Urinary Metabolite Concentrations Research Articles

Urinary polycyclic aromatic hydrocarbon metabolites and hyperlipidemia: NHANES 2007-2016.

The relationships between urinary polycyclic aromatic hydrocarbon (PAH) metabolites and hyperlipidemia have not been thoroughly studied. The primary goal of this research focused on investigating the linkage between PAH metabolite concentrations in urine and hyperlipidemia prevalence within US adults. A cross-sectional analysis was conducted using data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES). Logistic regression models were used to assess correlations between urinary PAH metabolite levels and the risk of hyperlipidemia, while restricted cubic spline models were used to examine dose‒response relationships. Subgroup and interaction analyses were performed to further elucidate these associations. Weighted quantile sum (WQS) regression analyzed the cumulative impact of various urinary PAH metabolites on hyperlipidemia risk. This study included 7,030 participants. Notably, individuals in the highest quintile of urinary PAH metabolite concentrations exhibited a significantly elevated prevalence of hyperlipidemia, even after comprehensive adjustments (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.01-1.75). Moreover, elevated levels of 1-hydroxyphenanthrene and 2-hydroxynaphthalene in the fourth quintile and 2-hydroxyfluorene in the third, fourth, and fifth quintiles demonstrated positive correlations with the prevalence of hyperlipidemia. These associations persisted across subgroup analyses. Additionally, a positive correlation between the urinary PAH metabolite mixture and hyperlipidemia (positive model: OR = 1.04, 95% CI: 1.00-1.09) was observed in the WQS model, and 2-hydroxynaphthalene showed the most substantial contribution. The cross-sectional analysis identified a significant correlation between urinary PAH metabolite and hyperlipidemia prevalence within the US demographic, with 2-hydroxynaphthalene being the predominant influencer. These findings underscore the need to mitigate PAH exposure as a preventive measure for hyperlipidemia.

Biomarkers of Organophosphate and Polybrominated Diphenyl Ether (PBDE) Flame Retardants of American Workers and Associations with Inhalation and Dermal Exposures.

This study evaluated workers' exposures to flame retardants, including polybrominated diphenyl ethers (PBDEs), organophosphate esters (OPEs), and other brominated flame retardants (BFRs), in various industries. The study aimed to characterize OPE metabolite urinary concentrations and PBDE serum concentrations among workers from different industries, compare these concentrations between industries and the general population, and evaluate the likely route of exposure (dermal or inhalation). The results showed that workers from chemical manufacturing had significantly higher (p <0.05) urinary concentrations of OPE metabolites compared to other industries. Spray polyurethane foam workers had significantly higher (p <0.05) urinary concentrations of bis(1-chloro-2-propyl) phosphate (BCPP) compared to other industries. Electronic scrap workers had higher serum concentrations of certain PBDE congeners compared to the general population. Correlations were observed between hand wipe samples and air samples containing specific flame-retardant parent chemicals and urinary metabolite concentrations for some industries, suggesting both dermal absorption and inhalation as primary routes of exposure for OPEs. Overall, this study provides insights into occupational exposure to flame retardants in different industries and highlights the need for further research on emerging flame retardants and exposure reduction interventions.

Sex and adrenal hormones in association with insecticide biomarkers among adolescents living in ecuadorian agricultural communities

BackgroundOrganophosphate, pyrethroid, and neonicotinoid insecticides have resulted in adrenal and gonadal hormone disruption in animal and in vitro studies; limited epidemiologic evidence exists in humans. We assessed relationships of urinary insecticide metabolite concentrations with adrenal and gonadal hormones in adolescents living in Ecuadorean agricultural communities. MethodsIn 2016, we examined 522 Ecuadorian adolescents (11-17y, 50.7% female, 22% Indigenous; ESPINA study). We measured urinary insecticide metabolites, blood acetylcholinesterase activity (AChE), and salivary testosterone, dehydroepiandrosterone (DHEA), 17β-estradiol, and cortisol. We used general linear models to assess linear (β = % hormone difference per 50% increase of metabolite concentration) and curvilinear relationships (β2 = hormone difference per unit increase in squared ln-metabolite) between ln-metabolite or AChE and ln-hormone concentrations, stratified by sex, adjusting for anthropometric, demographic, and awakening response variables. Bayesian Kernel Machine Regression was used to assess non-linear associations and interactions. ResultsThe organophosphate metabolite malathion dicarboxylic acid (MDA) had positive associations with testosterone (βboys = 5.88% [1.21%, 10.78%], βgirls = 4.10% [-0.02%, 8.39%]), and cortisol (βboys = 6.06 [-0.23%, 12.75%]. Para-nitrophenol (organophosphate) had negatively-trending curvilinear associations, with testosterone (β2boys = −0.17 (−0.33, −0.003), p = 0.04) and DHEA (β2boys = −0.49 (−0.80, −0.19), p = 0.001) in boys. The neonicotinoid summary score (βboys = 5.60% [0.14%, 11.36%]) and the neonicotinoid acetamiprid-N-desmethyl (βboys = 3.90% [1.28%, 6.58%]) were positively associated with 17β-estradiol, measured in boys only. No associations between the pyrethroid 3-phenoxybenzoic acid and hormones were observed. In girls, bivariate response associations identified interactions of MDA, Para-nitrophenol, and 3,5,6-trichloro-2-pyridinol (organophosphates) with testosterone and DHEA concentrations. In boys, we observed an interaction of MDA and Para-nitrophenol with DHEA. No associations were identified for AChE. ConclusionsWe observed evidence of endocrine disruption for specific organophosphate and neonicotinoid metabolite exposures in adolescents. Urinary organophosphate metabolites were associated with testosterone and DHEA concentrations, with stronger associations in boys than girls. Urinary neonicotinoids were positively associated with 17β-estradiol. Longitudinal repeat-measures analyses would be beneficial for causal inference.

