The objective of this study was to validate the hypothesis that increased serum concentrations of perfluoroalkyl substances (PFASs) cause kidney damage. A causal interpretative study was designed using the US 2003–2018 National Health and Nutrition Examination Survey (NHANES) datasets.Three statistical models, including multivariable linear regression, generalized additive model, and regression discontinuity model (RDM), were applied to the US 2003–2018 NHANES datasets to evaluate the causal relationship between the four PFAS agents and estimated glomerular filtration rate (eGFR). Directed acyclic graphs were plotted for a more valid causal inference.In the RDM, when the natural logarithm of each PFAS agent increases by 1 ng/mL after each cut-off value, eGFR decreased 4.63 mL/min/1.73 m² for perfluorooctanoic acid, 3.42 mL/min/1.73 m² for perfluorooctane sulfonic acid, 2.37 mL/min/1.73 m² for perfluorohexane sulfonic acid, and 2.87 mL/min/1.73 m² for perfluorononanoic acid. The possibility of reverse causation that increased serum PFAS concentration is the consequence of reduced eGFR, not the cause, was low, and an additional adjustment of potential confounders was not needed.This study contributes to the understanding of PFAS-induced kidney damage. Further longitudinal epidemiological and toxicological studies are recommended.

Although recent epidemiologic studies have focused on some of the health effects of perfluoroalkyl substance (PFASs) exposure in humans, the associations between PFASs exposure and the lipidome in children are still unclear. The purpose of this study was to assess lipid changes in children to understand possible molecular events of environmental PFASs exposure and suggest potential health effects. A total of 290 Taiwanese children (8–10 years old) were included in this study. Thirteen PFASs were analyzed in their serum by high-performance liquid chromatography-tandem mass spectrometry (LC-MS). MS-based lipidomic approaches were applied to examine lipid patterns in the serum of children exposed to different levels of PFASs. LC coupling with triple quadrupole MS technology was conducted to analyze phosphorylcholine-containing lipids. Multivariate analyses, such as partial least squares analysis along with univariate analyses, including multiple linear regression, were used to analyze associations between s exposure and unique lipid patterns. Our results showed that different lipid patterns were discovered in children exposed to different levels of specific PFASs, such as PFTrDA, PFOS, and PFDA. These changes in lipid levels may be involved in hepatic lipid metabolism, metabolic disorders, and PFASs-membrane interactions. This study showed that lipidomics is a powerful approach to identify critical PFASs that cause metabolite perturbation in the serum of children and suggest possible adverse health effects of these chemicals in children.

Environmental lead exposure has been linked with reduced kidney function. However, evidence about its role in diabetic kidney damage, especially when considering the nutritional status of vitamin D, is sparse. In this observational study, we investigated the association between low-level lead exposure and urinary albumin-to-creatinine ratio (UACR) and assessed potential impact of vitamin D among 4033 diabetic patients in Shanghai, China. Whole blood lead was measured by graphite furnace atomic absorption spectrometry. Serum 25-hydroxyvitamin D [25(OH)D] was tested using a chemiluminescence immunoassay. The associations of blood lead with UACR and albuminuria, defined as UACR ≥30 mg/g, according to 25(OH)D levels were analyzed using linear and Poisson regression models. A doubling of blood lead level was associated with a 10.7% higher UACR (95% CI, 6.19%–15.5%) in diabetic patients with 25(OH)D < 50 nmol/L, whereas the association was attenuated toward null (2.03%; 95% CI, −5.18% to 9.78%) in those with 25(OH)D ≥ 50 nmol/L. Similarly, the risk ratios of prevalent albuminuria per doubling of blood lead level between the two groups were 1.09 (95% CI, 1.03–1.15) and 0.99 (95% CI, 0.86–1.14), respectively. Joint analysis demonstrated that a combination of high blood lead and low 25(OH)D corresponded to significantly higher UACR. Among diabetic patients with 25(OH)D < 50 nmol/L, the increment of UACR relative to blood lead was more remarkable in those with reduced estimated glomerular filtration rate (<60 mL/min/1.73 m²). These results suggested that higher blood lead levels were associated with increased urinary albumin excretion in diabetic patients with vitamin D deficiency. Further prospective studies are needed to validate our findings and to determine whether vitamin D supplementation yields a benefit.

