Exposure to tobacco smoke during pregnancy has been associated with a series of adverse reproductive outcomes; however, the underlying molecular mechanisms are not well-established. We conducted an untargeted metabolome-wide association study to identify the metabolic perturbations and molecular mechanisms underlying the association between cotinine, a widely used biomarker of tobacco exposure, and adverse birth outcomes. We collected early and late pregnancy urine samples for cotinine measurement and serum samples for high-resolution metabolomics (HRM) profiling from 105 pregnant women from the Atlanta African American Maternal-Child cohort (2014–2016). Maternal metabolome perturbations mediating prenatal tobacco smoke exposure and adverse birth outcomes were assessed by an untargeted HRM workflow using generalized linear models, followed by pathway enrichment analysis and chemical annotation, with a meet-in-the-middle approach. The median maternal urinary cotinine concentrations were 5.93 μg/g creatinine and 3.69 μg/g creatinine in early and late pregnancy, respectively. In total, 16,481 and 13,043 metabolic features were identified in serum samples at each visit from positive and negative electrospray ionization modes, respectively. Twelve metabolic pathways were found to be associated with both cotinine concentrations and adverse birth outcomes during early and late pregnancy, including tryptophan, histidine, urea cycle, arginine, and proline metabolism. We confirmed 47 metabolites associated with cotinine levels, preterm birth, and shorter gestational age, including glutamate, serine, choline, and taurine, which are closely involved in endogenous inflammation, vascular reactivity, and lipid peroxidation processes. The metabolic perturbations associated with cotinine levels were related to inflammation, oxidative stress, placental vascularization, and insulin action, which could contribute to shorter gestations. The findings will support the further understanding of potential internal responses in association with tobacco smoke exposures, especially among African American women who are disproportionately exposed to high tobacco smoke and experience higher rates of adverse birth outcomes.

Toxicological and epidemiological studies implicate exposure to dithiocarbamate (DTC) fungicides in adverse health outcomes. However, there is limited information about human exposure to these chemicals. This systematic review determined to which extent human populations worldwide, including children, pregnant women, and adults, are exposed environmentally or occupationally to DTC pesticides and how these exposures compare to the NHANES 2003–2008 population, using urinary ETU data as an outcome measure. PubMed, Embase, and SciFinder were searched using the keywords “ethylenethiourea” or CAS No.: 96-45-7, and urine or urinary. Duplicates and irrelevant studies were removed from the search results based on predetermined exclusion criteria. This screening process identified 17 relevant papers. One additional paper was found independent of this search. Data from studies were extracted using a pre-established data collection form. Ten, two, and five manuscripts reported urinary levels in environmentally exposed adults, children, and pregnant women, respectively. Median ETU levels ranged from 0.15 to 4.7 μg/g creatinine in adults (1994–2017), 0.24–0.83 μg/g creatinine in children (2011), and 2.6–5.24 ng/ml in pregnant women (2011). Eight studies reported urinary ETU levels in mostly agriculturally exposed populations, with median ETU levels ranging from 0.42 to 49.6 μg/g creatinine (1999–2011). With one exception, all studies were conducted between 1994 and 2011. ETU levels in the NHANES 2003–2008 population appeared to be generally lower than most studies identified in this review. This finding suggests that, historically, DTC fungicide exposures in the general population of high-income countries, such as the US, were low, whereas agricultural populations may have experienced higher exposure. Unfortunately, more recent exposure data are missing, especially in countries where DTC pesticides are not being phased out.