Biomonitoring urinary pesticide metabolites in preschool children by supported liquid extraction and ultra-high performance liquid chromatography-tandem mass spectrometry and their association with oxidative stress

Investigating pesticide exposure and oxidative stress in preschool children is essential for elucidating the determinants of environmental health in early life, with human biomonitoring of urinary pesticide metabolites serving as a critical strategy for achieving this objective. This study demonstrated biomonitoring of 2 phenoxyacetic acid herbicides, 2 organophosphorus pesticide metabolites, and 4 pyrethroid pesticide metabolites in 159 preschool children and evaluated their association with oxidative stress biomarker 8-hydroxydeoxyguanosine. An enzymatic deconjugation process was used to release urinary pesticide metabolites, which were then extracted and enriched by supported liquid extraction, and quantified by ultra-high performance liquid chromatography-tandem mass spectrometry with internal standard calibration. Dichloromethane: methyl tert‑butyl ether (1:1, v/v) was optimized as the solvent for supported liquid extraction, and we validated the method for linear range, recovery, matrix effect and method detection limit. Method detection limit of the pesticide metabolites ranged from 0.01 μg/L to 0.04 μg/L, with satisfactory recoveries ranging from 70.5 % to 95.5 %. 2,4,5-Trichlorophenoxyacetic acid was not detected, whereas the other seven pesticide metabolites were detected with frequencies ranging from 10.1 % to 100 %. The concentration of urinary pesticide metabolites did not significantly differ between boys and girls, with the median concentrations being 9.39 μg/L for boys and 4.90 μg/L for girls, respectively. Spearman correlation analysis indicated that significant positive correlations among urinary metabolites. Bayesian kernel machine regression revealed a significant positive association between urinary pesticide metabolites and 8-hydroxydeoxyguanosine. Para-nitrophenol was the pesticide metabolite that contributed significantly to the elevated level of oxidative stress.

Prenatal exposure to pyrethroids and chlorpyrifos and IQ in 7-year-old children from the Odense Child Cohort

BackgroundOrganophosphates and pyrethroids are two major groups of insecticides used for crop protection worldwide. They are neurotoxicants and exposure during vulnerable windows of brain development may have long-term impact on human neurodevelopment. Only few longitudinal studies have investigated associations between prenatal exposure to these substances and intelligence quotient (IQ) at school age in populations with low, mainly dietary, exposure. ObjectiveTo investigate associations between maternal urinary concentrations of insecticide metabolites at gestational week 28 and IQ in offspring at 7-years of age. Materials and methodsData was derived from the Odense Child Cohort (OCC). Metabolites of chlorpyrifos (TCPy) and pyrethroids (3-PBA, cis- and trans-DCCA, 4-F-3PBA, cis-DBCA) were measured in maternal urine collected at gestational week (GW) 28. An abbreviated version of the Danish Wechsler Intelligence Scale for Children fifth edition (WISC-V) consisting of four subtests to estimate full scale IQ (FSIQ) was administered by trained psychologists. Data were analyzed by use of multiple linear regression and adjusted for confounders. Results812 mother/child-pairs were included. Median concentrations were 0.21 μg/L for 3-PBA, 1.67 μg/L for TCPy and the mean IQ for children were 99.4. Null association between maternal 3-PBA and child IQ at 7 years was seen, but with trends suggesting an inverse association. There was a significant association for maternal TCPy and child IQ at mid-level exposure. Trans-DCCA above the level of detection (LOD) was also associated with slightly lower child IQ, but the association was also not statistically significant. ConclusionsWe found no significant associations between maternal 3-PBA metabolites and child IQ at 7 years, but with trends suggesting an inverse association. A non-significant trend between maternal TCPy exposure and child IQ in 7-year-children was seen even in this low exposed population. Given the widespread exposure and increasing use of insecticides, this should be elaborated in future studies.