Exposure to outdoor fine particulate matter (PM₂.₅)-bound polycyclic aromatic hydrocarbons (PAHs) is linked to reproductive dysfunction. However, it is unclear which component of PAHs is responsible for the adverse outcomes. In the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study, we measured the exposure levels of 16 PAHs by collecting air PM₂.₅ particles and assessed eight PAHs metabolites from four parent PAHs, including naphthalene, fluorene, phenanthrene, and pyrene in urine samples. We investigated compositional profiles and variation characteristics for 16 PAHs in PM₂.₅, and then assessed the association between PAHs exposure and semen routine parameters, sperm chromatin structure, and serum hormone levels in 1452 samples. The results showed that naphthalene (95% CI: −17.989, −8.101), chrysene (95% CI: −64.894, −47.575), benzo[a]anthracene (95% CI: −63.227, −45.936) and all the high molecular weight (HMW) PAHs in PM₂.₅ were negatively associated with sperm normal morphology. Most of the low molecular weight (LMW) PAHs, such as acenaphthylene, fluorene, phenanthrene, fluoranthene, pyrene, chrysene, benzo[a]anthracene, ∑LMW PAHs and ∑16 PAHs, were correlated with increased sperm motility (all corrected P < 0.05). On the other hand, sperm normal morphology was all negatively associated with urinary metabolites of ∑OH-Nap (95% CI: −5.611, −0.536), ∑OH-Phe (95% CI: −5.741, −0.957), and ∑OH-PAHs (95% CI: −5.274, −0.361). Urinary concentrations of ∑OH-PAHs were found to be negatively associated with sperm high DNA stainability (HDS) (P = 0.023), while ∑OH-Phe were negatively associated with serum testosterone level and sperm HDS (P = 0.004). Spearman correlation analysis showed that except for the urinary OH-Nap metabolites, the rest of the urinary OH-PAHs metabolites were negatively correlated with their parent PAHs in air. The results of this study suggest that various PAHs’ components may affect reproductive parameters differently. Inhalation of PAHs in air, especially HMW PAHs, may be a potential risk factor for male reproductive health.

The number of deaths from air pollution worldwide is estimated at 8.8 million per year, more than the number of deaths from smoking. Air pollutants, such as PM₂.₅, are known to induce respiratory and cardiovascular diseases by inducing oxidative stress. Thioredoxin (Trx) is a 12-kDa endogenous protein that exerts antioxidant activity by promoting dithiol disulfide exchange reactions. We previously synthesized human serum albumin-fused thioredoxin (HSA-Trx), which has a longer half-life in plasma compared with Trx, and demonstrated its efficacy against various diseases including respiratory diseases. Here, we examined the effect of HSA-Trx on urban aerosol-induced lung injury in mice. Urban aerosols induced lung injury and inflammatory responses in ICR mice, but intravenous administration of HSA-Trx markedly inhibited these responses. We next analyzed reactive oxygen species (ROS) production in murine lungs using an in vivo imaging system. The results show that intratracheal administration of urban aerosols induced ROS production that was inhibited by intravenously administered HSA-Trx. Finally, we found that HSA-Trx inhibited the urban aerosol-induced increase in levels of neutrophilic extracellular trap (NET) indicators (i.e., double-stranded DNA, citrullinated histone H3, and neutrophil elastase) in bronchoalveolar lavage fluid (BALF). Together, these findings suggest that HSA-Trx prevents urban aerosol-induced acute lung injury by suppressing ROS production and neutrophilic inflammation. Thus, HSA-Trx may be a potential candidate drug for preventing the onset or exacerbation of lung injury caused by air pollutants.

