Urinary Metabolite Levels Research Articles

Tackling new psychoactive substances through metabolomics: UHPLC-HRMS study on natural and synthetic opioids in male and female murine models

Novel psychoactive substances (NPS) represent a broad class of drugs new to the illicit market that often allow passing drug-screening tests. They are characterized by a variety of structures, rapid transience on the drug scene and mostly unknown metabolic profiles, thus creating an ever-changing scenario with evolving analytical targets. The present study aims at developing an indirect screening strategy for NPS monitoring, and specifically for new synthetic opioids (NSOs), based on assessing changes in endogenous urinary metabolite levels as a consequence of the systemic response following their intake. The experimental design involved in-vivo mice models: 16 animals of both sex received a single administration of morphine or fentanyl. Urine was collected before and after administration at different time points; the samples were then analysed with an untargeted metabolomics LC-HRMS workflow. According to our results, the intake of opioids resulted in an elevated energy demand, that was more pronounced on male animals, as evidenced by the increase in medium and long chain acylcarnitines levels. It was also shown that opioid administration disrupted the pathways related to catecholamines biosynthesis. The observed alterations were common to both morphine and fentanyl: this evidence indicate that they are not related to the chemical structure of the drug, but rather on the drug class. The proposed strategy may reinforce existing NPS screening approaches, by identifying indirect markers of drug assumption.

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.

ENDOTHELIAL DYSFUNCTION AND GASTROESOPHAGEAL REFLUX DISEASE: STUDY OF COMMON PATHOGENETIC MECHANISMS AND WAYS OF CORRECTION

The aim. To determine the role and place of endothelial dysfunction in the pathogenesis of comorbid gastroesophageal reflux disease (GERD) and obesity by studying the levels of nitric oxide (NO) metabolites in blood and urine. To evaluate the efficacy and benefits of the prescribed therapy, which included the additional inclusion of a peptide compound analogous to leu-enkephalin tyrosine-2-alanine-glycine-phenylalanine-leucyl-arginine diacetate (Dalargin).
 Materials and methods. Clinical manifestations were assessed using the GERD-HRQL questionnaire, levels of stable nitric oxide metabolites NO2 and total metabolites NO2 + NO3 were determined by spectrophotometric method, leptin levels were determined by enzyme-linked immunosorbent assay, pH-metry and motor function was studied by ultrasound. 130 patients were examined, including 70 patients with GERD with comorbid obesity of the first degree, 40 patients with GERD without concomitant pathology and 20 healthy individuals. The study was divided into 3 groups.
 Results. It was determined that the levels of stable metabolites NO2, NO2 + NO3 in blood and urine in the group of GERD with obesity are significantly lower than in the group of isolated GERD (p<0.001). A direct correlation between the level of nitric oxide metabolites in blood and urine and acidity in the stomach and oesophagus was established; an inverse relationship between NO metabolites and the degree of gastrointestinal motor and functional disorders, the severity of clinical manifestations, and the level of hormonal secretion by adipocytes. The supplemental inclusion of Dalargin improved the effectiveness and quality of pathogenetic therapy and achieved a more positive disease dynamics and is recommended for prescription in practice.
 Conclusions. Obesity is a predictor of a more severe course of GERD and more severe endothelial dysfunction. There is a correlation between the severity of endothelial dysfunction and the degree of functional, motor and secretory disorders of the stomach and oesophagus.

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.

Exposure to biocides and its association with atopic dermatitis among children and adolescents: A population-based cross-sectional study in South Korea

BackgroundBiocides have emerged as a contributor to the rising cases of atopic dermatitis among children and adolescents. Previous animal studies suggested that phenols, parabens, and pyrethroid insecticides present in these products might play a role in atopic dermatitis. However, there's limited epidemiological evidence confirming the individual or combined effects of exposure to these chemicals on atopic dermatitis in young populations. This study aimed to investigate the association between phenol, paraben, and pyrethroid metabolite levels in urine and atopic dermatitis among Korean children and adolescents MethodsWe analyzed 556 preschool children (3–5 years), 701 schoolchildren (6–11 years), and 731 adolescents (12–17 years) enrolled in the 4th Korean National Environmental Health Survey (KoNEHS) (2018–2020). We used logistic regression and Bayesian kernel machine regression to evaluate the association between atopic dermatitis and individual or mixed exposure to urinary triclosan (TCS), parabens (methylparaben, ethylparaben, propylparaben, and butylparaben), and 3-phenoxybenzoic acid (3-PBA) levels. ResultsUrinary TCS levels were positively associated with atopic dermatitis in schoolchildren. When stratified by sex, male schoolchildren exhibited an increasing prevalence of atopic dermatitis as their urinary TCS and 3-PBA levels increased. The combined effect of biocide mixtures on atopic dermatitis was also significantly increased in male schoolchildren, with TCS as the main contributor. ConclusionsThese study findings suggest that biocides at levels found in Korean children and adolescents affect atopic dermatitis.