Active smoking in urban households: An association between urinary cotinine metabolite level and serum eGFR concentration.

Smoking stands as a primary contributor to preventable deaths globally and is linked to an increased risk of developing kidney failure and other diseases. A few studies have focused on the negative correlation between serum cotinine and estimated glomerular filtration rate (eGFR), indicating decreased kidney function. This study investigated the associations between urinary cotinine metabolite concentration and serum eGFR among active smokers in urban households. This was a cross-sectional study of active smokers in urban households' community Bangkok, Thailand from January to April 2023. The study involved 85 participants aged ≥18 years who were active smokers. Both urinary cotinine and serum eGFR concentrations were used as biomarkers. Independent sample t-tests were used to compare the urinary cotinine metabolite based on differences in the characteristic variable. We used multiple linear regression to test the association between cotinine metabolite and characteristics variables. Spearman's analysis was used to test the correlation between cotinine metabolite and eGFR concentration. The association between urinary cotinine metabolite and serum eGFR concentration decreased with increasing cotinine concentrations (r= -0.223, p=0.041), suggesting a decline in kidney function. However, this study found no significant difference between urinary cotinine metabolite and characteristic variables (p>0.05). Additionally, those who smoked for ≥10 years (117.40 ± 89.80 ng/mL), smoked ≥10 cigarettes per day (117.40 ± 89.80 ng/mL) and used conventional cigarettes (124.53 ± 115.10 ng/mL). The results of the multiple linear regression models analysis indicated that those who were smokers for ≥10 years (β=0.076; 95% CI: -31.575-59.715) and those who were smoked ≥10 cigarettes/day (β=0.126; 95% CI: -65.636-18.150) were not associated with urinary cotinine metabolite level. This study shows that the urinary cotinine metabolite level is associated with serum eGFR concentration among active smokers in urban households. The current study suggests that clinical identification and a prospective cohort study are needed before robust conclusions about how tobacco affects kidney efficiency.

Validation of putative biomarkers of furan exposure through quantitative analysis of furan metabolites in urine of F344 rats exposed to stable isotope labeled furan

Humans are chronically exposed to furan, a potent liver toxicant and carcinogen that occurs in a variety of heat-processed foods. Assessment of human exposure based on the furan content in foods is, however, subject to some uncertainty due to the high volatility of furan. Biomarker monitoring is thus considered an alternative or complementary approach to furan exposure assessment. Previous work suggested that urinary furan metabolites derived from the reaction of cis-2-butene-1,4-dial (BDA), the reactive intermediate of furan, with glutathione (GSH) or amino acids may serve as potential biomarkers of furan exposure. However, some metabolites were also reported to occur in urine of untreated animals, indicating either background contamination via animal feed or endogenous sources, which may limit their suitability as biomarkers of exposure. The overall aim of the present study was to accurately establish the correlation between external dose and concentration of furan metabolites in urine over time and to discriminate against endogenous formation and furan intake via feed. To this end, the furan metabolites GSH-BDA (N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-L-cysteinylglycine), NAcLys-BDA (R-2-(acetylamino)-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid), NAcCys-BDA-NAcLys (N-acetyl-S-[1-[5-(acetylamino)-5-carboxypentyl]-1H-pyrrol-3-yl]-L-cysteine) and NAcCys-BDA-NAcLys sulfoxide (N-acetyl-S-[1-[5-(acetylamino)-5-carboxypentyl]-1H-pyrrol-3-yl]-L-cysteine sulfoxide) were simultaneously analyzed by stable isotope dilution ESI–LC–MS/MS as unlabeled and [13C4]-furan dependent metabolites following oral administration of a single oral dose of isotopically labelled [13C4]-furan (0.1, 1, 10, 100 and 1000 µg/kg bw) to male and female F344/DuCrl rats. Although a linear correlation between urinary excretion of [13C4]-furan-dependent metabolites was observed, analysis of unlabeled NAcLys-BDA, NAcCys-BDA-NAcLys and NAcCys-BDA-NAcLys sulfoxide revealed substantial, fairly constant urinary background levels throughout the course of the study. Analysis of furan in animal feed excluded feed as a source for these background levels. GSH-BDA was identified as the only furan metabolite without background occurrence, suggesting that it may present a specific biomarker to monitor external furan exposure. Studies in humans are now needed to establish if analysis of urinary GSH-BDA may provide reliable exposure estimates.

