Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters.

BACKGROUND: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology. METHODS: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. RESULTS: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. CONCLUSION: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

Environmental risks and sphingolipid signatures in adult asthma and its phenotypic clusters: a multicentre study.

BACKGROUND: Adult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity. METHODS: Environmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables. FINDINGS: In the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28-3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108-0.311, p<0.05), but not with the accumulated levels of PM2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202-0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186-0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures. INTERPRETATION: These results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

Simultaneous determination of eight ß-adrenergic agonists in human urine by an isotope dilution-online clean-up system coupled with liquid chromatography-tandem mass spectrometry.

ß-Adrenergic agonist compounds are medicines that open up the lung's medium and large airways. ß-Adrenergic agonist compounds have been illegally or legally used to increase lean muscle mass in meat animals, bodybuilding, weight-loss programs, and athletes. Developing a rapid analytical approach for determining ß-adrenergic agonist compounds in biological samples is crucial for individual exposure assessment. This study established an analytical method for simultaneously measuring eight ß-adrenergic agonist compounds in human urine, including clenbuterol, terbutaline, salbutamol, ractopamine, zilpaterol, cimaterol, tulobuterol, and fenoterol. Two hundred microliters of a urine sample were added to eight deuterium-labeled internal standard mixtures and glucuronidase/arylsulfatase for enzymatic hydrolysis, and were then analyzed using an online clean-up system coupled with a liquid chromatography-tandem mass spectrometry system (LC-MS/MS). The limit of quantification ranged from 0.03 to 0.12 ng/mL urine for the eight ß-adrenergic agonist compounds. The relative standard deviations (RSD) of the within-run and between-run precisions were less than 10%, and the relative accuracy errors were less than 17% in the three-level spiked artificial urine samples. Two hundred eighty human urine samples collected from the general population in Taiwan were assessed to demonstrate the capability and feasibility of this method. The detection frequencies were 33% for clenbuterol, 5% for ractopamine, and less than 5% for the others. We concluded that the isotope dilution-online clean-up system coupled with LC-MS/MS method is a valuable analytical method for investigating urinary ß-adrenergic agonist compounds in humans and is valuable for human biomonitoring studies.

Association Between Prenatal Exposure to Metals and Atopic Dermatitis Among Children Aged 4 Years in Taiwan.

Importance: The prevalence of atopic dermatitis has substantially increased in recent decades, and atopic dermatitis could lead to allergic airway inflammation later in life. A previous study found that inorganic arsenic exposure was associated with allergic airway inflammation in children aged 8 to 14 years. However, the association between prenatal exposure to arsenic and other metals and the risk of atopic dermatitis among young children remains unknown. Objective: To assess the association between prenatal exposure to arsenic and other metals and the occurrence of atopic dermatitis in children at age 4 years. Design, Setting, and Participants: In total, 1152 pregnant women were enrolled in the original Taiwan Maternal and Infant Cohort Study (TMICS), a multicenter birth cohort study conducted at 9 hospitals in northern, central, southern, and eastern Taiwan from October 2012 to May 2015. Of those, 586 mothers and children aged 4 years participated in follow-up questionnaire interviews from August 2016 to January 2019. After excluding 216 participants with missing data, the final statistical analysis of follow-up data included 370 mother and child pairs from the central and eastern regions of Taiwan. Data were analyzed from February 2 to August 12, 2021. Exposures: Arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc during pregnancy. Main Outcomes and Measures: The outcome was parent-reported atopic dermatitis history among children aged 4 years. The presence of atopic dermatitis was defined as a positive response to the question, "Has your child ever had atopic dermatitis diagnosed by a physician?" During the initial TMICS study period, concentrations of arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc were measured in maternal urine during the third trimester of pregnancy using an inductively coupled plasma mass spectrometer. Estimated total inorganic arsenic exposure was calculated using a model that included data on both total arsenic and arsenic species (arsenite, arsenate, monomethylarsonate, and dimethylarsenate) obtained from a previous TMICS cohort. Results: Among 370 children included in the analysis, the mean (SD) age was 3.94 (0.59) years; 208 children (56.2%) were male, and 267 children (72.2%) were from the central region of Taiwan. A total of 110 children (29.7%) had atopic dermatitis at age 4 years. Maternal estimated total inorganic arsenic exposure during pregnancy was associated with increased odds of atopic dermatitis among children at age 4 years (odds ratio [OR], 2.42 [95% CI, 1.33-4.39] for every doubled increase of total inorganic arsenic) after adjusting for parental allergies, child's sex, geographic area, maternal educational level, and exposure to tobacco smoke. Every increased unit in the weighted quantile sum index of maternal metal exposure was significantly associated with atopic dermatitis (OR, 1.63; 95% CI, 1.28-2.07). Arsenic (40.1%) and cadmium (20.5%) accounted for most of the metal mixture index. Conclusions and Relevance: This cohort study found that prenatal exposure to inorganic arsenic and coexposure to inorganic arsenic and cadmium were associated with a higher risk of atopic dermatitis in young children. These findings suggest that prevention of exposure to inorganic arsenic and cadmium during pregnancy may be helpful for the control of atopic dermatitis and other potential allergies in children.