Perfluoroalkyl ether carboxylic acids (PFECAs), including hexafluoropropylene oxide dimer acid (HFPO-DA, GenX), have been widely used as alternatives to perfluorooctanoic acid (PFOA) and subsequently detected in various environmental matrices. Despite this, public information regarding their hepatotoxicity remains limited. Here, to compare the hepatotoxicity of PFECAs and identify better alternatives for GenX, adult male mice were exposed to different concentrations (0.4, 2, and 10 mg/kg/d) of PFOA, GenX, and its analogs (PFMO2HpA and PFMO3NA) for 28 d. Results demonstrated increased hepatomegaly and disturbed fatty acid metabolism with increasing treatment doses. After dimensionality reduction analysis, significant differences were observed in the relative liver weights and liver and serum biochemical parameters among the four clusters. Furthermore, when chemical concentrations in the liver were similar, no differences in the indicators of liver injury associated with fatty acid metabolism were observed among groups in the same clusters. Our results suggest that dimensionality reduction analysis is a useful strategy for analyzing samples exposed to multiple compounds at different doses. Furthermore, PFECAs exhibit similar hepatotoxicities at the same cumulative hepatic concentration in mice with constant body weight, while PFMO2HpA exhibits lower hepatotoxicity compared to GenX at the same dose.

Polycyclic aromatic hydrocarbons (PAHs) are compounds with two or more benzene rings whose hydroxylated metabolites (OH-PAHs) are excreted in urine. Human PAH exposure is therefore commonly estimated based on urinary OH-PAH concentrations. However, no study has compared PAH exposure estimates based on urinary OH-PAHs to measurements of PAH levels in blood samples. Estimates of PAH exposure based solely on urinary OH-PAHs may thus be subject to substantial error. To test this hypothesis, paired measurements of parent PAHs in serum and OH-PAHs in urine samples from 480 participants in Guangzhou, a typical developed city in southern China, were used to investigate differences in the estimates of human PAH exposure obtained by sampling different biological matrices. The median PAH concentration in serum was 4.05 ng mL⁻¹, which was lower than that of OH-PAHs in urine (8.33 ng mL⁻¹). However, serum pyrene levels were significantly higher than urinary levels of its metabolite 1-hydroxypyrene. Concentrations of parent PAHs in serum were not significantly correlated with those of their metabolites in urine with the exception of phenanthrene, which exhibited a significant negative correlation. Over 28% of the participants had carcinogenic risk values above the acceptable cancer risk level of 10⁻⁶. Overall, estimated human exposure and health risks based on urinary 1-hydroxypyrene levels were only 13.6% of those based on serum pyrene measurements, indicating that estimates based solely on urine sampling may substantially understate health risks due to PAH exposure.

Studies have documented that exposure to organochlorine pesticides (OCPs) is linked with breast cancer, but the underlying biological mechanisms are still unknown. This study included 313 women diagnosed with breast cancer and 313 controls in Wuhan, China, and measured 18 OCPs in serum and 3 oxidative stress biomarkers in urine. Multivariable adjusted regression models were used to evaluate the associations among OCPs, oxidative stress biomarkers, and breast cancer. The mediating effect of oxidative stress was assessed by mediation analysis. We observed that most OCPs were positively associated with risk of breast cancer (all FDR-P values < 0.05 or 0.10). Moreover, we found that p,p'-DDT, p,p'-DDD, dieldrin, heptachlor, and heptachlor epoxide were positively associated with 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) and 8-iso-prostaglandin F₂α (8-isoPGF₂α), which in turn were positively associated with risk of breast cancer. Mediation analysis indicated that HNE-MA and 8-isoPGF₂ɑ mediated the positive associations between these OCPs and risk of breast cancer, with mediating proportion ranging from 6.23% to 19.9%. Our results suggest that lipid peroxidation may mediate the positive associations between OCP exposures and risk of breast cancer.

