Metabolite Exposure Research Articles

Population Pharmacokinetics of Intravenous Paracetamol and Its Metabolites in Extreme Preterm Neonates in the Context of Patent Ductus Arteriosus Treatment.

Our aim was to describe the pharmacokinetics of paracetamol and its metabolites in extreme preterm neonates in the context of patent ductus arteriosus treatment. Factors associated with inter-individual variability and metabolic pathways were studied. The association between drug exposure and clinical outcomes were investigated. Preterm neonates of 23-26 weeks' gestational age received paracetamol within 12 h after birth. Plasma concentrations of paracetamol and its metabolites were measured throughout 5 days of treatment. Clinical success was defined as ductus closure on two consecutive days or at day 7. Aspartate aminotransferase and alanine aminotransferase levels were used as surrogates for liver damage. Data from 30 preterm neonates were available for pharmacokinetic analysis. Paracetamol pharmacokinetics were described using a two-compartment model with significant positive effects of weight on clearance and of birth length on peripheral compartment volume. Paracetamol was mainly metabolised into sulphate (89%) then glucuronide (6%), and the oxidative metabolic pathway was reduced (4%). The glucuronidation pathway increased with gestational age, whereas the sulfation pathway decreased. No difference was observed in drug exposure between successful and unsuccessful patients. No increase in aspartate aminotransferase and alanine aminotransferase levels were observed during treatment, and no association was found with either paracetamol or oxidative metabolite exposures. The relative proportions of the metabolic pathways were characterised with gestational age. In the range of observed drug exposures, no association was found with clinical response or liver biomarkers. These findings may suggest that paracetamol concentrations were within the range that already guarantee a maximum effect on ductus closure.

Efficacy of Bd metabolite prophylaxis dose and duration on host defence against the deadly chytrid fungus Batrachochytrium dendrobatidis

Abstract Batrachochytrium dendrobatidis (Bd), an aquatic pathogenic fungus, is responsible for the decline of hundreds of amphibian species worldwide and negatively impacts biodiversity globally. Prophylactic exposure to the metabolites produced by Bd can provide protection for naïve tree frogs and reduce subsequent Bd infection intensity. Here, we used a response surface design crossing Bd metabolite prophylaxis concentration and exposure duration to determine how these factors modulate prophylactic protection against Bd in Pacific chorus frog (Pseudacris regilla) tadpoles (5 × 5 surface design) and metamorphs (3 × 3 surface design). We exposed individuals every weekday to one of five Bd metabolite concentrations or a water control for 1–5 weeks, after which all animals were challenged with live Bd to evaluate their susceptibility. Exposure to the Bd metabolite prophylaxis reduced Bd load and prevalence compared to the control for both the tadpoles and metamorphs. Increasing Bd metabolite prophylaxis concentration did not confer additional protection for either life stage, but increasing duration of exposure did benefit metamorphs by decreasing Bd prevalence but not Bd load. On average, control tadpoles and metamorphs had 66.2% and 99.4% higher Bd loads, respectively, than tadpoles and metamorphs exposed to any Bd metabolite prophylaxis. Additionally, Bd metabolite prophylaxis reduced Bd prevalence relative to controls in both tadpoles (20.5% vs. 56.3%, respectively) and metamorphs (21.9% vs. 87.5%, respectively). Synthesis and applications: The efficacy of short‐term exposures of relatively low concentrations of Bd metabolites at reducing Bd infections suggests that this approach has the potential to be scaled up to field use to aid in disease mitigation and conservation. Our results, combined with additional research on Bd metabolite prophylaxis for other amphibian species, suggest that this strategy may represent a broadly useful tool to protect at‐risk amphibian populations.

Detection and Quantification of Drug-Protein Adducts in Human Liver.

Covalent protein adducts formed by drugs or their reactive metabolites are risk factors for adverse reactions, and inactivation of cytochrome P450 (CYP) enzymes. Characterization of drug-protein adducts is limited due to lack of methods identifying and quantifying covalent adducts in complex matrices. This study presents a workflow that combines data-dependent and data-independent acquisition (DDA and DIA) based liquid chromatography with tandem mass spectrometry (LC-MS/MS) to detect very low abundance adducts resulting from CYP mediated drug metabolism in human liver microsomes (HLMs). HLMs were incubated with raloxifene as a model compound and adducts were detected in 78 proteins, including CYP3A and CYP2C family enzymes. Experiments with recombinant CYP3A and CYP2C enzymes confirmed adduct formation in all CYPs tested, including CYPs not subject to time-dependent inhibition by raloxifene. These data suggest adducts can be benign. DIA analysis showed variable adduct abundance in many peptides between livers, but no concomitant decrease of unadducted peptides. This study sets a new standard for adduct detection in complex samples, offering insights into the human adductome resulting from reactive metabolite exposure. The methodology presented will aid mechanistic studies to identify, quantify and differentiate between adducts that result in adverse drug reactions and those that are benign.