Measurement of urinary arsenic profiles and DNA hypomethylation in a case-control study of urothelial carcinoma.

Environmental exposure to arsenic may be involved in the disturbance of DNA hypomethylation. The aim of this study is the first to explore the effect of interactions of urinary total arsenic levels, arsenic methylation capacity, 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma folate, and global 5-methyl-2'-deoxycytidine (5-MedC) levels on the risk of urothelial carcinoma (UC). A hospital-based case-control study was constructed. The research involved the histological recruitment and pathological verification of 178 UC patients and 356 age-/sex-matched controls without prior history of cancer. Arsenic species were determined by high-performance liquid chromatography (HPLC)-hydride generation and atomic absorption. 5-MedC levels were detected by HPLC and triple-quadrupole mass spectrometry (MS). 8-OHdG was processed by an online solid-phase extraction LC-MS/MS. Plasma folate levels were measured using the chemiluminescent technology. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by multiple logistic regression analysis. Results indicate that the high levels of total urinary arsenic, inorganic arsenic percentage, and 8-OHdG and the low levels of DMA % and plasma folate were independent factors of UC. In addition, global 5-MedC levels in the first quartile versus fifth quartile significantly increased the twofold OR of UC after potential factors were adjusted (95% CI:1.10-4.03). The interaction of 5-MedC level and high total arsenic level, insufficient arsenic capacity, high 8-OHdG, and low folate levels was insignificant. Results of stepwise logistic regression analysis indicate that high total urinary arsenic levels (Q3 versus Q1), low plasma folate level, and low global 5-MedC (Q4 versus Q5) significantly increased the ORs of UC. The above results suggest that high total arsenic, low plasma folate, and 5-MedC levels affect the ORs of UC independently.

Health risk of metal exposure via inhalation of cigarette sidestream smoke particulate matter.

Cigarette sidestream smoke particulate matter (CSSP) is a major source of airborne metals in the indoor environment. However, the health impacts of inhalation of CSSP-bound metals are rarely studied. In this study, we quantify the amount of 37 metals discharged through CSSP from a leading Taiwan brand of cigarette, Long Life. We also estimate cancer and non-cancer risks due to inhalation of these metals and investigate possible modes of toxic action. Long Life CSSP exhibits a distinctive carcinogenic metal profile compared with Western brands. When released to a 60-m3 poorly ventilated room, Long Life CSSP metals increase the risk for cancer by a 9.26 or 20.90 in a million chance and the hazard quotient for non-cancer toxicity by 0.496 or 0.286 per cigarette depending on risk estimation system. Cd accounts for more than 90% and 80% of cancer and non-cancer risk, respectively. Long Life CSSP also contains considerable amounts of Al, Ba, and Fe. Metals are not responsible for CSSP-induced cytotoxicity, oxidative stress, and transactivation activity of AhR, Nrf2, and ERα. However, they diminish resveratrol-activated Nrf2 activity and downstream antioxidant gene expression in low-AhR-expressing lung cells. Our results suggest that chronic exposure to Long Life CSSP elevates Cd-associated cancer and non-cancer risks. Furthermore, exposure to Long Life CSSP metals may impair Nrf2-mediated antioxidant protection.

Risk of Alzheimer's disease with metal concentrations in whole blood and urine: A case-control study using propensity score matching.