Urinary biomarkers of exposure to organophosphate, pyrethroid, neonicotinoid insecticides and oxidative stress: A repeated measurement analysis among pregnant women

Exposure to insecticides may be associated with increased oxidative stress (OS), but few studies have assessed the associations of OS biomarkers (OSBs) with exposure to multiple insecticides and their mixture, especially in pregnant women who are a vulnerable population. In the present study, 1,094 Chinese pregnant women were recruited and a total of 3,282 urine samples were collected at their three trimesters to measure eight metabolites of organophosphates, three metabolites of pyrethroids, nine typical neonicotinoids/their metabolites, and three OSBs of DNA damage (8-OHdG), RNA damage (8-OHG), and lipid peroxidation (HNE-MA). Among the twenty target insecticide metabolites, sixteen of them were frequently detected; thirteen of them were detected in over 86% of all the urine samples except for imidacloprid (IMI, detection frequency: 72.9%), desnitro-imidacloprid (DN-IMI, 70.0%), and clothianidin (CLO, 79.6%). The reproducibility of their concentrations across the three trimesters was poor to fair (intraclass correlation coefficients <0.50). Multiparity and warm season were related to higher urinary levels of some insecticide metabolites, while higher education level and inadequate weight gain during pregnancy were significantly associated with lower concentrations of certain insecticide metabolites. Linear mixed model analyses suggested that almost all the frequently detected insecticide metabolites [other than 3-phenoxybenzoic acid (3-PBA)] were significantly associated with elevated levels of the three OSBs (8-OHdG, 8-OHG, and HNE-MA), where the percent change (Δ%) ranged 8.10–36.0% for 8-OHdG, 8.49–34.7% for 8-OHG, and 5.92–182% for HNE-MA, respectively, with each interquartile ratio (IQR)-fold increase in the concentrations of the individual exposure biomarkers. Weighted quantile sum models demonstrated that the insecticide metabolite mixture was positively associated with the three OSBs. Overall, urinary desmethyl-clothianidin (DM-CLO) and 3,5,6-trichloro-2-pyridinol (TCPy) were the top insecticide exposure biomarkers contributing to the association with 8-OHdG and 8-OHG levels, while PNP contributed the most to the association with HNE-MA levels. These findings suggested that gestational exposure to organophosphates, pyrethroids, neonicotinoids, their transformation products, and their mixture may increase oxidative damage to lipids, RNA, and DNA during pregnancy.

Evaluation of urinary limonene metabolites as biomarkers of exposure to greenness

Exposure to plants is known to improve physical and mental health and living in areas of high vegetation is associated with better health. The addition of quantitative measures of greenness exposure at individual-level to other objective and subjective study measures will help establish cause-and-effect relationships between greenspaces and human health. Because limonene is one of the most abundant biogenic volatile organic compounds emitted by plants, we hypothesized that urinary metabolites of inhaled limonene can serve as biomarkers of exposure to greenness. To test our hypothesis, we analyzed urine samples collected from eight human volunteers after limonene inhalation or after greenness exposure using liquid chromatography-high resolution mass spectrometry-based profiling. Eighteen isomers of nine metabolites were detected in urine after limonene inhalation, and their kinetic parameters were estimated using nonlinear mixed effect models. Urinary levels of most abundant limonene metabolites were elevated after brief exposure to a forested area, and the ratio of urinary limonene metabolites provided evidence of recent exposure. The identities and structures of these metabolites were validated using stable isotope tracing and tandem mass spectral comparison. Together, these data suggest that urinary metabolites of limonene, especially uroterpenol glucuronide and dihydroperillic acid glucuronide, could be used as individualized biomarkers of greenness exposure.