Effects of single and combined urinary polycyclic aromatic hydrocarbon effects on lung function in the U.S. adult population

BackgroundThe impact of polycyclic aromatic hydrocarbons (PAHs) on lung function has garnered attention, but studies mostly focus on individual effect. This study investigates urinary PAH metabolites as biomarkers of exposure and assesses the relationships between single and combined exposures to nine urinary PAH metabolites and lung function in adults.MethodsData from 4040 adults in the 2007–2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Weighted generalized linear models estimated the effects of individual PAH metabolites on lung function. Additionally, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) were employed to evaluate the combined impacts of multiple PAH metabolites.ResultsAnalyses of individual PAH metabolites revealed negative associations with lung function, excluding forced vital capacity (FVC). The WQS, qgcomp, and BKMR models consistently showed that exposure to multiple PAH metabolites was associated with lung function decrease. WQS indicated that 2-hydroxynaphthalene (2-NAP) was the largest contributor to the reductions in forced expiratory volume in 1 s (FEV1), FVC, peak expiratory flow (PEF), and forced expiratory flow from 25 to 75% of FVC (PEF25-75%). Additionally, 1-hydroxypyrene (1-PYR) was the primary PAH metabolite contributing to the decreases in FEV1/FVC and fractional exhaled nitric oxide (FeNO). The combined effect of urinary PAH metabolites did not affect FVC in the current smokers or FeNO in nonsmokers, but decreased FEV1/FVC in current smokers.ConclusionThis study strengthens the negative relationships between multiple PAH metabolites exposure and lung function in adults. Given the limitations of this study, including the lack of knowledge of other exposure pathways and the uncertainty of urinary metabolites, further research is necessary to explore the mechanisms underlying these associations and to address the limitations in exposure assessment.

Associations between Urinary Phthalate Metabolites with BDNF and Behavioral Function among European Children from Five HBM4EU Aligned Studies.

Based on toxicological evidence, children's exposure to phthalates may contribute to altered neurodevelopment and abnormal regulation of brain-derived neurotrophic factor (BDNF). We analyzed data from five aligned studies of the Human Biomonitoring for Europe (HBM4EU) project. Ten phthalate metabolites and protein BDNF levels were measured in the urine samples of 1148 children aged 6-12 years from Italy (NACII-IT cohort), Slovakia (PCB-SK cohort), Hungary (InAirQ-HU cohort) and Norway (NEBII-NO). Serum BDNF was also available in 124 Slovenian children (CRP-SLO cohort). Children's total, externalizing and internalizing behavioral problems were assessed using the Child Behavior Checklist at 7 years of age (only available in the NACII-IT cohort). Adjusted linear and negative binomial regression models were fitted, together with weighted quantile sum (WQS) regression models to assess phthalate mixture associations. Results showed that, in boys but not girls of the NACII-IT cohort, each natural-log-unit increase in mono-n-butyl phthalate (MnBP) and Mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) was cross-sectionally associated with higher externalizing problems [incidence rate ratio (IRR): 1.20; 95% CI: 1.02, 1.42 and 1.26; 95% CI: 1.03, 1.55, respectively]. A suggestive mixture association with externalizing problems was also observed per each tertile mixture increase in the whole population (WQS-IRR = 1.15; 95% CI: 0.97, 1.36) and boys (IRR = 1.20; 95% CI: 0.96, 1.49). In NACII-IT, PCB-SK, InAirQ-HU and NEBII-NO cohorts together, urinary phthalate metabolites were strongly associated with higher urinary BDNF levels, with WQS regression confirming a mixture association in the whole population (percent change (PC) = 25.9%; 95% CI: 17.6, 34.7), in girls (PC = 18.6%; 95% CI: 7.92, 30.5) and mainly among boys (PC = 36.0%; 95% CI: 24.3, 48.9). Among CRP-SLO boys, each natural-log-unit increase in ∑DINCH concentration was associated with lower serum BDNF levels (PC: -8.8%; 95% CI: -16.7, -0.3). In the NACII-IT cohort, each natural-log-unit increase in urinary BDNF levels predicted worse internalizing scores among all children (IRR: 1.15; 95% CI: 1.00, 1.32). Results suggest that (1) children's exposure to di-n-butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP) metabolites is associated with more externalizing problems in boys, (2) higher exposure to DINCH may associate with lower systemic BDNF levels in boys, (3) higher phthalate exposure is associated with higher urinary BDNF concentrations (although caution is needed since the possibility of a "urine concentration bias" that could also explain these associations in noncausal terms was identified) and (4) higher urinary BDNF concentrations may predict internalizing problems. Given this is the first study to examine the relationship between phthalate metabolite exposure and BDNF biomarkers, future studies are needed to validate the observed associations.

