Profiles, variability and predictors of concentrations of blood trihalomethanes and urinary haloacetic acids along pregnancy among 1760 Chinese women.

Blood trihalomethanes (THMs) and urinary haloacetic acids (HAAs) are the leading candidate biomarkers for disinfection byproduct (DBP) exposure. However, no studies have assessed the exposure profiles, temporal variability, and potential predictors of these biomarkers during pregnancy. Here we collected blood (n = 4304) and urine samples (n = 4165) from 1760 Chinese pregnant women during early, mid-, and late pregnancy, which were separately analyzed for 4 THMs and 2 HAAs. We calculated the intraclass correlation coefficients (ICCs) to assess the variability of these biomarkers and estimated their correlations with sociodemographic, water-use behavioral, dietary and sample collection factors using mixed models. The median concentrations of TCM, BDCM, Br-THMs [sum of BDCM, dibromochloromethane (DBCM), bromoform (TBM)], total THMs (TTHMs, sum of TCM and Br-THMs), DCAA and TCAA in the water distribution system were 4.2 µg/L, 1.7 µg/L, 2.9 µg/L, 7.1 µg/L, 3.4 µg/L and 8.2 µg/L, respectively. Chloroform (TCM), bromodichloromethane (BDCM), dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were detected in > 75% of the biospecimens. Repeated measurements of blood TCM, BDCM, Br-THMs and TTHMs and urinary DCAA and TCAA uniformly exhibited high variability (ICCs = 0.01-0.13); the use of a single measurement to classify gestational average exposure resulted in a high degree of exposure misclassification. The sampling season was a strong predictor of all analyzed DBPs. Additionally, we detected a positive association of blood TCM and BDCM with household income, urinary DCAA with age, and urinary TCAA with tap water usage, education level and amount of tap water consumed. Inverse associations were found between blood BDCM and vegetable consumption, and between blood Br-THM and TTHM and time interval since the last bathing/showering. Afternoon samples had lower DCAA concentrations than did early morning samples. Our results indicate that blood THM and urinary HAA concentrations vary greatly over the course of pregnancy and are affected by sampling season, time of day of blood/urine collection, sociodemographic factors, recent water-use activities and dietary intake.

Variability and exposure classification of urinary levels of non-essential metals aluminum, antimony, barium, thallium, tungsten and uranium in healthy adult men.

Arsenic, cadmium and lead are well-known toxic metals, and there are substantial studies on variability of these metals in urine to optimize design of exposure assessment. For urinary levels of other nonessential metals such as aluminum (Al), antimony (Sb), barium (Ba), thallium (Tl), tungsten (W) and uranium (U), however, their within-individual and between-individual variability are unclear. Therefore, we collected 529 samples from 11 healthy adult men on 8 days during a 3-month period. We measured urinary metals and creatinine (Cr) levels, assessed the reproducibility using intraclass correlation coefficients (ICCs), and performed sensitivity and specificity analyses to assess how well 1, 2 or 3 specimens could classify exposure. Al, Sb, Ba, W and U levels measured from spot samples varied greatly over days and months (Cr-adjusted ICCs = 0.01-0.14). Serial measures of Tl levels measured from spot samples had fair-to-good reproducibility over 5 consecutive days (Cr-adjusted ICC = 0.40), but worsened when the specimens were collected months apart (Cr-adjusted ICC = 0.16). To identify men who were highly exposed (top 33%) based on their 3-month averages, tests of single spot samples and tests of first-morning voids had high specificities (0.73-0.85) but relatively low sensitivities (0.27-0.60). Collection of repeated urine specimens from each individual improved the classification.

First-trimester blood concentrations of drinking water trihalomethanes and neonatal neurobehavioral development in a Chinese birth cohort.

Toxicological evidence indicates that exposure to drinking water trihalomethanes (THMs) can impair neural development. However, no epidemiologic study to date has evaluated the relation of trihalomethanes exposure with neonatal neurobehavioral development. Here we aimed to evaluate if prenatal exposure to THMs during early pregnancy is associated with neonatal neurobehavioral development in 451 Chinese mother-child pairs. First trimester blood THMs [chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM)] were determined by solid phase micro-extraction gas chramatography. Neonatal neurobehavioral development was assessed using neonatal behavioral neurological assessment (NBNA) on the third day after birth. Multivariable linear regression models and restricted cubic spline models were constructed to evaluate the associations between blood THMs and neonatal neurological development scores. Blood concentrations of BDCM, whether modeled as continuous or categorical variables, were inversely associated with total NBNA score of newborns based on the multivariable linear regression. The association was further confirmed in the cubic spline model, and a linear dose-response relationship was observed. Stratified analysis showed that the inverse association between blood BDCM and total NBNA score was more evident in male infants than females. Our findings suggest that exposure to THMs during early pregnancy may be associated with impaired neonatal neurobehavioral development.

Prenatal phthalate exposure, birth outcomes and DNA methylation of Alu and LINE-1 repetitive elements: A pilot study in China.

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.