The East Bay Diesel Exposure Project: a biomonitoring study of parents and their children in heavily impacted communities

Abstract Background Diesel exhaust (DE) exposures pose concerns for serious health effects, including asthma and lung cancer, in California communities burdened by multiple stressors. Objective To evaluate DE exposures in disproportionately impacted communities using biomonitoring and compare results for adults and children within and between families. Methods We recruited 40 families in the San Francisco East Bay area. Two metabolites of 1-nitropyrene (1-NP), a marker for DE exposures, were measured in urine samples from parent–child pairs. For 25 families, we collected single-day spot urine samples during two sampling rounds separated by an average of four months. For the 15 other families, we collected daily spot urine samples over four consecutive days during the two sampling rounds. We also measured 1-NP in household dust and indoor air. Associations between urinary metabolite levels and participant demographics, season, and 1-NP levels in dust and air were evaluated. Results At least one 1-NP metabolite was present in 96.6% of the urine samples. Detection frequencies for 1-NP in dust and indoor air were 97% and 74%, respectively. Results from random effect models indicated that levels of the 1-NP metabolite 6-hydroxy-1-nitropyrene (6-OHNP) were significantly higher in parents compared with their children (p-value = 0.005). Urinary 1-NP metabolite levels were generally higher during the fall and winter months. Within-subject variability was higher than between-subject variability (~60% of total variance versus ~40%, respectively), indicating high short-term temporal variability. Impact Biomonitoring, coupled with air monitoring, improves understanding of hyperlocal air pollution impacts. Results from these studies will inform the design of effective exposure mitigation strategies in disproportionately affected communities.

Relationship between endocrine disrupting chemicals (phthalate metabolites, triclosan and bisphenols) and vitamin D in female subjects: An exploratory pilot study

IntroductionEvidence suggests that endocrine disrupting chemicals (EDCs), commonly used in plastics and personal care products, may be associated with reduced levels of vitamin D. Therefore, this study examined the relationship between phthalate metabolites, 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan; TCS) and bisphenols (BPs) with vitamin D3 (25(OH)D3) and active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), and their relationship to calcium homeostasis. Methods57 female participants (age 31.8 ± 4.6 years; BMI 25.6 ± 3.7 kg/m2) were analyzed for urinary levels of phthalate metabolites, TCS and BPs, and serum levels of 25(OH)D3 and 1,25(OH)2D3, determined by isotope-dilution liquid chromatography tandem mass spectrometry. Serum calcium/calmodulin-dependent (CaM) associated proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan. ResultsIn the study cohort, 25(OH)D3 and 1,25(OH)2D3 levels were 22.9 ± 11.2 ng/mL and 0.05 ± 0.02 ng/mL, respectively: mono-3-carboxypropyl-phthalate (MCPP) correlated negatively with 25(OH)D3 (ρ = −0.53, p = 0.01). 28 of the 57 women recruited were 25(OH)D3 deficient, <20 ng/mL (50 nmol/L): in this group, mono-iso-butylphthalate (MiBP) and mono-butylphthalate (MBP) negatively correlated with 25(OH)D3; (ρ = −0.47, p = 0.049) and (ρ = −0.64, p = 0.005), respectively. EDCs did not correlate with 1,25(OH)2D3, measures of renal function or CaM proteins. ConclusionThese putative data indicate that MCPP is related to 25(OH)D3, while MiBP and MBP were related to vitamin D deficiency; however, no correlations were observed with TCS and BPs. No phthalate metabolites correlated with 1,25(OH)2D3, CaM associated proteins or renal function, suggesting that effects occur earlier in the vitamin D pathway and not through modulation of cellular calcium flux. The observed correlations are surprisingly strong compared to other predictors of 25(OH)D3, and larger studies adjusting for potential confounders are warranted.

The role of estrogen receptors (ERs)-Notch pathway in thyroid toxicity induced by Di-2-ethylhexyl phthalate (DEHP) exposure: Population data and in vitro studies