Temporal trends in phthalate metabolite exposure of girls in the United States across sociodemographic factors and intersectional social identities: National Health and Nutrition Examination Survey (NHANES) 2001–2018

BackgroundExposure to phthalates during the pubertal window is linked to an increased risk of chronic diseases. Understanding temporal trends in exposure can inform public health initiatives. ObjectiveCharacterize temporal trends in phthalate metabolite levels in adolescent girls overall and by sociodemographic characteristics. MethodsWe used the cross-sectional data from each cycle of NHANES from years 2001–2018. We included participants aged 8–14 years who had at least one urinary measurement of the selected 12 phthalate metabolites within the study period (n = 2063). We used multivariable linear regression to assess temporal trends for selected individual phthalate metabolite concentrations (ng/ml) and source groupings of parent metabolites (sum low and high molecular weight phthalates; ∑LMW and ∑HMW), overall and by sociodemographic characteristics (race/ethnicity), nativity, socioeconomic status (SES), intersection of race/ethnicity-SES) to assess for modification. ResultsOverall, levels of ∑HMW and ∑LMW declined between 2001 and 2018; however, only ∑LMW consistently differed by all sociodemographic characteristics. Trends in ∑LMW concentration were significantly higher across all racial/ethnic groups, ranging from an average of 35% (Other Hispanic) to 65% (Mexican American and non-Hispanic Black) higher than non-Hispanic White (all p-values <0.0001). Compared to non-Hispanic White, a significant decrease in MiBP concentrations was observed for non-Hispanic Black (15% decrease βSpline = −0.16, p < 0.0001) and Other Hispanic (28% decrease, βSpline = −0.33, p = 0.01) in 2011–2018 versus 2001–2010. Summary and individual LMW metabolite phthalate concentrations were 11%–49% higher among girls with low vs. high SES. LMW metabolites MBP and MiBP were on average 22% and 35% higher, respectively, among foreign-born vs. U.S.-born girls. Compared to non-Hispanic Whites, all racial/ethnic groups had statistically significant higher trends in ∑LMW concentrations irrespective of SES. SignificanceGirls identifying with a historically disadvantaged racial/ethnic groups exhibited elevated ∑LMW concentrations irrespective of SES; suggesting the need for targeted interventions to mitigate exposure among the most historically disadvantaged strata.

Effects of the Thiol Methyltransferase Inhibitor (±)-2,3-Dichloro-α-Methylbenzylamine (DCMB) on the Pharmacokinetics and Metabolism of Vicagrel in Rats.