Environmental exposure to heavy metals is suspected to result in neuropathology damage and cognitive impairment. We aimed to explore the association of Alzheimer's disease (AD) risk with the internal dose of heavy metals by constructing a hospital-based case-control study and using propensity-score-matching methods. We investigated 170 patients with AD and 264 controls from the Department of Neurology and Family Medicine, China Medical University Hospital in Taiwan. All patients with AD received clinical neuropsychological examination and cognitive-function assessments, including the mini-mental status examination and clinical dementia rating scale. We also constructed a propensity-score-matched population of 82 patients with AD and 82 controls by matching age, gender, education, and AD-related comorbidity. Blood levels with cadmium, lead, mercury, selenium, and urinary arsenic profile were measured. Logistic regression models and 95% confidence intervals (CIs) were applied to estimate AD risk. After stratification by respective quartile cutoffs of heavy metals, the AD risk of study participants with high urinary inorganic arsenic (InAs%) or low dimethylarsinic acid (DMA%) significantly increased (p < 0.05), as similarly found in the propensity-score-matched population. In addition, people with a low median level of selenium and high median level of InAs%, or/and a low median level of DMA% had approximately two- to threefold significant AD risk. Urinary arsenic profiles may be associated with increased AD risk. Repeat measurements of heavy metals with large sample size and the surveying of potential exposure sources are recommended in future studies.

Early-life arsenic exposure promotes atherogenic lipid metabolism in adolescence: A 15-year birth cohort follow-up study in central Taiwan.

BACKGROUND: Inorganic arsenic (iAs) exposure potentially causes diabetes and cardiovascular diseases in adults. However, its effect on glucose and lipid metabolism in early life remains unknown. OBJECTIVE: We evaluated the associations between early-life arsenic exposure and profiles of glucose and lipids in a 15-year birth cohort in central Taiwan. METHODS: We studied 237 adolescents through 5 waves of follow-up interviews and examinations at ages of approximately 2, 5, 8, 11, and 14 y. We obtained at least one follow-up urine measurement for arsenic species and blood sample collection up to 14 y of age and identified group-based trajectories of serial iAs by semiparametric mixture modeling. Multiple linear and logistic regressions were performed to assess the effect of the arsenic exposure trajectory on serum fasting glucose, total cholesterol (TCHO), triglycerides (TGs), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL). RESULTS: Three trajectories of postnatal arsenic exposure were identified, namely stable-low (31.4%), stable-high (48.2%), and rising-high (20.4%) groups. Compared with the stable-low trajectory group, the percent changes in TCHO and LDL was 14% (95% confidence interval 4-24%) and 23% (9-38%) for the group with "rising-high" trajectory and was 8% (-1-16%) and 16% (4-29%) for the group with "stable-high" trajectory. The rising-high group was also associated with an increase in the TCHO/HDL ratio by 14% (95% CI 3%-25%). The adjusted odds ratios of high developmental trajectories of TCHO, TG, LDL, and non-HDL levels were 4.0 (95% CI 1.2-13.7), 12.2 (2.2-67), 7.3 (1.8-30), and 3.6 (0.9-14.6), respectively, in the rising-high group (reference: stable-low group). CONCLUSION: Our findings suggest that conversion to an atherogenic lipid profile in adolescents may be associated with early-life exposure to environmental arsenic, particularly during the pre-adolescent period. An environmental modification approach for preventing As-related cardiovascular disease is recommended to begin early in life.

Relationships among DNA hypomethylation, Cd, and Pb exposure and risk of cigarette smoking-related urothelial carcinoma.

Cigarette smoking and environmental exposure to heavy metals are important global health issues, especially for urothelial carcinoma (UC). However, the effects of cadmium and lead exposure, as well as the levels of DNA hypomethylation, on UC risk are limited. We evaluated the possible exposure sources of Cd and Pb and the relationship among DNA hypomethylation, urinary Cd and Pb levels, and UC risk. We recruited 209 patients with UC and 417 control patients for a hospital-based case-control study between June 2011 and August 2014. We collected environmental exposure-related information with questionnaires. Blood and urine samples were analyzed to measure the Cd and Pb exposure and 5-methyl-2'-deoxycytidine levels as a proxy for DNA methylation. Multivariate logistic regression and 95% confidence intervals were applied to estimate the risk for UC. Study participants with high Cd and Pb exposure in blood or urine had significantly increased risk of UC, especially among the smokers. After adjusting for age and gender, the possible connections of individual cumulative cigarette smoking or herb medicine exposure with the increased levels of Cd and Pb were observed in the controls. Participants with 8.66%-12.39% of DNA hypomethylation had significantly increased risk of UC compared with those with ≥12.39% of DNA hypomethylation. Environmental factors including cigarette smoking and herb medicine may contribute to the internal dose of heavy metals levels. Repeat measurements of heavy metals with different study design, detailed dietary information, and types of herb medicine should be recommended for exploring UC carcinogenesis in future studies.

