windows of early life may differentially alter cellular immune responses, and these effects appear to be sex-specific., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Toxicological and epidemiologic evidence has suggested that exposure to disinfection by-products (DBPs) impairs semen quality, while the underlying biological mechanisms remain unclear. This study aimed to examine the mediating role of oxidative stress in association between DBP exposure and semen quality. We measured a urinary biomarker of DBP exposure [trichloroacetic acid (TCAA)] and three urinary biomarkers of oxidative stress [8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2 α (8-isoPGF2 α ) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] among men from an infertility clinic (n = 299). The associations of oxidative stress biomarkers with urinary TCAA and semen quality were evaluated using multivariable linear regression models, and the mediating role of oxidative stress biomarkers was assessed by a mediation analysis. Urinary TCAA was positively associated with urinary 8-OHdG and 8-isoPGF2 α in a dose-response manner (both P for trend < 0.001). Significantly inverse dose-response associations were observed between urinary 8-isoPGF2 α and sperm concentration and between urinary 8-OHdG and sperm motility (both P for trend < 0.05). The mediation analysis indicated a significant indirect effect of urinary 8-isoPGF2 α in the association between urinary TCAA and decreased sperm concentration (P = 0.01). Our results suggest that lipid peroxidation may be an intermediate mechanism by which DBP exposure impairs semen quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Bisphenol A (BPA) has been shown to affect normal fetal growth, but human evidence on its analogues (BPF and BPS) is limited., Object: To examine the associations between prenatal exposure to BPA and its analogues (BPF and BPS) and ultrasound parameters of fetal growth., Methods: We measured urinary BPA, BPF, and BPS concentrations among 322 pregnant women during late pregnancy from a cohort study in Wuhan, China. Fetal biparietal diameter (BPD), head circumference (HC), femur length (FL), and abdominal circumference (AC) were measured by ultrasonography. The associations of maternal urinary BPA, BPF, and BPS concentrations with ultrasound parameters of fetal growth were estimated by multivariable adjusted models., Results: We observed a gender difference in association of maternal urinary BPA concentrations and fetal HC (P for interaction = 0.003); each ln-unit increase in maternal urinary BPA concentration was associated with a mean decrease of 0.10 cm (95%CI: 0.18, -0.02) among boys and a mean increase of 0.14 cm (95%CI: 0.00, 0.28) among girls for HC. The associations were robust for urinary BPA concentrations modeled as tertiles or including urinary BPA, BPF, and BPS into mutual adjustment models. We did not observe robust associations between maternal urinary BPF and BPS concentrations and ultrasound parameters of fetal growth, though an inverse association with AC and a positive association with FL were estimated for maternal urinary BPF concentrations modeled as continuous variables., Conclusions: Prenatal exposure to BPA but not BPF and BPS was sex-specifically associated with certain fetal growth parameters., Competing Interests: Declaration of competing interest None., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Epigenetic mechanisms, such as altered DNA methylation, may participate in the relationship between prenatal phthalate exposure and adverse birth outcomes., Objective: To explore the mediation effect of DNA methylation in the associations of phthalate exposure before delivery with birth outcomes in a Chinese cohort., Methods: Eight phthalate metabolites in maternal urine before delivery and DNA methylation of Alu and long interspersed nucleotide elements (LINE-1) in cord blood were determined among 106 mother-infant pairs. General additive models were used to assess the associations of maternal urinary phthalate metabolites with birth outcomes and DNA methylation; the mediating role of DNA methylation in cord blood was evaluated by mediation analysis., Results: We found sex-specific associations between prenatal phthalate exposure and birth outcomes and DNA methylation of cord blood. For example, the molar sum of di-2-(ethylhexyl) phthalate (∑DEHPm) metabolites in maternal urine was positively associated with gestational age among male newborns only (P < 0.05); maternal urinary monobenzyl phthalate (MBzP) was negatively associated with Alu methylation among female newborns only (P < 0.05). Mediation analysis did not find that methylation of Alu and LINE-1 to be a direct mediator in the relationships between maternal urinary phthalate metabolites before delivery and birth outcomes., Conclusion: Prenatal exposure to certain phthalates was associated with altered birth outcomes and decreased repetitive element methylation of newborns. However, the altered birth outcomes exerted by prenatal phthalate exposure does not seem to be directly mediated through repetitive element methylation in cord blood., (Copyright © 2018 Elsevier Ltd. All rights reserved.)