BackgroundThis study aimed to assess the exposure level and risk of Di-2-ethylhexyl Phthalate (DEHP) among adults in Jilin Province, China, clarify the impact of DEHP on human thyroid function, and to explore the role of estrogen receptors (ERs)-Notch signaling pathway in the effect of DEHP metabolites on thyroid hormones based on population data and in vitro experiments. Methods312 adults participated in this study. Urinary DEHP metabolites were determined by high performance liquid chromatography coupled to a tandem mass spectrometer (HPLC-MS/MS). Two pharmacokinetic models were used to evaluate the estimated daily intake (EDI) and hazard quotient (HQ) of the adults. Multiple linear regression and mediating effect models were used to evaluate the target associations. In cell experiments, thyroid follicular epithelial (Nthy-ori3–1) cells were exposed to mono (2-ethylhexyl) phthalate (MEHP) for testing. The inhibitions of ERα and Notch pathway were conducted by siRNA and Notch pathway inhibitor DAPT. ResultsThe detection rate of five DEHP metabolites was 97.1∼100.0%. The HQ value of 0.3% of adults was higher than 1. The levels of urinary DEHP metabolites were significantly correlated with thyrotropin (TSH), thyrotropin-releasing hormone (TRH), total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3) and free thyroxine (FT4) and gene (estrogen receptor α (ERα), Notch1, Dll4) levels. The ERα-Notch pathway played a mediating role in the association between DEHP metabolite levels and FT4. The cell results showed, the levels of FT3 and FT4 in cell supernatant decreased after MEHP exposure, and the downward trend was reversed after ERα and notch pathways were inhibited, notch pathway genes also decreased after ERα inhibition. ConclusionAdults in the Jilin Province of China were widely exposed to DEHP. ERs-Notch pathway played an important role in the effect of DEHP metabolites on thyroid hormones.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): , 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: , 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Antioxidant, Antistress, Nootropic activity and its Correlation studies of aqueous extract of Punica granatum fruit estimated by Noninvasive biomarkers and Y-maze test in rodents

The memory loss associated with increased oxidative stress due to increased level of free radicals. Oxidative stress has been involved in several diseases includes cancer, atherosclerosis and neurodegenerative diseases.This study aimed to estimate the correlation of antioxidant and antistress activity with nootropic activity of aqueous extract of pomegranate (Punica granatum) by in-vivo noninvasive studies using rats. The in-vitro antioxidant activity was determined based on the ability of the Punica granatum to scavenge free radicals and lipid peroxidation inhibiting activity. The antistress effect of the aqueous extract of Punica granatum for 24h treatment (100 and 300mg/kg, p.o.) was evaluated by using the forced swim stress test in rats. The 24h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and ascorbic acid (AA) was determined in all groups under normal and stressed conditions by HPLC and spectrophotometric methods in all groups, were selected as noninvasive biomarkers. Nootropic activity activities of Punica granatum fruit extract were estimated as locomotor and working memory in rats in a Y-maze apparatus. Administration of aqueous extract of Punica granatum at a dose of 100 and 300mg/kg reduced the urinary metabolite levels. Punica granatum treatment showed significant dose dependent variation in non-invasive biomarker levels in urine samples of rats taken after 24h. The treatment with Punica granatum extracts improved the percentage entry of rats into safer zone, it means acquisition (learning) retention and retrieval (memory) were improved in rats compared to stress controls. Cognition determined by working memory and locomotor activity results were shown to be dose-dependent. The results of this study strongly suggestedantioxidant, antistress and nootropic activity effect of Punica granatumin rodents were correlated. The data obtained were analyzed by one-way ANOVA followed bytukey test. p&lt;0.05 was considered to be significant. There is substantial evidence that flavonoids play an active role in providing antioxidant, antistress and nootropic activities of Punica granatum extracts. The findings of the present investigations indicate that the Punica granatum has significant antistress activity, which may be due to the immunostimulating property and increased resistance, nonspecifically, against all experimental stress conditions. The study provided scientific evidence for their utility as nootropic agents and to advocate their use in foods.

Bioavailability and excretion profile of betacyanins – Variability and correlations between different excretion routes

The present study addresses the knowledge gap in betalain bioavailability, transformation and excretion. Analysis of renal and fecal excretion profiles in humans after consumption of beetroot revealed very low bioavailability (renal recovery of 0.13 %) and fast elimination of pigments (renal elimination rate constant of 0.16 h−1), while the majority of betalains underwent severe depletion during GI transit, evidenced by decarboxylation, deglucosidation and dehydrogenation. Betacyanin metabolite levels in human urine were positively associated with those in stools (p < 0.05), indicating significant impact of pigment metabolism in the gut on their bioavailability. In addition, the current study revealed large inter-individual and compositional variabilities of pigment after colonic fermentation compared with systemic metabolism, likely attributed to the increasing complexity of intestinal environment with diverse gut microbiota. To conclude, intestinal uptake and systemic metabolism of betacyanins are intimately associated with their intestinal biotransformation, with gut microbiota serving as a crucial factor.

