Urinary Metabolite Concentrations Research Articles

Urinary Organophosphate Metabolite Concentrations and Pregnancy Outcomes among Women Conceiving through in Vitro Fertilization in Shanghai, China.

Background:Animal studies suggest that pesticide exposure elicits endocrine changes, increases embryo implantation failure, and decreases litter size. However, only a few epidemiological studies have evaluated the effects of pesticides on the outcomes of in vitro fertilization (IVF) pregnancies.Objectives:This study examined the associations between preconception organophosphate pesticides (OP) exposure and pregnancy outcomes among women undergoing IVF in a Chinese population.Methods:This study included 522 women with infertility who underwent IVF. Women were recruited from a prospective study, the China National Birth Cohort (CNBC), from Shanghai, China, between July 2017 and December 2018. Demographic and clinical information were collected from medical records and through questionnaires. Preconception exposure to OP was assessed by measuring six nonspecific dialkylphosphate (DAP) metabolites [diethylthiophosphate (DETP), diethylphosphate (DEP), diethyldithiophosphate (DEDTP), dimethylthiophosphate (DMTP), dimethylphosphate (DMP), dimethyldithiophosphate (DMDTP)] in urine samples collected at recruitment. Generalized estimating equation (GEE) models were used to evaluate the associations between OP and pregnancy outcomes.Results:Compared with women in the lowest quartile () of individual DEP and (the sum of DMP, DMTP, DEP, and DETP), women in the highest quartile () had lower odds of successful implantation, clinical pregnancy, and live birth, and most of the negative trends were significant (). There were no significant associations between urinary DAP concentrations and early IVF outcomes, including total and mature oocyte counts, best embryo quality, fertilization, trigger levels, and endometrial wall thickness.Conclusion:Preconception OP exposure was inversely associated with successful implantation, clinical pregnancy, and live birth in women who underwent IVF. https://doi.org/10.1289/EHP7076

Exposure to tobacco smoke measured by urinary nicotine metabolites increases risk of p16/Ki-67 co-expression and high-grade cervical neoplasia in HPV positive women: A two year prospective study

BackgroundHuman papillomavirus (HPV) is considered the strongest epidemiologic risk factor for cervical cancer. However, it is not a sufficient cause given the high prevalence of transient infections. We examined the relationship between exposure to tobacco smoke, measured using urinary nicotine metabolite concentrations, and p16/Ki-67 co-expression in cervical smears and subsequent risk of developing CIN2+/CIN3+ lesions in HPV positive women. MethodsThis prospective longitudinal study enrolled women presenting to colposcopy with cytological abnormalities LSIL/ASCUS at the National Maternity Hospital, Dublin. Women gave a urine sample which was used to perform the Nicotine Metabolite Assay (Siemens). HPV positive (HC2) cervical smears were stained by immunocytochemistry for p16/Ki-67 (CINtec PLUS, Roche). Two year follow-up data, including histological diagnosis, was collected for each woman. Crude and adjusted odds ratios were calculated using logistic regression to investigate associations between tobacco smoke, p16/Ki-67 positivity and CIN2+/CIN3 +. ResultsIn total, 275 HPV positive women were included. Women with nicotine metabolite concentrations above 500 ng/mL, indicative of smoking, were classified as smokers. Smokers were at an increased risk of testing positive for p16/Ki-67 (OR 1.678; 1.027−2.740) and CIN2+ and CIN3+ (OR 1.816; 1.107−2.977 and OR 2.453; 1.200−5.013) in compared to non-smokers. In p16/Ki-67 positive women, smoking further increased their risk of CIN2+/CIN3+ (OR 2.290; 1.017−5.159 and OR 3.506 (1.534−8.017). ConclusionHPV positive women exposed to tobacco smoke are at a higher risk of testing positive for p16/Ki-67 co-expression. Risk of high-grade disease is almost doubled in women who are exposed to tobacco smoke.

Prenatal exposure to organophosphate pesticides and brain morphology and white matter microstructure in preadolescents