Coke oven emissions (COEs), usually composed of polycyclic aromatic hydrocarbons (PAHs) and so on, may alter the relative telomere length of exposed workers and have been linked with adverse health events. However, the relevant biological exposure limits of COEs exposure has not been evaluated from telomere damage. The purpose of this study is to estimate benchmark dose (BMD) of urinary PAHs metabolites from COEs exposure based on telomere damage with RTL as a biomarker. A total of 544 exposed workers and 238 controls were recruited for participation. High-performance liquid chromatography and qPCR were used to detect concentrations of urinary mono-hydroxylated PAHs and relative telomere length in peripheral blood leukocytes for all subjects. The benchmark dose approach was used to estimate benchmark dose (BMD) and its lower 95% confidence limit (BMDL) of urinary OH-PAHs of COEs exposure based on telomere damage. Our results showed that telomere length in the exposure group (0.75 (0.51, 1.08)) was shorter than that in the control group (1.05 (0.76,1.44))(P < 0.05), and a dose-response relationship was shown between telomere damage and both 1-hydroxypyrene and 3-hydroxyphenanthrene in urine. The BMDL of urinary 1-hydroxypyrene from the optimal model for telomere damage was 1.96, 0.40, and 1.01 (μmol/mol creatinine) for the total, males, and females group, respectively. For 3-hydroxyphenanthrene, the BMDL was 0.94, 0.33, and 0.49 (μmol/mol creatinine) for the total, males, and females. These results contribute to our understanding of telomere damage induced by COEs exposure and provide a reference for setting potential biological exposure limits.

Due to worldwide regulations on the application of the high production volume industrial chemical bisphenol A (BPA) in various consumer products, alternative bisphenols such as bisphenol F (BPF) and bisphenol S (BPS) are increasingly used. To assess human exposure to these chemicals, biomonitoring of urinary concentrations is frequently used. However, the short-term variability of alternative bisphenols has not been evaluated thoroughly yet, which is essential to achieve a correct estimation of exposure. In this study, we collected all spot urine samples from ten healthy adults for five consecutive days, and an additional 24 h pooled sample. We measured the concentrations of seven bisphenols (BPAF, BPF, BPA, BPB, BPZ, BPS and BPAP) in these samples using gas chromatography coupled to tandem mass spectrometry. BPA, BPF and BPS were frequently found in spot samples (>80%), while bisphenol AP (BPAP) was detected in 43% of spot samples. Calculations of intra-class correlation coefficients (ICCs) showed that reproducibility of these four bisphenols was relatively poor (<0.01–0.200) but improved when concentrations were corrected for urine dilution using creatinine levels (0.128–0.401). Of these four bisphenols, BPF showed the best reproducibility (ICC 0.200–0.439) and BPS the most variability (ICC <0.01–0.128). In general, the within-participant variability of bisphenol levels was the largest contributor to the total variance (47–100%). We compared repeated first morning voids to 24 h pooled urine and found no significantly different concentrations for BPA, BPF, BPS, or BPAP. Levels of BPA and BPF differed significantly depending on the sampling time throughout the day. The findings in this study suggest that collecting multiple samples per participant over a few days, in predefined time windows throughout the day, could result in a more reliable estimation of internal exposure to bisphenols.

We used real-world exposure scenarios to evaluate the effect of six ambient air pollutant (PM₂.₅, PM₁₀, NO₂, SO₂, CO, and O₃) exposure on renal function among older adults without chronic kidney disease (CKD). We recruited 169 older adults without CKD in Beijing, China, for a longitudinal study from 2016 to 2018. The Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (EPI) equations were employed to derive the estimated glomerular filtration rate (eGFR). A linear mixed-effects model with random intercepts for participants was employed to determine the effects of air pollutants on renal function evaluated on the basis of eGFR and urinary albumin/creatinine ratio at different exposure windows (1-, 2-, 3-, 5-, 7-, 14-, 28-, 45-, and 60-days moving averages). An interquartile range (IQR) increase in NO₂ for was associated with significant decreases of in eGFR (MDRD equation) [percentage changes: −4.49 (95% confidence interval: −8.44, −0.37), −5.51 (−10.43, −0.33), −2.26 (−4.38, −0.08), −3.71 (−6.67, −0.65), −5.44 (−9.58, −1.11), −5.50 (−10.24, −0.51), −6.15 (−10.73, −1.33), and −6.34 (−11.17, −1.25) for 1-, 2-, 5-, 7-, 14-, 28-, 45-, and 60-days moving averages, respectively] and in eGFR (EPI equation) [percentage changes: −5.04 (−7.09, −2.94), −6.25 (−8.81, −3.62), −5.16 (−7.34, −2.92), −5.10 (−7.85, −2.28), −5.83 (−8.23, −3.36), −6.04 (−8.55, −3.47) for 1-, 2-, 14-, 28-, 45-, and 60-days moving averages, respectively]. In two-pollutant model, only the association of NO₂ exposure with eGFR remained robust after adjustment for any other pollutant. This association was stronger for individuals with hypertension for the EPI equation or BMI <25 kg/m² for the MDRD equation at lags 1 and 1–2. Our findings suggest that NO₂ exposure is associated with eGFR reduction among older adults without CKD for short (1-, 2-days) and medium (14-, 28-, 45-, 60-days) term exposure periods; thus, NO₂ exposure may contribute to renal impairment.