Childhood exposure to pyrethroids and neurodevelopment in Canadian preschoolers

BackgroundPyrethroid insecticides are used both residentially and agriculturally and their toxicity targets the nervous system of insects. They might also interfere with development and function of the human brain. A few epidemiological studies suggest that exposure to pyrethroids may be associated with neurobehavioral problems in children but there is little data on potential associations with cognitive outcomes. Furthermore, many studies showed that the neurotoxic effects of several pesticides are modified by sex, hence, considerations of potential sex-differences are important to investigate. ObjectiveTo study the cross-sectional association between urinary levels of pyrethroid metabolites and neurodevelopment, including neurobehavioral and cognitive outcomes, in preschool-age children, and to examine whether sex might modify these associations. MethodsWe used data from a follow-up examination of the Maternal-Infant Research on Environmental Chemicals (MIREC), the MIREC Child Development study (MIREC-CD Plus) on children at age 3–4 years living in 6 Canadian cities. For each participant, we collected a urine sample for measurements of pyrethroids metabolites (cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA, 4-F-3-PBA). We assessed neurodevelopment with the Wechsler Primary and Preschool Scale of Intelligence–III (WPPSI-III) and two scales of the Behavior Rating Inventory of Executive Function–Preschool (BRIEF-P). Parents reported children’s behavior using the Behavior Assessment System for Children–2 (BASC-2) and the Social Responsiveness Scale-2 (SRS-2). We examined associations between children’s urinary pyrethroid metabolite concentrations and neurodevelopmental scores with multiple linear regression models, adjusting for confounders, in boys and girls separately. ResultsThe study included 179 children (mean age: 3.2 y, range 2.8–4.0). The detection frequencies were high for most pyrethroid metabolites (83–100%), but lower for 4-F-3-PBA (36%). Higher concentrations of cis-DBCA were significantly associated with lower verbal, performance and full-scale IQ scores in boys (e.g., for a 2-fold increase in cis-DBCA, β = −2.0; 95% CI: −3.4, −0.6 for full-scale IQ). In girls, the only metabolite associated with cognitive scores was 3-PBA, which was associated with lower verbal IQ scores (β = −1.3, 95% CI: −2.6, −0.1). For neurobehavioral outcomes in boys, there were associations between poorer BASC-2 Adaptive Skills scores with higher concentrations of cis-DCCA (β = −1.6, 95% CI: −2.3, −0.9), trans-DCCA (β = −1.5, 95% CI: −2.2, −0.8), 3-PBA (β = −1.7, 95% CI: −2.5, −0.9), and sum of pyrethroid metabolites (β = −1.8, 95% CI: −2.6, −0.9). In girls, we observed a significant association between higher concentration of cis-DCCA and better BASC-2 Adaptive Skills score (β = 1.0; 95% CI, 0.2, 1.8), but not with other urinary pyrethroids metabolites. Scores on the SRS-2 and BRIEF-P were not associated with pyrethroid metabolites. ConclusionThere were associations between some pyrethroid pesticide metabolites and indicators of neurodevelopmental disorder, especially among boys. These associations are in agreement with previous studies and could suggest that exposure to pyrethroid pesticides represents a risk of potential toxicity for the cognitive development of children, and a risk for behavioral development. However, the cross-sectional nature of this study limits causal inferences.

Dietary Inflammatory Potential and the Risk of Serrated and Adenomatous Colorectal Polyps

Studies of dietary inflammation potential and risks of colorectal cancer precursors are limited, particularly for sessile serrated lesions (SSLs). This study examines the association using the energy-adjusted dietary inflammatory index (E-DIITM), a measure of anti- and/or pro-inflammatory diet, in a large US colonoscopy-based case-control study of 3246 controls, 1530 adenoma cases, 472 hyperplastic polyp cases, and 180 SSL cases. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression models. Analyses were stratified by participant characteristics, and urinary prostaglandin E2 metabolite (PGE-M) and high-sensitivity plasma C-reactive protein (hs-CRP) levels, inflammation biomarkers. Highest E-DII™ intake was associated with significantly increased risks of colorectal adenomas (OR 1.36, 95% CI 1.11, 1.67), and hyperplastic polyps (OR 1.43, 95% CI 1.06, 1.98), compared with participants consuming the lowest E-DII™ quartile. A similar, but non-significant, increased risk was also observed for SSLs (OR 1.41, 95% CI 0.82, 2.41). The positive association was stronger in females (pinteraction <0.001), normal weight individuals (ptrend 0.01), and in individuals with lower inflammatory biomarkers (ptrend 0.02 and 0.01 for PGE-M and hs-CRP, respectively). A high E-DII™ is associated with colorectal polyp risk, therefore promoting an anti-inflammatory diet may aid in preventing colorectal polyps.