BackgroundPrenatal exposure to organophosphate (OP) pesticides associate with impaired neurodevelopment in humans and animal models. However, much uncertainty exists about the brain structural alterations underlying these associations. The objective of this study was to determine whether maternal OP pesticide metabolite concentrations in urine repeatedly measured during gestation are associated with brain morphology and white matter microstructure in 518 preadolescents aged 9–12 years. MethodData came from 518 mother–child pairs participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. Maternal urine concentrations were determined for 6 dialkylphosphates (DAPs) including 3 dimethyl (DM) and 3 diethyl (DE) alkyl phosphate metabolites, collected at early, mid, and late pregnancy. At child's age 9–12 years, magnetic resonance imaging was performed to obtain T1-weighted images for brain volumes and surface-based cortical thickness and cortical surface area, and diffusion tensor imaging was used to measure white matter microstructure through fractional anisotropy (FA) and mean diffusivity (MD). Linear regression models were fit for the averaged prenatal exposure across pregnancy. ResultsDM and DE metabolite concentrations were not associated with brain volumes, cortical thickness, and cortical surface area. However, a 10-fold increase in averaged DM metabolite concentrations across pregnancy was associated with lower FA (B = −1.00, 95%CI = −1.80, −0.20) and higher MD (B = 0.13, 95%CI = 0.04, 0.21). Similar associations were observed for DE concentrations. ConclusionsThis study provides the first evidence that OP pesticides may alter normal white matter microstructure in children, which could have consequences for normal neurodevelopment. No associations were observed with structural brain morphology, including brain volumes, cortical thickness, and cortical surface area.

Exposure to pyrethroid pesticides and ovarian reserve

IntroductionSynthetic pyretroids are among the most common pesticides currently used worldwide. Animal studies suggest that exposure to pyrethroids could dysregulated the function of the ovary, mainly follicular development and/or synthesis of the reproductive hormone. Nevertheless data regarding the effect of exposure on female ovarian function is limited. So the aim of the present study is to assess the effect of exposure to synthetic pyrethroids on ovarian reserve. Materials and MethodsThe study population consists of 511 females aged 25–39 years attending infertility clinics for diagnostic purposes, because of couples’ infertility. Validated gas chromatography ion-tap mass spectrometry method was used to assess the urinary concentrations of pyrethroid metabolites (CDDCA (cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid), TDDCA (trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid), 3PBA (3-phenoxybenzoic acid) and DBCA (cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid)). Ovarian reserve was assessed using parameters of ovarian reserve (antral follicle count and concentrations of hormones: AMH (anti-Mullerian hormone), FSH (follicle stimulating hormone) and E2 (estradiol)). ResultsIn the present analysis the association was found between urinary concentrations of 3-PBA and levels of AMH (p = 0.03), FSH (p = 0.04) and antral follicle count (p = 0.02). Urinary level of CDCCA, TDCCA and DBCA was not associated with any examined parameters of ovarian reserve. ConclusionsSynthetic pyrethroids may affect female ovarian reserve. As this is the first, preliminary study the results need confirmation in a further detailed investigations.

Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment

Human biomonitoring (HBM) data can provide insight into co-exposure patterns resulting from exposure to multiple chemicals from various sources and over time. Therefore, such data are particularly valuable for assessing potential risks from combined exposure to multiple chemicals.One way to interpret HBM data is establishing safe levels in blood or urine, called Biomonitoring Equivalents (BE) or HBM health based guidance values (HBM-HBGV). These can be derived by converting established external reference values, such as tolerable daily intake (TDI) values. HBM-HBGV or BE values are so far agreed only for a very limited number of chemicals. These values can be established using physiologically based kinetic (PBK) modelling, usually requiring substance specific models and the collection of many input parameters which are often not available or difficult to find in the literature.The aim of this study was to investigate the suitability and limitations of generic PBK models in deriving BE values for several compounds with a view to facilitating the use of HBM data in the assessment of chemical mixtures at a screening level. The focus was on testing the methodology with two generic models, the IndusChemFate tool and High-Throughput Toxicokinetics package, for two different classes of compounds, phenols and phthalates. HBM data on Danish children and on Norwegian mothers and children were used to evaluate the quality of the predictions and to illustrate, by means of a case study, the overall approach of applying PBK models to chemical classes with HBM data in the context of chemical mixture risk assessment.Application of PBK models provides a better understanding and interpretation of HBM data. However, the study shows that establishing safety threshold levels in urine is a difficult and complex task. The approach might be more straightforward for more persistent chemicals that are analysed as parent compounds in blood but high uncertainties have to be considered around simulated metabolite concentrations in urine. Refining the models may reduce these uncertainties and improve predictions. Based on the experience gained with this study, the performance of the models for other chemicals could be investigated, to improve the accuracy of the simulations.

Metabolites of the fragrance 2-(4-tert-butylbenzyl)propionaldehyde (lysmeral) in urine of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V).