Phthalate metabolites and sex steroid hormones in relation to obesity in US adults: NHANES 2013-2016.

Obesity and metabolic syndrome pose significant health challenges in the United States (US), with connections to disruptions in sex hormone regulation. The increasing prevalence of obesity and metabolic syndrome might be associated with exposure to phthalates (PAEs). Further exploration of the impact of PAEs on obesity is crucial, particularly from a sex hormone perspective. A total of 7780 adult participants in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016 were included in the study. Principal component analysis (PCA) coupled with multinomial logistic regression was employed to elucidate the association between urinary PAEs metabolite concentrations and the likelihood of obesity. Weighted quartiles sum (WQS) regression was utilized to consolidate the impact of mixed PAEs exposure on sex hormone levels (total testosterone (TT), estradiol and sex hormone-binding globulin (SHBG)). We also delved into machine learning models to accurately discern obesity status and identify the key variables contributing most to these models. Principal Component 1 (PC1), characterized by mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) as major contributors, exhibited a negative association with obesity. Conversely, PC2, with monocarboxyononyl phthalate (MCNP), monocarboxyoctyl phthalate (MCOP), and mono(3-carboxypropyl) phthalate (MCPP) as major contributors, showed a positive association with obesity. Mixed exposure to PAEs was associated with decreased TT levels and increased estradiol and SHBG. During the exploration of the interrelations among obesity, sex hormones, and PAEs, models based on Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) algorithms demonstrated the best classification efficacy. In both models, sex hormones exhibited the highest variable importance, and certain phthalate metabolites made significant contributions to the model's performance. Individuals with obesity exhibit lower levels of TT and SHBG, accompanied by elevated estradiol levels. Exposure to PAEs disrupts sex hormone levels, contributing to an increased risk of obesity in US adults. In the exploration of the interrelationships among these three factors, the RF and XGBoost algorithm models demonstrated superior performance, with sex hormones displaying higher variable importance.

Prenatal polycyclic aromatic hydrocarbon exposure and asthma at age 8–9 years in a multi-site longitudinal study

Background and aimStudies suggest prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) may influence wheezing or asthma in preschool-aged children. However, the impact of prenatal PAH exposure on asthma and wheeze in middle childhood remain unclear. We investigated these associations in socio-demographically diverse participants from the ECHO PATHWAYS multi-cohort consortium.MethodsWe included 1,081 birth parent–child dyads across five U.S. cities. Maternal urinary mono-hydroxylated PAH metabolite concentrations (OH-PAH) were measured during mid-pregnancy. Asthma at age 8–9 years and wheezing trajectory across childhood were characterized by caregiver reported asthma diagnosis and asthma/wheeze symptoms. We used logistic and multinomial regression to estimate odds ratios of asthma and childhood wheezing trajectories associated with five individual OH-PAHs, adjusting for urine specific gravity, various maternal and child characteristics, study site, prenatal and postnatal smoke exposure, and birth year and season in single metabolite and mutually adjusted models. We used multiplicative interaction terms to evaluate effect modification by child sex and explored OH-PAH mixture effects through Weighted Quantile Sum regression.ResultsThe prevalence of asthma in the study population was 10%. We found limited evidence of adverse associations between pregnancy OH-PAH concentrations and asthma or wheezing trajectories. We observed adverse associations between 1/9-hydroxyphenanthrene and asthma and persistent wheeze among girls, and evidence of inverse associations with asthma for 1-hydroxynathpthalene, which was stronger among boys, though tests for effect modification by child sex were not statistically significant.ConclusionsIn a large, multi-site cohort, we did not find strong evidence of an association between prenatal exposure to PAHs and child asthma at age 8–9 years, though some adverse associations were observed among girls.