Maternal di-(2-ethylhexyl) phthalate exposure elicits offspring IFN-λ upregulation: Insights from birth cohort, murine model, and in vitro mechanistic analysis.

Maternal exposure to di-(2-ethylhexyl)-phthalate (DEHP), an environmental endocrine disruptor, may lead to developmental immunotoxicity in offspring. The causal relationship and underlying mechanism require further study. A subset of Taiwan Maternal and Infant Cohort Study data (n=283) was analyzed and found a significant association between urinary DEHP metabolite levels from the third trimester of pregnancy and plasma levels of IL-28A and IL-29, named IFNλs, in cord blood. A trans-maternal murine model mimicking human DEHP exposure way showed that bone marrow-derived dendritic cells from maternal DEHP-exposed F1 offspring secreted higher IL-28A levels than control cells, indicating a potential causal relationship. Human bronchial epithelial cell lines treated with DEHP or its primary metabolite, mono-(2-ethyl-5-hexyl) phthalate (MEHP), expressed significantly higher levels of IFNλs mRNA or protein than controls. MEHP's effect on IFNλs expression was blocked by peroxisome proliferator-activated receptor α (PPARα) and PPARγ antagonists, and inhibited by a histone acetyltransferase inhibitor or a histone methyltransferase inhibitor. Chromatin immunoprecipitation assay showed that MEHP treatment promoted histone modifications at H3 and H4 proteins at the promoter regions of Il28a and Il29 genes. These results suggest maternal DEHP exposure could result in high IFNλ expression in offspring, and the health risk of early-life exposure requires further investigation.

Development and validation of an HPLC-MS/MS method for the simultaneous analysis of volatile organic compound metabolites, hydroxylated polycyclic aromatic hydrocarbons, and 8-hydroxy-2′-deoxyguanosine in human urine

Humans are widely and concurrently exposed to volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs). However, few studies have reported the internal co-exposure levels of these chemicals in occupational and general populations. Specifically, the associations revealed between the urinary levels of metabolites of VOCs (mVOCs), hydroxylated PAHs (OH-PAHs), and oxidative stress biomarkers for humans remain limited. In this study, a method based on solid-phase extraction (SPE) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed for the simultaneous analysis of 22 mVOCs, 12 OH-PAHs, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in human urine samples. The method was validated with all target analyte accuracies and precisions in the range of 76 %–120 % and 1 %–14 % at three levels of spiked urine samples, respectively. The limit of detection (LOD) and limit of quantification (LOQ) of the target analytes were 0.01–0.34 ng/mL and 0.01–7.57 ng/mL, respectively. And the method was applied to measure urinary levels of target analytes from 38 petrochemical workers in Guangzhou, South China. Except for 3-hydroxy-benzo[a]pyrene, all target analytes were detected in the urine samples. The average levels were 0.05–12.6 ng/mL for individual OH-PAHs, 0.20–73620 ng/mL for individual mVOCs, and 1.00 ng/mL for 8-OHdG. Additionally, 3-hydroxy-phenanthrene, 1-hydroxy-pyrene, 6-hydroxy-chrysene, N-acetyl-S-(trichlorovinyl)-L-cysteine, 2-methylhippuric acid, thiodiacetic acid, trans, trans-Muconic acid, and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine had statistically significant positive effects on 8-OHdG levels, while 1-hydroxy-naphthalene, 1,2-dihydroxybenzene, and hippuric acid showed a negative effect on 8-OHdG, indicating these metabolites could lead to synergistic or antagonistic oxidative DNA damage. This study provides a robust analytical method that permits a comprehensive assessment of co-exposure to PAHs and VOCs and their potential adverse health effects.