P2Y12 receptor inhibitors are commonly used in clinical antiplatelet therapy, typically alongside other medications. Vicagrel, a promising P2Y12 receptor inhibitor, has submitted a new drug marketing application to the United States Food and Drug Administration. Its primary metabolites and some metabolic pathways are identical to those of clopidogrel. The aim of this study was to investigate the effects of the thiol methyltransferase inhibitor (±)-2,3-dichloro-α-methylbenzylamine (DCMB) on the metabolism and pharmacokinetics of vicagrel. In vitro incubation with human and rat liver microsomes revealed that DCMB significantly inhibited the methylation of vicagrel's thiol metabolite M15-1. Rats were orally administered 6 mg/kg [14C]vicagrel (100 μCi/kg) 1 hour after peritoneal injection with or without DCMB (80 mg/kg). Compared with the control group, the plasma of DCMB-pretreated rats exhibited maximum plasma concentration (C max) decrease and time to reach C max (T max) delay for all vicagrel-related substances, the methylation product of the thiol metabolite (M9-2), and the derivatization product of the active thiol metabolite (MP-M15-2). However, no significant changes in area under the curve (AUC) or half-life (t 1/2) were observed. DCMB had negligible effect on the total radiological recovery of vicagrel within 72 hours, although the rate of vicagrel excretion slowed down within 48 hours. DCMB had a negligible impact on the metabolic pathway of vicagrel. Overall, the present study found that DCMB did not significantly affect the total exposure, metabolic pathways, metabolite profiles, or total excretion rates of vicagrel-related metabolites in rats, but led to C max decrease, T max delay, and slower excretion rate within 48 hours. SIGNIFICANCE STATEMENT: This study used liquid chromatography-tandem mass spectrometry combined with radiolabeling technology to investigate the effects of the thiol methyltransferase inhibitor (±)-2,3-dichloro-α-methylbenzylamine on the absorption, metabolism, and excretion of vicagrel in rats. This work helps to better understand the in vivo metabolism of active thiol metabolites of P2Y12 inhibitors such as clopidogrel, vicagrel, etc.

Essential Role of Gut Microbiome in Determining Circulating Levels of Blueberry Polyphenol Metabolite Exposure

Essential Role of Gut Microbiome in Determining Circulating Levels of Blueberry Polyphenol Metabolite Exposure

The role of the gut microbiome in disorders of gut–brain interaction

Disorders of Gut‐Brain Interaction (DGBI) are widely prevalent and commonly encountered in gastroenterology practice. While several peripheral and central mechanisms have been implicated in the pathogenesis of DGBI, a recent body of work suggests an important role for the gut microbiome. In this review, we highlight how gut microbiota and their metabolites affect physiologic changes underlying symptoms in DGBI, with a particular focus on their mechanistic influence on GI transit, visceral sensitivity, intestinal barrier function and secretion, and CNS processing. This review emphasizes the complexity of local and distant effects of microbial metabolites on physiological function, influenced by factors such as metabolite concentration, duration of metabolite exposure, receptor location, host genetics, and underlying disease state. Large‐scale in vitro work has elucidated interactions between host receptors and the microbial metabolome but there is a need for future research to integrate such preclinical findings with clinical studies. The development of novel, targeted therapeutic strategies for DGBI hinges on a deeper understanding of these metabolite‐host interactions, offering exciting possibilities for the future of treatment of DGBI.

Seasonal variation in urinary PAH metabolite levels and associations with neonatal birth outcomes.

Previous studies have demonstrated that exposure to polycyclic aromatic hydrocarbons (PAHs) can affect maternal and infant health. However, the conclusions regarding the effects of seasonal PAH exposure on maternal and infant health have been inconsistent. To further elucidate this issue, this study included data from 2282 mother-infant pairs in the Zuni birth cohort. The objective was to investigate the association between maternal late-pregnancy urinary PAH metabolite concentrations and neonatal birth outcomes during the heating and non-heating seasons. The results demonstrated that PAH exposure in Zunyi was primarily dominated by 2-OHNAP and 1-OHNAP and that the concentrations of PAH metabolites were significantly higher during the heating season. Furthermore, PAH metabolite exposure was found to affect neonatal birth weight, birth length, and parity index with seasonal differences. Further dose-effect analyses revealed nonlinear relationships and seasonal differences between PAH metabolites and neonatal birth weight, birth length, and parity index. Bayesian kernel mechanism regression modeling demonstrated that the inverted U-shaped relationship between PAH metabolites and neonatal birth weight and parity index was exclusive to the heating season. Consequently, it can be posited that maternal exposure to PAH metabolites during late pregnancy exerts a detrimental influence on neonatal growth and development, which is further compounded by the use of heating fuels. This highlights the necessity to either control or alter the use of heating fuels during pregnancy.

Assessment of Microbial Contamination and Metabolite Exposure in Cosmetic Products Used in Women's Beauty Salons.