Effect of children secondhand smoke exposure associated with GABA concentration: Influence from parents who are extremely heavy smokers in urban households

BackgroundSecondhand smoke (SHS) poses the most considerable health risk to children in urban households. However, limited evidence exists regarding the impact of children exposure to SHS on gamma-aminobutyric acid (GABA) levels. This study aimed to investigate the level of cotinine and GABA and their association with variables related to children exposed to SHS. MethodsA cross-sectional analysis was conducted to assess urinary cotinine and GABA levels in respondents. The study involved 85 participants aged 2–4 years who resided with parents exhibiting heavy smoking habits in urban households in Bangkok, Thailand. Urinary cotinine and GABA concentrations were utilized as biomarkers and measured using an enzyme-linked immunosorbent assay kit. An independent t-test was employed to compare contributing factors with urinary cotinine metabolites. Spearman's correlation test was utilized to assess the relationship between cotinine metabolites and GABA concentration. ResultsThe study found a correlation between urinary cotinine metabolites and GABA concentration among children's (r = 0.260, p-value = 0.016), particularly influenced by parents exhibiting extreme heavy smoking in urban households. Male children exhibited significantly higher urinary cotinine metabolite concentrations than females (p-value = 0.040). Moreover, significantly elevated levels of cotinine metabolites (57.37 ± 10.27 ng/ml) were observed in households where parents engaged in extreme heavy smoking. ConclusionsThis research establishes a link between urinary cotinine metabolite levels and GABA concentration among children exposed to extreme heavy smoking by their parents in urban households. Consequently, smoking might impact neurobehavioral effects, potentially leading to insomnia. The study emphasizes the importance of promoting and safeguarding non-smokers from exposure to SHS in indoor workplaces, public spaces, and households, advocating for the implementation of smoke-free public health regulations.

Stability of volatile organic compound metabolites in urine at various storage temperatures and freeze-thaw cycles for 8 months

The urinary concentrations of mercapturic acid metabolites of volatile organic compounds (VOCs) have been used as biomarkers of human exposure to this class of chemicals. However, long-term stability of these VOC metabolites (VOCMs) in urine at various storage conditions such as temperature, duration, and freeze-thaw cycles is not known. In this study, spot urine samples collected from three volunteers, stored at 22 °C (room temperature: RT), 4 °C (refrigerator) and −20 °C (freezer) for up to 240 days were analyzed at weekly to monthly interval for a total of 19 time points. Samples stored at 4 °C and −20 °C underwent 18 freeze-thaw cycles at RT for 30 min at each of the time points. Among 38 VOCMs analyzed, up to 18 metabolites were detected at concentrations above their respective detection limits on Day 0 (baseline concentration), and the concentrations of several VOCMs declined with the storage duration. Eight to ten VOCMs were lost completely within 240 days of storage at RT, compared to between two and five at 4 °C and between one and seven at −20 °C. The loss rate varied depending on the sample, storage temperature, VOCM, and number of freeze-thaw cycles. Storage of urine at RT led to a rapid loss of VOCMs in comparison to that stored at 4 °C or −20 °C. Among VOCMs measured, CEMA, SBMA, GAMA, DHBMA, AMCC, TCVMA, and HPMMA were lost more rapidly than the other metabolites. CMEMA, a major VOCM found in all three urines at baseline, exhibited a rapid loss in those of two volunteers but not of the other volunteer, suggesting sample to sample variation in lose rates. Freeze-thaw cycles considerably affected VOCM concentrations in urines stored at 4 °C or −20 °C. It is recommended that urine samples are analyzed for VOCMs within a couple of months of collection and stored at temperatures below −20 °C, with minimal or no freeze-thaw cycles. This study highlights the need for appropriate storage conditions to maintain the integrity of samples for biomonitoring studies.

Relationship between phthalates exposure, risk of decreased ovarian reserve, and oxidative stress levels.

Phthalates (PAEs), a group of environmental endocrine disruptors, are associated with oxidative stress and have adverse effects on female ovarian reserves. However, this association has been poorly investigated, particularly with respect to clinical evidence. In this study, we provided clinical evidence of a relationship between exposure levels of PAEs, oxidative stress and decreased ovarian reserve (DOR). Firstly, the urinary concentrations of metabolites of PAEs were measured by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH), and the biomarkers of oxidative stress, malondialdehyde (MDA), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC), were determined. Finally, statistical analyses were conducted to describe the relationship between the PAEs exposure, oxidative stress and DOR. We found that the levels of monomethyl phthalate (MMP), monoisobutyl phthalate (MiBP), mono-(2-ethylhexyl) phthalate (MEHP), and mono-(2-ethyl-5-hydroxypentyl) phthalate (MECPP) in the DOR group were significantly higher than those in the control group. There was a significant negative association between AMH and MMP, MiBP levels. and a significant positive association between FSH and MMP levels. PAEs exposure was also associated with a significant increase in MDA levels and decrease in SOD levels. In conclusion, the exposure of PAEs was closely associated with DOR, potentially mediated by oxidative stress pathways; however, small sample size was a limitation in this study.

Association between polycyclic aromatic hydrocarbons exposure with red cell width distribution and ischemic heart disease: insights from a population-based study.