Chlorinated paraffins (CPs) are pervasive environmental pollutants which have been reported to be hepatotoxic by laboratory cell and animal studies. However, the related epidemiological reports on their hepatotoxic effects to humans are sparse. In this study, we evaluated the associations between six liver enzymes and serum short-chain CP (SCCP) or medium-chain CP (MCCP) concentrations of 197 residents in Jinan, China. Serum S/MCCPs were detected by quadrupole time-of-flight high-resolution mass spectrometry coupled with atmospheric pressure chemical ionization source (APCI-QTOF-HRMS), and quantified by pattern deconvolution method. The associations between total serum S/MCCP concentrations (ΣS/MCCPs) and continuous liver enzyme levels were assessed by linear regression. Odds ratios (ORs) for the effects of serum ΣS/MCCPs concentrations on liver function biomarkers dichotomized by clinical reference intervals were predicted by logistic regression, either treating ΣS/MCCPs as continuous or categorical dependents. After multivariable adjustment, linear regression results illustrated that 1-ln unit increase in serum ΣSCCPs was negatively associated with male PA levels [-6.08, 95% confidence interval (CI): −11.90, −3.25, p < 0.05], positively associated with male TB levels (1.80, 95% CI: 0.28, 3.31, p < 0.05), and positively associated with female AST levels (1.39, 95% CI: 0.07, 2.70, p < 0.05). One-ln unit increase in serum ΣMCCPs was negatively associated male PA levels (−7.56, 95% CI: −17.15, −4.03, p < 0.05). Logistic regression results suggested that male serum ΣSCCPs were associated with increased prevalence of abnormal PA (OR = 1.47 per 1 ln-unit increase, CI = 1.18, 1.82) and TB (OR = 1.75, 95% CI = 1.12, 2.76) levels, and male serum ΣMCCPs were significantly associated with increased prevalence of abnormal PA (OR = 1.43, 95% CI = 1.03, 1.97) levels. In addition, male participants with concentrations above the median ΣS/MCCPs were associated with increased risk for abnormal PA levels [SCCPs, 2.11-fold (95% CI = 1.15, 3.87); MCCPs, 1.94-fold (95% CI = 1.24, 3.03)]. Male participants with concentrations above the median ΣSCCPs were also associated with increased risk for abnormal TB levels (OR = 1.75, 95% CI = 1.12, 2.76). Conclusively, our results revealed that CP internal exposure was associated with disturbed liver biomarker levels, suggesting the hepatotoxicity of both SCCPs and MCCPs to humans.

Emerging per-/polyfluoroalkyl substances (PFASs), such as chlorinated polyfluorinated ether sulfonates (Cl-PFESAs), have been detected in human samples, yet investigation on their occurrence in pregnant women remains limited. Herein, ten legacy PFASs, branched perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA), two Cl-PFESAs, perfluoro-2-propoxypropanoic acid (HFPO-DA), and ammonium 4,8-dioxa-3H-perfluorononanoate (ADONA) were detected in serum samples from 480 pregnant women in Tianjin, China. The influencing effects of age, body mass index, gravidity, and parity were also evaluated. PFOS [geographic mean (GM): 7.05 ng/mL], 6:2Cl-PFESA (GM: 5.31 ng/mL), and PFOA (GM: 2.82 ng/mL) were the dominant PFASs in the serum of pregnant women, while neither HFPO-DA nor ADONA was detectable in any serum. The serum concentration of Cl-PFESAs and 6:2Cl-PFESA/PFOS ratio in the present study were 2–5 times higher than that in previous studies of pregnant women in China. Serum concentrations of Cl-PFESAs were significantly correlated with all detected PFAAs (Spearman’s Rho: 0.15–0.69, p < 0.01) excepting perfluoropentanesulfonate (PFPeS), indicating common exposure sources for Cl-PFESAs and PFAAs and some particular exposure source for PFPeS. Younger age and multi-parity were associated with lower serum concentrations of PFOS and several perfluoroalkyl sulfonates but not associated with Cl-PFESAs or PFOA, suggesting an increasing exposure to Cl-PFESAs and PFOA which neutralized the impact of age and parity. Overall, this study indicated a relatively high exposure level and composition of 6:2Cl-PFESA in pregnant women in the north coast of China, which highlights the need to investigate the exposure sources in this area.