An important route of microbial transmission is the shared use of these products in beauty salons. We aimed to investigate level of contamination with microorganisms and their metabolites in shared-use cosmetics in several women's beauty salons. Bacterial and fungal strains from 320 opened/used cosmetic samples were identified according to the Iranian standards for microbial quality of cosmetic products in Golestan Province (North of Iran) during Jul-Sep 2021. In order to assess production of toxins and protease by the predominant bacterial and fungal isolates, multiplex-polymerase chain reaction and the Lowry protein assay were performed, respectively. Microbial contamination was detected in 180 samples (56.5%), and the highest and lowest rates of microbial contamination were related to skin products (63.88%) and eye beauty products (20%), respectively. The highest level of S. aureus contamination (> 4,000 colony-forming units/g) was found in toner and face wash samples, and the highest level of C. albicans contamination was seen in lipstick samples (>20,000 colony-forming units/g). Only one (2%) S. aureus isolate produced staphylococcal enterotoxin B, while 3 out of 12 (25%) C. albicans isolates were able to produce protease. The shared-used health and beauty products, face products, in the study area are heavily contaminated. Therefore, it is essential to store used cosmetics in dry and cool places, establish strict inspection regulations for cosmetic products before and after entering the market, and increase awareness of beauty salon workers regarding the appropriate use, sanitary control, and maintenance of health and beauty products.

Physiologically based pharmacokinetic modeling of CYP2C8 substrate rosiglitazone and its metabolite to predict metabolic drug-drug interaction

Rosiglitazone is an activator of nuclear peroxisome proliferator-activated (PPAR) receptor gamma used in the treatment of type 2 diabetes mellitus. The elimination of rosiglitazone occurs mainly via metabolism, with major contribution by enzyme cytochrome P450 (CYP) 2C8. Primary routes of rosiglitazone metabolism are N-demethylation and hydroxylation. Modulation of CYP2C8 activity by co-administered drugs lead to prominent changes in the exposure of rosiglitazone and its metabolites. Here, we attempt to develop mechanistic parent-metabolite physiologically based pharmacokinetic (PBPK) model for rosiglitazone. Our goal is to predict potential drug-drug interaction (DDI) and consequent changes in metabolite N-desmethyl rosiglitazone exposure. The PBPK modeling was performed in the PKSim® software using clinical pharmacokinetics data from literature. The contribution to N-desmethyl rosiglitazone formation by CYP2C8 was delineated using vitro metabolite formation rates from recombinant enzyme system. Developed model was verified for prediction of rosiglitazone DDI potential and its metabolite exposure based on observed clinical DDI studies. Developed model exhibited good predictive performance both for rosiglitazone and N-desmethyl rosiglitazone respectively, evaluated based on commonly acceptable criteria. In conclusion, developed model helps with prediction of CYP2C8 DDI using rosiglitazone as a substrate, as well as changes in metabolite exposure. In vitro data for metabolite formation can be successfully utilized to translate to in vivo conditions.

Prenatal arsenic metabolite exposure is associated with increased newborn mitochondrial DNA copy number: evidence from a birth cohort study.

While mitochondria are susceptible to environmental detriments, little is known about potential associations between arsenic metabolites and mitochondria DNA copy number (mtDNAcn). We attempted to examine whether maternal urinary arsenic metabolite levels in different trimesters were related to neonatal cord blood mtDNAcn. We included 819 mother-newborn pairs embedded in an in-progress birth cohort survey performed from April 2014 to October 2016 in Wuhan, China. We determined maternal urinary arsenic species concentrations in different trimesters. We determined cord blood mtDNAcn using quantitative real-time polymerase chain reaction. In covariate-adjusted models, each one-unit increment of dimethylated arsenic (DMA) and total arsenic (TAs) in the third trimester was related to 8.43% (95% CI 1.13%, 16.26%) and 12.15% (95% CI 4.35%, 20.53%) increases in mtDNAcn, respectively. The dose-response trend with statistical significance was observed across tertiles of DMA and TAs in the third trimester with mtDNAcn (DMA percent changes (%Δ) = 25.60 (95% CI 6.73, 47.82), for the highest vs the lowest tertile (P = 0.02); TAs %Δ = 40.31 (95% CI 19.25, 65.10), for the highest vs the lowest tertile (P = 0.0002)). These findings may prove the relationships between prenatalarsenic species levelsand neonatalmitochondrial dysfunction.

Current Phthalate Exposure Risks of Rural Population in the Northwest China: Evidence from an Internal Exposure Study.