The synthetic fragrance 2-(4-tert-butylbenzyl)propionaldehyde, also known as lysmeral, butylphenyl methylpropional, lilial, or lily aldehyde, is widely used in cosmetics, personal care products, laundry detergents, and air fresheners. It is classified as suspected to be harmful to fertility and possibly endocrine disrupting. Its maximum concentration in cosmetics is limited. First-morning void urine samples (N=2133) were analysed for several metabolites of lysmeral (Chemical Abstract Service (CAS) No.: 80-54-6). Samples were collected in the population-representative German Environmental Survey for Children and Adolescents 2014-2017 (GerES V) from German residents aged 3-17 years. Four main metabolites tert-butylbenzoic acid, lysmerol, lysmerylic acid, and hydroxy-lysmerylic acid were found in quantifiable amounts in 100%, 99%, 40%, and 23% of the samples, respectively, with geometric mean concentrations of 10.21μg/L (8.658 μg/gcrea) for tert-butylbenzoic acid, 1.528μg/L (1.296 μg/gcrea) for lysmerol, and below the limit of quantification of 0.2μg/L and 0.4μg/L for lysmerylic acid and hydroxy-lysmerylic acid, respectively. Girls had higher urinary concentrations of lysmeral metabolites than boys. Usage of fragrances, fabric softener, and personal care products, especially perfume, was positively associated with urinary concentrations of lysmeral metabolites. Source identification builds a basis to derive proposals for reduction of exposure. These results can also provide the foundation for developing reference values for urinary metabolite concentrations of lysmeral in children and adolescents in Germany that will facilitate recognising future exposure trends.

Comparison of aggregated exposure to di(2-ethylhexyl) phthalate from diet and personal care products with urinary concentrations of metabolites using a PBPK model – Results from the Norwegian biomonitoring study in EuroMix

Phthalates are widely used as plasticisers in flexible plastics and containers for food and personal care products (PCPs) and contaminates foods and PCPs. A human biomonitoring (BM) study was performed to study exposure of chemicals from foods and PCPs. For two 24-h periods, adult volunteers (n = 144) in Norway kept diaries on food eaten and usage of PCPs, and collected 24-h urine. Aggregated exposure to di(2-ethylhexyl) phthalate (DEHP) from dietary and PCPs was estimated by Monte-Carlo simulation using Oracle Crystal Ball©. Simulated urinary concentrations using physiologically based pharmacokinetic (PBPK) models were compared with measured urinary metabolites of DEHP, mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono-2-ethyl 5-carboxypentyl phthalate (MECCP). DEHP exposure from food are approximately 10 times higher than exposure than from PCPs. The main contributors to dietary exposure are dairy, grain, fruits and vegetables, meat and fish. Body lotion contribute most to the exposure of DEHP from PCPs. Forward-dosimetry gives good convergence with 24-h urinary concentrations of simulated and measured BM data. The measured concentration of the MECCP metabolite correlated well with simulated high exposure, while the measured concentrations of MEHP, MEHHP and MEOHP partly overlapped with both simulated low, medium and high metabolite exposure.

Assessing population exposure to phthalate plasticizers in thirteen Spanish cities through the analysis of wastewater

Phthalates are widely used plasticizers that produce endocrine-disrupting disorders. Quantifying exposure is crucial to perform risk assessments and to develop proper health measures. Herein, a wastewater-based epidemiology approach has been applied to estimate human exposure to six of the mostly used phthalates within the Spanish population. Wastewater samples were collected over four weekdays from seventeen wastewater treatment plants serving thirteen cities and ca. 6 million people (12.8 % of the Spanish population). Phthalate metabolite loads in wastewater were transformed into metabolite concentrations in urine and into daily exposure levels to the parent phthalates. Considering all the sampled sites, population-weighted overall means of the estimated concentrations in urine varied between 0.7 ng/mL and 520 ng/mL. Very high levels, compared to human biomonitoring data, were estimated for monomethyl phthalate, metabolite of dimethyl phthalate. This, together with literature data pointing to other sources of this metabolite in sewage led to its exclusion for exposure assessments. For the remaining metabolites, estimated concentrations were closer to those found in urine. Their 4-days average exposure levels ranged from 2 to 1347 μg/(day∙inh), exceeding in some sites the daily exposure thresholds set for di-i-butyl phthalate and di-n-buthyl phthalate by the European Food Safety Authority.

High concentrations of urinary ethanol metabolites in neonatal intensive care unit infants.