While several mechanisms may explain metal-related health effects, the exact cellular processes are not fully understood. We evaluated the association between leukocyte telomere length (LTL) and urine arsenic (ΣAs), cadmium (Cd) and tungsten (W) exposure in the Strong Heart Study (SHS, N = 1702) and in the Strong Heart Family Study (SHFS, N = 1793).Urine metal concentrations were measured using ICP-MS. Arsenic exposure was assessed as the sum of inorganic arsenic, monomethylarsonate and dimethylarsinate levels (ΣAs). LTL was measured by quantitative polymerase chain reaction.In the SHS, median levels were 1.09 for LTL, and 8.8, 1.01 and 0.11 μg/g creatinine for ΣAs, Cd, and W, respectively. In the SHFS, median levels were 1.01 for LTL, and 4.3, 0.44, and 0.10 μg/g creatinine. Among SHS participants, increased urine ΣAs, Cd, and W was associated with shorter LTL. The adjusted geometric mean ratio (95% confidence interval) of LTL per an increase equal to the difference between the percentiles 90th and 10th in metal distributions was 0.85 (0.79, 0.92) for ΣAs, 0.91 (0.84, 1.00) for Cd and 0.93 (0.88, 0.98) for W. We observed no significant associations among SHFS participants. The findings also suggest that the association between arsenic and LTL might be differential depending on the exposure levels or age.Additional research is needed to confirm the association between metal exposures and telomere length.

Thallium (Tl) is a well-recognized hazardous toxic heavy metal that has been reported to have embryotoxicity and fetotoxicity. However, little is known about its association with preterm birth (PTB) in humans. We aimed to evaluate the predictors of Tl exposure and assessed its relation with PTB. The study population included 7173 mother-infant pairs from a birth cohort in Wuhan, China. Predictors of Tl concentrations were explored using linear regression analyses, and associations of Tl exposure with risk of PTB or gestational age at birth were estimated using logistic regression or generalized linear models. The geometric mean and median values of urinary Tl concentrations were 0.28 μg/L (0.55 μg/g creatinine) and 0.29 μg/L (0.53 μg/g creatinine). We found that maternal urinary Tl concentrations varied by gestational weight gain, educational attainment, multivitamin and iron supplementations. Women with Tl concentrations higher than 0.80 μg/g creatinine were at higher risk of giving birth prematurely versus those with Tl concentrations lower than 0.36 μg/g creatinine [adjusted odds ratio (95% confidence interval (CI)): 1.55 (1.05, 2.27)], and the association was more pronounced in PTB with premature rupture of membranes (PROM) rather than in PTB without PROM. About 3-fold increase in creatinine-corrected Tl concentrations were associated with 0.99-day decrease in gestational length (95% CI: −1.36, −0.63). This is the first report on the associations between maternal Tl exposure and the risk of PTB.

Concentrations of the pesticide DDT (dichlorodiphenyltrichloroethane) and its metabolite DDE (dichlorodiphenyldichloroethylene), in the blood of Mexican Americans, were evaluated to determine their relationships with diabetes and diabetic nephropathy. The data were derived from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 (unweighted N = 1,411, population estimate = 13,760,609). The sample included teens, 12–19 years old, which accounted for 19.8% of the data. The time of the study overlapped the banning of DDT in Mexico in the year 2000, and those participants born in Mexico were exposed to DDT before they immigrated to the US. We sought to better understand the relationship of DDT with diabetes in a race/ethnicity group prone to develop diabetes and exposed to DDT. In this study, nephropathy was defined as urinary albumin to creatinine ratio >30 mg/g, representing microalbuminuria and macroalbuminuria, and total diabetes was defined as diagnosed and undiagnosed diabetes (glycohemoglobin, A1c ≥ 6.5%). The proportion with the isomer p,p′-DDT >0.086 ng/g (above the maximum limit of detection) was 13.3% for Mexican Americans born in the US, and 36.9% for those born in Mexico. Levels of p,p′-DDT >0.086 ng/g were associated with total diabetes with nephropathy (odds ratio = 4.42, 95% CI 2.23–8.76), and with total diabetes without nephropathy (odds ratio = 2.02, 95% CI 1.19–3.44). The third quartile of p,p′-DDE (2.99–7.67 ng/g) and the fourth quartile of p,p′-DDE (≥7.68 ng/g) were associated with diabetic nephropathy and had odds ratios of 5.32 (95% CI 1.05–26.87) and 14.95 (95% CI 2.96–75.48) compared to less than the median, respectively, whereas p,p′-DDE was not associated with total diabetes without nephropathy. The findings of this study differ from those of a prior investigation of the general adult US population in that there were more associations found with the Mexican Americans sample.