Phthalates (PAEs) are synthetic chemicals widely used in industrial and personal consumer products as adhesives or plasticizers. PAEs have been demonstrated to have toxic effects on the human body. However, biological monitoring data for the internal PAE exposure levels of Chinese rural residents are still limited. The present study investigated the exposure levels of ten phthalate metabolites (mPAEs) of rural residents in Northwest China. The results showed that mPAEs were wildly prevalent in urine and the geometric mean concentration of Σ10mPAEs was 957.02 ng mL-1 (adjusted by specific gravity). Mono-n-butyl phthalate (MBP) and metabolites of di(2-ethylhexyl)-phthalate (DEHP) were the most dominant mPAEs in urine, with specific gravity adjusted median concentrations of 174.67 and 156.30 ng mL-1, respectively. Urinary concentrations of mPAEs were significantly associated with age, body mass index and economic level (p < 0.05). By calculating the percentage and relative conversion rate of DEHP metabolites, it was found that the degree of oxidative metabolism of DEHP in children was significantly higher than that in adults (p < 0.05), indicating that the pathway and degree of DEHP oxidation were age-related. The risk assessment showed that 59.12% of rural residents may have a noncancer risk from PAE exposure. This study provides important basis for assessing the occurrence and exposure of urinary phthalate metabolites among rural residents in China.

Activation of Notch Signaling Pathway is involved in Extracellular Matrix Degradation in human induced pluripotent stem cells chondrocytes induced by HT-2 toxin

Notch signaling regulates cartilage formation and homeostasis. Kashin-Beck Disease (KBD), an endemic osteochondropathy, is characterized by severe cartilage degradation. The etiology of KBD is related to the exposure of HT-2 toxin, a mycotoxin and primary metabolite of T-2 toxin. This study aims to explore the role of HT-2 toxin in the Notch signaling regulation and extracellular matrix (ECM) metabolism of hiPSCs-Chondrocytes. Immunohistochemistry and qRT-PCR were employed to investigate the expression of Notch pathway molecules in KBD articular cartilage and primary chondrocytes. hiPSCs-Chondrocytes, derived from hiPSCs, were treated with 100 ng/mL HT-2 toxin and the γ-secretase inhibitor (DAPT) for 48h, respectively. The markers related to the Notch signaling pathway and ECM were assessed using qRT-PCR and Western blot. Notch pathway dysregulation was prominent in KBD cartilage. HT-2 toxin exposure caused cytotoxicity in hiPSCs-Chondrocytes, and activated Notch signaling by increasing the mRNA and protein levels of NOTCH1 and HES1. HT-2 toxin also upregulated ECM catabolic enzymes and downregulated ECM components (COL2A1 and ACAN), indicating ECM degradation. DAPT-mediated Notch signaling inhibition suppressed the mRNA and protein level of ADAMTS5 expression while enhancing ECM component expression in hiPSCs-Chondrocytes. This study suggests that HT-2 toxin may induce ECM degradation in hiPSCs-Chondrocytes through activating Notch signaling.

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.

Therapeutic efficacy of generic artemether–lumefantrine in the treatment of uncomplicated malaria in Ghana: assessing anti-malarial efficacy amidst pharmacogenetic variations

BackgroundDespite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether–lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy.MethodsPatients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR–RFLP.ResultsA total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0–2666/μL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors.ConclusionsThe study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.

Prenatal exposure to environmental contaminants and cord serum metabolite profiles in future immune-mediated diseases

BackgroundPrenatal exposure to environmental contaminants is a significant health concern because it has the potential to interfere with host metabolism, leading to adverse health effects in early childhood and later in life. Growing evidence suggests that genetic and environmental factors, as well as their interactions, play a significant role in the development of autoimmune diseases.ObjectiveIn this study, we hypothesized that prenatal exposure to environmental contaminants impacts cord serum metabolome and contributes to the development of autoimmune diseases.MethodsWe selected cord serum samples from All Babies in Southeast Sweden (ABIS) general population cohort, from infants who later developed one or more autoimmune-mediated and inflammatory diseases: celiac disease (CD), Crohn’s disease (IBD), hypothyroidism (HT), juvenile idiopathic arthritis (JIA), and type 1 diabetes (T1D) (all cases, N = 62), along with matched controls (N = 268). Using integrated exposomics and metabolomics mass spectrometry (MS) based platforms, we determined the levels of environmental contaminants and metabolites.ResultsDifferences in exposure levels were found between the controls and those who later developed various diseases. High contaminant exposure levels were associated with changes in metabolome, including amino acids and free fatty acids. Specifically, we identified marked associations between metabolite profiles and exposure levels of deoxynivalenol (DON), bisphenol S (BPS), and specific per- and polyfluorinated substances (PFAS).Impact statementAbnormal metabolism is a common feature preceding several autoimmune and inflammatory diseases. However, few studies compared common and specific metabolic patterns preceding these diseases. Here we hypothesized that exposure to environmental contaminants impacts cord serum metabolome, which may contribute to the development of autoimmune diseases. We found differences in exposure levels between the controls and those who later developed various diseases, and importantly, on the metabolic changes associated with the exposures. High contaminant exposure levels were associated with specific changes in metabolome. Our study suggests that prenatal exposure to specific environmental contaminants alters the cord serum metabolomes, which, in turn, might increase the risk of various immune-mediated diseases.