Association between levels of urinary heavy metals and increased risk of urothelial carcinoma.

OBJECTIVES: To evaluate possible sources of exposure to heavy metals in the general population, and to determine the association between urinary heavy metals and urothelial carcinoma risk. METHODS: We recruited 205 patients with urothelial carcinoma and 406 control participants for a case-control study between June 2011 and December 2013. The control participants were frequency-matched with cases according to sex and age. We measured the urinary levels of arsenic, cadmium, chromium, nickel and lead by using inductively coupled plasma mass spectrometry. We collected environmental exposure-related information through questionnaires. Multivariate logistic regression and 95% confidence intervals were applied to estimate the urothelial carcinoma risk and potential effects of urothelial carcinoma-related risk factors on the levels of urinary heavy metals. RESULTS: Patients with urothelial carcinoma showed higher urinary levels of arsenic, cadmium, chromium, nickel and lead than the controls. After considering other potential risk factors, a significantly increased risk for urothelial carcinoma was observed in patients with increased urinary levels of cadmium, chromium, nickel and lead. Smokers showed a high urinary cadmium level. In addition to cadmium, a high urinary lead level was associated with cumulative cigarette smoking and herbal medicine use. CONCLUSION: Environmental factors might contribute to higher urinary levels of heavy metals and ultimately result in urothelial carcinoma carcinogenesis. These findings can promote proper environmental surveillance of exposure to heavy metals in the general population.

Identification of trans,trans-2,4-decadienal metabolites in mouse and human cells using liquid chromatography-mass spectrometry.

trans,trans-2,4-Decadienal (tt-DDE), a lipid peroxidation product of linolieic acid, is the most abundant aldehyde identified in cooking oil fumes and is readily detectable in food products as well as in restaurant emissions. Previously, we have reported the toxicological effects of tt-DDE in vitro and in vivo. However, the metabolic pathways of tt-DDE in vivo remain unclear. In our present study, we combined liquid chromatography-mass spectrometry with triple quadrupole and time-of-flight to identify tt-DDE metabolites in the urine of mice orally administered tt-DDE. We identified two tt-DDE metabolites, 2,4-decadienoic acid and cysteine-conjugated 2,4-decadien-1-ol, in the urine of mice gavaged with tt-DDE and in human hepatoma cell cultures. The structure of 2,4-decadienoic acid was confirmed upon comparison of its tandem mass spectrometry (MS/MS) spectrum and retention time with those of synthetic standards. The moieties of cysteine and alcohol on cysteine-conjugated 2,4-decadien-1-ol were validated by treating cell cultures with stable-isotope-labeled cysteine and 4-methylpyrazole, an alcohol dehydrogenase inhibitor. The MS/MS spectra of a cysteine standard and ionized cysteine detached from cysteine-conjugated 2,4-decadien-1-ol were identical. Two metabolic pathways for the biotransformation of tt-DDE in vivo are proposed: (i) the oxidation of tt-DDE to the corresponding carboxylic acid, 2,4-decadienoic acid, in liver cells and (ii) glutathione (GHS) conjugation, GSH breakdown, and aldehyde reduction, which generate cysteine-conjugated 2,4-decadien-1-ol in both liver and lung cells. In conclusion, this platform can be used to identify tt-DDE metabolites, and cysteine-conjugated 2,4-decadien-1-ol can serve as a biomarker for assessing exposure to tt-DDE.

Metabolomic profiling of mice urine and serum associated with trans-trans 2, 4-decadienal induced lung lesions by liquid chromatography-mass spectrometry.

Metabolomics has become an important tool in clinical research and the diagnosis of human disease. Intratracheal instillation of trans-trans 2,4-decadienal (tt-DDE), a major component in cooking oil fumes, has been demonstrated to cause lung lesions in mice at 8 weeks after treatment. The objective of this study was to identify any changes in metabolite profiles associated with the development of tt-DDE-induced lung lesions. Using a metabolomics strategy involving a liquid chromatography-mass spectrometry-based approach in conjunction with principal component analysis and confirmation by liquid chromatography triple quadrupole tandem mass spectrometry, we have demonstrated that the amino acid profiles of the urine and serum of tt-DDE-treated mice are changed. Ten amino acids were significantly reduced in serum of tt-DDE-treated mice at 8 weeks after treatment. Our results suggest that amino acid profiles may be useful as an early indicator of the presence of tt-DDE-induced lung lesions.