Currently, studies on the association between per-/polyfluoroalkyl substances (PFAS) concentrations and the renal function of residents, especially teenagers, living near fluorochemical industrial plants, are relatively rare, and not all these studies suggested associations. In this cross-sectional study, 775 local teenagers (11–15 years old) were included, and serum concentrations of 18 PFAS were measured. Perfluorooctanoic acid (PFOA) was found to be the dominant PFAS with a concentration of 22.3–3310 ng/mL (mean = 191 ng/mL), accounting for 71.5–99.1% of ΣPFAS. Statistical analyses demonstrated that internal exposure of perfluoroalkyl carboxylic acids (PFCA, C8–C10) was related to the plant. In addition, the prevalence rate of chronic kidney disease (CKD) (35.0%) in the participants was relatively high. A significantly positive association was observed between the increase in PFOA concentration and increasing risk of CKD (OR = 1.741; 95% CI: 1.004, 3.088; p = 0.048) by adjusting for gender, age, body mass index (BMI), and household income. Similar positive correlation was also observed in PFHpA with CKD (OR = 1.628, 95% CI: 1.031, 2.572; p = 0.037). However, no significant correlation was observed for concentrations of other PFAS and CKD (p > 0.05). Furthermore, linear regression analyses demonstrated that none of the PFAS concentrations were significantly correlated with estimated glomerular filtration rate (eGFR) or urine albumin/urine creatinine ratio (ACR) (p > 0.05). However, a significantly negative correlation was observed between PFOA concentration and abnormal ACR (β = −0.141, 95% CI: −0.283, 0.001; p = 0.048) after stratifying by CKD. Sensitivity analyses further confirmed these results. This cross-sectional study is the first, to our knowledge, to investigate the association between PFAS concentrations and renal function in teenagers living near a Chinese industrial plant. Further prospective and metabonomic studies are needed to interpret the results and clarify the biological mechanisms underlying this association.

Breast cancer is the most commonly diagnosed female cancer and the second leading cause of death in women in the US, including Hawaii. Accumulating evidence suggests that aminomethylphosphonic acid (AMPA), the primary metabolite of the herbicide glyphosate—a probable human carcinogen, may itself be carcinogenic. However, the relationship between urinary AMPA excretion and breast cancer risk in women is unknown. In this pilot study, we investigated the association between pre-diagnostic urinary AMPA excretion and breast cancer risk in a case-control study of 250 predominantly postmenopausal women: 124 cases and 126 healthy controls (individually matched on age, race/ethnicity, urine type, date of urine collection, and fasting status) nested within the Hawaii biospecimen subcohort of the Multiethnic Cohort. AMPA was detected in 90% of cases and 84% of controls. The geometric mean of urinary AMPA excretion was nearly 38% higher among cases vs. controls (0.087 vs 0.063 ng AMPA/mg creatinine) after adjusting for race/ethnicity, age and BMI. A 4.5-fold higher risk of developing breast cancer in the highest vs. lowest quintile of AMPA excretion was observed (ORQ₅ ᵥₛ. Q₁: 4.49; 95% CI: 1.46–13.77; pₜᵣₑₙd = 0.029). To our knowledge, this is the first study to prospectively examine associations between urinary AMPA excretion and breast cancer risk. Our preliminary findings suggest that AMPA exposure may be associated with increased breast cancer risk; however, these results require confirmation in a larger population to increase study power and permit careful examinations of race/ethnicity differences.