This study investigates the association between polycyclic aromatic hydrocarbon (PAH) exposure, red blood cell distribution width (RDW), and ischemic heart disease (IHD) in a sample of 3003 participants from the National Health and Nutrition Examination Survey (NHANES). We hypothesize that RDW may mediate the effect of hydroxylated PAHs (OH-PAH) on IHD. Logistic regression models reveal significant associations between increased urinary PAH metabolite concentrations and IHD, as well as positive associations between PAH metabolites and RDW. Weighted Quantile Sum (WQS) regression and Bayesian Kernel Machine Regression (BKMR) analyses confirm the significant associations of the OH-PAH mixture with IHD and RDW. Mediation analysis demonstrates that RDW partially mediates the relationship between PAH exposure and IHD, accounting for 2-4.6% of the total effects. Our findings highlight the potential underlying mechanisms linking PAH exposure, RDW, and IHD and emphasize the importance of addressing environmental pollutants like PAHs in maintaining cardiovascular health and informing public health policies.

New insight into PAH4 induced hepatotoxicity and the dose-response assessment in rats model

PAH4 (sum of benzo[a]pyrene, chrysene, benz[a]anthracene and benzo[b]fluoranthene) has been proposed as better marker than benzo[a]pyrene to assess total PAHs exposure in foodstuffs. However, the toxicological behaviors of PAH4 combined exposure remain unclear. This study aimed to investigate PAH4 toxicity effects with non-targeted metabolomics approach and evaluate the external and internal dose-response relationships based on benchmark dose (BMD) analysis. Male Sprague-Dawley rats were treated by gavage with vehicle (corn oil) or four doses of PAH4 (10, 50, 250, 1000 μg/kg·bw) for consecutive 30 days. After the final dose, the liver, blood and urine samples of rats were subsequently collected for testing. The concentrations of urinary mono-hydroxylated PAHs metabolites (OH-PAHs) including 3-hydroxybenzo[a]pyrene (3-OHB[a]P), 3-hydroxychrysene (3-OHCHR) and 3-hydroxybenz[a]anthracene (3-OHB[a]A) were determined to reflect internal PAH4 exposure. Our results showed PAH4 exposure increased relative liver weight and serum aspartate aminotransferase (AST) activity and caused hepatocyte swelling and degeneration, implying hepatotoxicity induced by PAH4. Serum metabolomics suggested PAH4 exposure perturbed lipid metabolism through upregulating the expression of glycerolipids metabolites, which was evidenced by markedly increased serum triglyceride (TG) level and hepatic TG content. Additionally, urinary OH-PAHs concentrations presented strong positive correlations with the external dose, indicating they were able to reflect PAH4 exposure. Furthermore, PAH4 exposure led to a dose-response increase of hepatic TG content, based on which the 95% lower confidence value of BMDs for external and internal doses were estimated as 5.45 μg/kg·bw and 0.11 μmol/mol·Cr, respectively. In conclusion, this study suggested PAH4 exposure could induce hepatotoxicity and lipid metabolism disorder, evaluating the involved dose-response relationships and providing a basis for the risk assessment of PAHs.

Association of co-exposure to polycyclic aromatic hydrocarbons and phthalates with oxidative stress and inflammation

Exposure to multiple environmental pollutants is ubiquitous and inevitable, but studies investigating their exposure effects on oxidative stress or inflammation have mainly been restricted to single-pollutant models. This study investigated the association of co-exposure to polycyclic aromatic hydrocarbons and phthalates with oxidative stress and inflammation. Using a cross-sectional study in adults, we measured urinary concentrations of metabolites of polycyclic aromatic hydrocarbons (OH-PAHs) and phthalates (mPAEs), urinary oxidative stress biomarker 8-hydroxy-2′-deoxyguanosine, and 9 inflammatory biomarkers in paired blood samples. The associations of urinary OH-PAHs and mPAEs with oxidative stress and inflammation biomarkers were evaluated by different statistical models. The Bayesian kernel machine regression and quantile g-computation was used to examine the joint effects, and increased levels of urinary concentrations of OH-PAHs and mPAEs were associated with elevated 8-hydroxy-2′-deoxyguanosine level and white blood cell counts. Exposure to polycyclic aromatic hydrocarbons contributed more significantly to inflammation, while exposure to phthalates contributed more to oxidative stress. Monoisobutyl phthalate was identified as the most significant metabolite contributing to elevated oxidative stress levels. 1-Hydroxypyrene was negatively associated with platelet, and monomethyl phthalate was significantly positively associated with interleukin 6 in multivariate linear regression. The restricted cubic spline analysis revealed non-linear patterns of 3-hydroxyfluorene with white blood cell, lymphocyte, neutrophil, and C-reactive protein. The results indicated significant associations between increased co-exposure to polycyclic aromatic hydrocarbons and phthalates with elevated oxidative stress and inflammation. Further investigation is needed to elucidate the underlying biological mechanisms and to determine the potential public health implications.