Prenatal urinary polycyclic aromatic hydrocarbon metabolites, global DNA methylation in cord blood, and birth outcomes: A cohort study in China.

BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is a potential risk factor for adverse birth outcomes. Epigenetic mechanisms may play a key role in which PAHs exert its effects. OBJECTIVE: Our study aimed to examine whether prenatal PAH exposure was associated with adverse birth outcomes and altered DNA methylation and to explore potential mediating roles of DNA methylation. METHODS: Ten urinary PAH metabolites were measured from 106 pregnant women during late pregnancy in a Chinese cohort study. Cord blood DNA methylation in long interspersed nucleotide element-1 (LINE-1) and Alu repetitive elements as surrogates of global DNA methylation was analyzed by bisulfite pyrosequencing. Multivariable linear regression was used to estimate the associations of urinary PAH metabolites with birth outcomes and DNA methylation, and a mediation analysis was also conducted. RESULTS: Prenatal urinary 2-hydroxynaphthalene (2-OHNa), ∑OHNa (sum of 1- and 2-OHNa), and sum of monohydroxy-PAH (∑OH-PAHs) were associated with lower birth length (e.g., -0.80%, 95% CI: -1.39%, -0.20% for the third vs. first tertile of 2-OHNa; p for trend = 0.01). Prenatal urinary 2-OHNa and 1-hydroxyphenanthrene (1-OHPh) were associated with lower Alu and LINE-1 methylation (e.g., -1.88%, 95% CI: -3.73%, -0.10% for the third vs. first tertile tertile of 2-OHNa in Alu methylation; p for trend = 0.04). Mediation analysis failed to show a mediator effect of global DNA methylation in the association between prenatal urinary OH-PAHs and birth outcomes. CONCLUSIONS: Prenatal specific PAH exposures are associated with decreased birth length and global DNA methylation. However, global DNA methylation does not mediate the associations of prenatal PAH exposure with birth outcomes. Further studies are needed to confirm the results.

Predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men.

BACKGROUND: Certain phthalates are suspected to be endocrine disruptors that are adversely associated with male reproductive health. However, the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men have not been thoroughly studied. OBJECTIVE: To investigate the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among adult Chinese males. METHOD: We measured mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-octyl phthalate (MOP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) concentrations in seminal plasma and repeated spot-urine samples from 687 men who visited a reproductive center. Mixed-effect models were used to examine the associations of sociodemographic, lifestyle and medical factors with urinary metabolite concentrations. Linear regression models were used to identify predictors of metabolite concentrations in seminal plasma and correlations between metabolite concentrations in spot urine samples and seminal plasma. RESULTS: Measurements taken from spot urine samples poorly predicted same-day seminal plasma concentrations (all R2<0.10). Inverse associations were observed between education level and urinary MBP and MEOHP and between household income and urinary MMP; receiving intravenous infusion therapy was associated with increased urinary MBP, MEHHP and MEOHP, use of facial cleanser/cream was associated with increased MEP, and smoking was associated with increased MEHP. The predictors of metabolite concentrations in seminal plasma differed from those in urine, except for the association of intravenous infusion therapy with MBP. BMI was associated with increased seminal plasma MBP, MEHP and MEOHP, smoking was associated with increased MEP, and contact with plastics was associated with increased MEOHP. CONCLUSIONS: Phthalate metabolite concentrations in adult men varied in accordance with sociodemographic variables, lifestyle factors and intravenous therapy. Measures of metabolite levels in urine may not directly reflect the exposure status of the male reproductive system.

Repeated measures of urinary polycyclic aromatic hydrocarbon metabolites in relation to altered reproductive hormones: A cross-sectional study in China.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are a group of ubiquitous environmental pollutants. In vivo and in vitro studies have demonstrated that PAHs can alter endocrine function, yet evidence from human studies is limited. OBJECTIVES: The objective of this study was to investigate whether environmental exposure to PAHs was associated with altered reproductive hormone levels, using repeated measures of urinary OH-PAHs as biomarkers. METHODS: We measured 10 monohydroxylated PAHs (OH-PAHs) in repeated urine samples from 371 men in an infertility clinic in Wuhan, China. Multivariable linear regression models were used to estimate the associations between average urinary OH-PAH levels and serum reproductive hormones, and restricted cubic spline models were further used to examine the shapes of dose-response relationships. RESULTS: We observed dose-response associations of urinary 2-hydroxynaphthalene (2-OHNa) with decreased serum free testosterone (fT) and urinary 1-hydroxypyrene (1-OHP), 9-hydroxyphenanthrene (9-OHPh), and 9-hydroxyfluorene (9-OHFlu) with decreased serum estradiol (all P for trends <0.05). These associations were linear and significant when these four OH-PAHs were modeled as continuous variables in restricted cubic spline models. Furthermore, a U-shaped association was observed across urinary 4-OHPh levels, with lower levels of serum sex hormone-binding globulin (SHBG) at median concentrations compared with 5th and 95th percentile concentrations. CONCLUSION: Environmental levels of PAH exposure in our study are associated with altered reproductive hormones. However, further research is needed to confirm our findings.