Assessment of the plasticizer exposure of hospital workers regularly handling medical devices: A pilot study

Plastic medical devices, e.g. infusion sets, blood bags or tubing material, that are used manifold in the medical treatment of hospital patients, usually contain considerable amounts of plasticizers. Whereas several studies showed highly elevated inner plasticizer levels of patients treated with plasticized medical devices, little is known about the exposure situation of hospital staff. The present pilot study aimed to evaluate the urinary plasticizer metabolite levels of selected hospital workers of the blood bank (medical technical assistants, MTA) and of perfusionists that are regularly handling plasticized medical devices in order to estimate the work-related amount of the inner individual plasticizer exposure. The study subjects were asked to collect pre- and post-shift spot urine samples over the course of a working week, that were subsequently analyzed for selected urinary metabolites of the plasticizers DEHP, DINCH, DEHTP and TEHTM. Although the observed differences were rather low, a differentiated approach revealed a perceptible impact of the respective workplace environment on the individual urinary plasticizer metabolite levels. Thus, the group of blood bank MTA showed significantly elevated increment levels of urinary DEHP and DINCH metabolites, while the group of perfusionists, showed a considerable higher detection frequency of the main urinary TEHTM metabolite. All in all, however, it can be cautiously concluded by the results of the presented pilot study that a regular handling of plasticized medical devices by hospital employees (via inhalation or dermal contact) contributes demonstrably but yet only marginally to the individual internal plasticizer exposure.

Metyrosine-associated endocrinological changes in pheochromocytoma and paraganglioma.

Metyrosine (alpha-methyl-para-tyrosine) effectively reduces catecholamine levels in patients with pheochromocytoma/paraganglioma. However, improvements in physiological and metabolic parameters and changes in endocrine function associated with metyrosine administration should be validated in comparison to surgery. This study was performed to confirm the effects of metyrosine on the physiological, metabolic, and endocrinological functions of patients with pheochromocytoma/paraganglioma in the perioperative period. This retrospective cohort study was performed at a single university hospital. We included ten patients with pheochromocytoma/paraganglioma who received oral metyrosine after α-blocker therapy and consecutive surgeries. Urinary catecholamine metabolite levels and other clinical parameters were evaluated before and after metyrosine administration, and 1 week after surgery. The mean age was 53.1 ± 16.1 years. Of the ten participants (four men and six women), nine had pheochromocytoma and one had paraganglioma. The median maximum metyrosine dose was 750 mg/day. Urinary catecholamine metabolite levels significantly decreased in a dose-dependent manner after metyrosine administration. Both systolic and diastolic blood pressure significantly decreased after metyrosine and surgical treatment. Metyrosine administration significantly improved insulin sensitivity, although surgery improved the the basal insulin secretion. Additionally, serum prolactin and thyroid-stimulatory hormone levels were significantly increased by metyrosine treatment, whereas plasma renin activity was decreased. Metyrosine significantly reduced catecholamines in patients with pheochromocytoma/paraganglioma and ensured the safety of the surgery. Adjustment of metyrosine administration may make surgical pretreatment more effective in achieving stabilized blood pressure and improving glucose metabolism. Endocrine parameters may manifest as the systemic effects of metyrosine administration.

Air, Dermal, and Urinary Metabolite Levels of Backpack and Tractor Sprayers Using the Herbicide Acetochlor in Thailand.

Acetochlor is a chloroacetanilide selective pre-emergent herbicide used for controlling grass and broadleaf weeds in crops. This study compared the acetochlor exposures of backpack and tractor sprayers and assessed whether dermal or air exposures were more important contributors to the overall body burden as measured by urinary metabolites. Sixty sugarcane farmers in Nakhonsawan province, Thailand participated in the study, and breathing zone air and dermal patch samples were collected during spraying. Urine samples were collected before spraying, at the end of the spraying task, and on the day after spraying. For backpack and tractor sprayers, there was no significant difference in their breathing zone air concentrations, total body dermal samples, or urinary 2-methy-6-methyaniline (EMA) concentrations on the day after spraying. In addition, although most backpack and tractor sprayers wore long pants and long sleeve shirts, they were still exposed to acetochlor, as evidenced by a significant increase in the urinary EMA from before spraying (GM = 11.5 µg/g creatinine) to after spraying (GM = 88.5 µg/g creatinine) to the next day (GM = 111.0 µg/g creatinine). Breathing zone air samples were significantly correlated with those of total body dermal patch samples and with urinary EMA concentrations after spraying. This suggests that both air and dermal exposure contribute to urinary EMA levels.