Modeling clothing as a secondary source of exposure to SVOCs across indoor microenvironments.

Evidence suggests that clothing can influence human exposure to semi-volatile organic compounds (SVOCs) through transdermal uptake and inhalation. The objectives of this study were [1] to investigate the potential for clothing to function as a transport vector and secondary source of gas-phase SVOCs across indoor microenvironments, [2] to elucidate how clothing storage, wear, and laundering can influence the dynamics of transdermal uptake, and [3] to assess the potential for multiple human occupants to influence the multimedia dynamics of SVOCs indoors. A computational modeling framework (ABICAM) was expanded, applied, and evaluated by simulating and augmenting two "real-world" chamber experiments. A primary strength of this framework was its representation of occupants and their clothing as unique entities with the potential for location changes. Estimates of transdermal uptake of diethyl phthalate (DEP) and di(n-butyl) phthalate (DnBP) were generally consistent with those extrapolated from measured concentrations of urinary metabolites, and those predicted by two other mechanistic models. ABICAM predicted that clean clothing (long sleeves, long pants, and socks, 100% cotton, 1 mm thick) readily accumulated DEP (6900-9700 μg) and DnBP (4500-4800 μg) from the surrounding chamber air over 6 h of exposure to average concentrations of 233 (DEP) and 114 (DnBP) μg·m-3. Because of their high capacity, clean clothing also effectively minimized transdermal uptake. In addition, ABICAM predicted that contaminated clothing functioned as a vector for transporting DEP and DnBP across indoor microenvironments and reemitted 13-80% (DEP) and 3-27% (DnBP) of the accumulated masses over 48 h. Though the estimated secondary inhalation exposures from contaminated clothing were low compared to the corresponding primary exposures, these secondary exposures could be accentuated in other contexts, for example, involving longer timeframes of clothing storage, multiple occupants wearing contaminated clothing, and/or repeated instances of clothing-mediated transport of contaminants (e.g., from an occupational setting). This modeling study reaffirms the effectiveness of clean clothing in reducing transdermal uptake of airborne SVOCs and conversely, that contaminated clothing could be a source of SVOC exposure via transdermal uptake and by acting as a vector for transporting those contaminants to other locations.

Maternal and newborn metabolomic changes associated with urinary polycyclic aromatic hydrocarbon metabolite concentrations at delivery: an untargeted approach.

Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.

Prenatal exposure to organophosphate esters and growth trajectory in early childhood

Maternal exposure to organophosphate esters (OPEs) has been linked to an increased risk of adverse birth outcomes. However, the impact of OPEs on childhood growth remains uncertain. This study assessed the associations between prenatal concentrations of OPE metabolites and the growth trajectory in early childhood. 212 singleton pregnant women were included in this study, and they were recruited between August 2014 and August 2016 in Wuhan, China. We measured the urinary concentrations of OPE metabolites during the 1st, 2nd, and 3rd trimesters. Standard deviation scores for weight and length were calculated for children at birth, 1, 6, 12, and 24 months. Trajectories of weight-for-age z-score (WAZ) and weight-for-length z-score (WLZ) were classified into four groups using group-based trajectory modeling. Trajectories of length-for-age z-score (LAZ) were classified into three groups with the same model. Then, we calculated odds ratios (ORs) and 95 % confidence interval (95%CI) using multinomial logistic regression to estimate increases in odds of different growth trajectories per doubling in OPE concentrations compared with moderate-stable trajectory. For average concentrations of OPE metabolites and growth trajectory, our results indicated that higher bis(2-butoxyethyl) phosphate, total aromatic OPE metabolites, and total OPE metabolites during pregnancy were associated with a higher likelihood of children falling into the low-stable and low-rising WAZ trajectory. Furthermore, compared to the moderate-stable LAZ trajectory, increased concentrations of 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate were linked to an elevated risk of a low-stable LAZ trajectory. Additionally, the 1st and 2nd trimesters may represent critical windows of heightened vulnerability to the effects of OPE metabolites on childhood growth. In conclusion, our study proves that prenatal exposure to OPE metabolites is inversely related to childhood growth. It is essential to conduct further research involving larger populations and to consider other compounds with known developmental toxicity to obtain more reliable and comprehensive results.