Gender-specific abdominal fat distribution and insulin resistance associated with organophosphate esters and phthalate metabolites exposure

The worldwide prevalence of obesity highlights the potential contribution of endocrine-disrupting chemicals (EDCs). However, common epidemiological measures such as body mass index and waist circumference may misrepresent the intricate obesity risks these chemicals pose across genders. This study delves deeper into abdominal fat by differentiating between subcutaneous and visceral regions by analyzing data from National Health and Nutrition Examination Surveys (NHANES). We particularly investigated the gender-specific associations between organophosphorus flame-retardant metabolites (mOPFRs), phthalates (mPAEs) and accumulated fat indexes from 2536 people. Aiding by Bayesian Kernel Machine Regression (BKMR), we found while co-exposure to mOPFRs and mPAEs was linked to general and abdominal obesity across the entire and gender-specific populations, a gender-specific fat distribution emerged. For women, urinary BDCPP and MBzP were linked to an increased subcutaneous fat index (SFI) [BDCPP OR: 1.12 (95% CI: 1.03–1.21), MBzP OR: 1.09 (95% CI: 1.01–1.18)], but not to visceral fat index (VFI). These metabolites had a combined linkage with SFI, with BDCPP (weighting 22.0%) and DPHP (weighting 31.0%) being the most influential in Quantile g-computation model (qgcomp) model. In men, BCEP exposure exclusively associated with the elevated VFI [OR: 1.14 (95% CI: 1.03–1.26)], a trend further highlighted in mixture models with BCEP as the predominant association. Intriguingly, only males displayed a marked correlation between these metabolites and insulin resistance in subpopulation. An attempted mediation analysis revealed that elevated C-reactive protein mediated 12.1% of the association between urinary BCEP and insulin resistance, suggesting a potential role of inflammation. In conclusion, the gender-specific fat distribution and insulin resistance that associated with mOPFRs represented the potential risk of these chemicals to man.

A Metabolome-Wide Mendelian Randomization Study Identifies Dysregulated Arachidonic Acid Synthesis as a Potential Causal Risk Factor for Bipolar Disorder

BackgroundBipolar disorder (BPD) is a debilitating mood disorder with an unclear etiology. A better understanding of the underlying pathophysiological mechanisms will help to identify novel targets for improved treatment options and prevention strategies. In this metabolome-wide Mendelian randomization study, we screened for metabolites that may have a causal role in BPD. MethodsWe tested a total of 913 circulating metabolite exposures assessed in 14,296 Europeans using a mass spectrometry-based platform. For the BPD outcome, we used summary data from the largest and most recent genome-wide association study reported to date, including 41,917 BPD cases. ResultsWe identified 33 metabolites associated with BPD (padjusted < 5.48 × 10−5). Most of them were lipids, including arachidonic acid (β = −0.154, SE = 0.023, p = 3.30 × 10−11), a polyunsaturated omega-6 fatty acid, along with several complex lipids containing either an arachidonic or a linoleic fatty acid side chain. These associations did not extend to other closely related psychiatric disorders like schizophrenia or depression, although they may be involved in the regulation of lithium response. These lipid associations were driven by genetic variants within the FADS1/2/3 gene cluster, which is a robust BPD risk locus encoding a family of fatty acid desaturase enzymes that are responsible for catalyzing the conversion of linoleic acid into arachidonic acid. Statistical colocalization analyses indicated that 27 of the 33 metabolites shared the same genetic etiology with BPD at the FADS1/2/3 cluster, demonstrating that our findings are not confounded by linkage disequilibrium. ConclusionsOverall, our findings support the notion that arachidonic acid and other polyunsaturated fatty acids may represent potential targets for BPD.