Maternal exposure to pyrethroid insecticides during pregnancy and respiratory allergy symptoms among children participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE)

BackgroundPyrethroid insecticides use for indoor residual spraying (IRS) in malaria-endemic areas results in high levels of exposure to local populations. Pyrethroids may cause asthma and respiratory allergies but no prior study has investigated this question in an IRS area. MethodsWe measured maternal urinary concentrations of pyrethroid metabolites (cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA) in samples collected at delivery from 751 mothers participating in the Venda Health Examination of Mothers, Babies, and their Environment (VHEMBE), a birth cohort study based in Limpopo, South Africa. At 3.5-year and 5-year follow-up visits, caregivers of 647 and 620 children, respectively, were queried about children's respiratory allergy symptoms based on validated instruments. We applied marginal structural models for repeated outcomes to estimate associations between biomarker concentrations and asthma diagnosis as well as respiratory allergy symptoms at ages 3.5 and 5 years. ResultsWe found that a10-fold increase in maternal urinary cis-DCCA, trans-DCCA and 3-PBA concentrations were associated with more than a doubling in the risk of doctor-diagnosed asthma (cis-DCCA: RR = 2.1, 95% CI = 1.3, 3.3; trans-DCCA: RR = 2.1, 95% CI = 1.1, 3.9; 3-PBA: RR = 2.4, 95% CI = 1.0, 5.8) and an about 80% increase in the risk of wheezing or whistling in the chest (cis-DCCA: RR = 1.8, 95% CI = 1.1, 3.0; trans-DCCA: RR = 1.7, 95% CI = 1.1, 2.6; 3-PBA: RR = 1.8, 95% CI = 1.0, 3.3) and suspected asthma (cis-DCCA: RR = 1.8, 95% CI = 1.1, 3.1; trans-DCCA: RR = 1.8, 95% CI = 1.1, 2.8). We also observed that higher concentrations of cis-DBCA and 3-PBA were related to increases in the risks of dry cough at night (RR = 3.5, 95% CI = 1.3, 9.5) and seasonal rhinoconjunctivitis (RR = 2.0, 95% CI = 1.1, 3.9), respectively. ConclusionMaternal exposure to pyrethroids may increase the risk of asthma and other respiratory allergy symptoms among preschool children from an IRS area.

Systemic inflammation mediates environmental polycyclic aromatic hydrocarbons to increase chronic obstructive pulmonary disease risk in United States adults: a cross-sectional NHANES study.

This study explored the relationship between environmental polycyclic aromatic hydrocarbons (PAHs) and Chronic obstructive pulmonary disease (COPD), and identified systemic inflammation as a mediator of the increased risk of COPD from PAHs. Data were obtained from 60,936 middle-aged and older Americans recruited in the National Health and Nutrition Examination Survey 2005-2016. Environmental PAHs were measured in terms of urinary concentrations of PAHs metabolites (NAP: 1-hydroxynaphthalene, FLU: 2-hydroxyfluorene, PA: 1-hydroxyphenanthrene, and PYR: 1-hydroxypyrene). We used multifactor logical analysis to figure out the link between PAHs and COPD, and the non-linear relationship was examined using Restricted cubic spline. Spearman correlation analysis was utilized to analyze the connection between PAHs and systemic immune-inflammation index (SII). The results showed that the COPD population had higher NAP (3.550 vs. 3.282, p < 0.001), FLU (2.501 vs. 2.307, p < 0.001), PA (2.155 vs. 2.082, p = 0.005), and PYR (2.013 vs. 1.959, p = 0.008) levels than non-COPD population. In unadjusted logistics analysis, the risk of COPD with log NAP was higher [OR = 1.461, 95% CI (1.258-1.698), p < 0.001]. Upon taking into account, confounders like sex, age, race, and log NAP still increased a possible COPD risk [OR = 1.429, 95% CI (1.224-1.669), p < 0.001]. Similarly, FLU, PA, and PYR significantly increased the risk of COPD (all OR > 1, p < 0.05), both unadjusted and adjusted. Furthermore, Restricted cubic spline demonstrated a strong link between PAHs levels and COPD risk (p < 0.05). Additionally, a Spearman correlation analysis revealed a favorable association between log FLU and log SII (R = 0.43, p = 0.006), while NAP, PA, and PYR levels were not associated with log SII (all p > 0.05). Ultimately, the mediating effect analysis revealed a mediating effect capacity of 5.34% for the SII-mediated association between FLU and COPD. The findings suggest that the risk of COPD is significantly increased when environmental PAHs exposure is at high levels, and that systemic inflammation may be involved in the process.