Infants in the neonatal intensive care unit may be exposed to ethanol via medications that contain ethanol as an excipient and through inhalation of ethanol vapor from hand sanitizers. We hypothesized that both pathways of exposure would result in elevated urinary biomarkers of ethanol. Urine samples were collected from infants in incubators and in open cribs. Two ethanol metabolites, ethyl sulfate (EtS) and ethyl glucuronide (EtG), were quantified in infants' urine. A subset of infants both in incubators and open cribs had ethanol biomarkers greater than the cutoff concentration that identifies adult alcohol consumption. These concentrations were associated with the infant having received an ethanol-containing medication on the day of urine collection. When infants who received an ethanol-containing medication were excluded from analysis, there was no difference in ethanol biomarker concentrations between the incubator and crib groups. Some infants who received ethanol-containing medications had concentrations of ethanol biomarkers that are indicative of adult alcohol consumption, suggesting potential exposure via ethanol excipients. Infants and newborns in the neonatal intensive care unit are exposed to concerning amounts of ethanol. No one has shown exposure to ethanol in these infants before this study. The impact is that better understanding of the excipients in medications given to patients in the NICU is needed. When physicians order medications in the NICU, the amount of excipient needs to be indicated.

Interaction effect of polycyclic aromatic hydrocarbon metabolites and cadmium on semen quality in nonsmokers.

Both cadmium (Cd) and polycyclic aromatic hydrocarbons (PAHs) are known reproductive toxicants, but their co-exposure and interaction effect on semen quality particularly in nonsmokers remain unknown. We included 333 nonsmoking men and analyzed their urine and semen samples for heavy metals and PAH metabolites. Restricted cubic spline models were used to explore the dose-response relationship between each OH-PAHs, Cd, and semen quality parameters; the generalized linear model was performed to examine the interaction of each urinary OH-PAH metabolite and Cd concentration on semen quality. Also, stratified analysis was applied to further illustrate the independent effect of PAHs on semen quality parameters in low and high concentration Cd subgroups. The dose-response and interaction effect of PAHs and Cd on male semen quality was observed. Stratified analysis in the high concentration Cd subgroup showed a negative association of 1-OHPyr concentration with semen motility. Our findings indicate that Cd not only modifies the association between PAHs and semen quality but can also exacerbate the toxic effect of pyrene on semen quality parameters. However, further studies with larger samples are needed to confirm the findings.

Urinary Concentrations of Phthalate Metabolite Mixtures in Relation to Serum Biomarkers of Thyroid Function and Autoimmunity among Women from a Fertility Center.

Background:Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women.Objective:We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity.Methods:This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005–2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (, ) and triiodothyronine (, ), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores.Results:We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of , , , and [absolute difference: ; 95% confidence interval (CI): , ; ; absolute difference: ; 95% CI: , ; ; absolute difference: ; 95% CI: 0.54, ; ; and absolute difference: ; 95% CI: , ; , respectively]. Using BKMR, we observed that mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was the primary contributor to these negative associations. DEHP and non-DEHP factor scores were not associated with serum TSH, TgAb, or TPOAb.Conclusions:Mixtures of urinary DEHP metabolites were inversely associated with serum biomarkers of thyroid function but not with autoimmunity, which were within normal ranges for healthy adult women. https://doi.org/10.1289/EHP6740

RETRACTED ARTICLE: Dietary metabotype modelling predicts individual responses to dietary interventions.

Habitual consumption of poor quality diets is linked directly to risk factors for many non-communicable diseases. This has resulted in the vast majority of countries and the World Health Organization developing policies for healthy eating to reduce the prevalence of non-communicable diseases in the population. However, there is mounting evidence of variability in individual metabolic responses to any dietary intervention. We have developed a method for applying a pipeline for understanding interindividual differences in response to diet, based on coupling data from highly controlled dietary studies with deep metabolic phenotyping. In this feasibility study, we create an individual Dietary Metabotype Score (DMS) that embodies interindividual variability in dietary response and captures consequent dynamic changes in concentrations of urinary metabolites. We find an inverse relationship between the DMS and blood glucose concentration. There is also a relationship between the DMS and urinary metabolic energy loss. Furthermore, we use a metabolic entropy approach to visualize individual and collective responses to dietary interventions. Potentially, the DMS offers a method to target and to enhance dietary response at the individual level, thereby reducing the burden of non-communicable diseases at the population level.

THU0321 URINARY T CELLS IDENTIFY ACTIVE RENAL ANCA ASSOCIATED VASCULITIS

Background:ANCA-associated vasculitis (AAV) causes necrotizing crescentic glomerulonephritis (NCGN) which is a major contributor to morbidity and mortality in AAV. Since therapy relies on cytotoxic agents with potentially severe adverse effects, a reliable non-invasive biomarker of disease activity is needed to determine the right balance between over- and undertreatment. Using the urine space as a window into the local inflammatory milieu of the kidney, quantification of urinary leukocytes using flow cytometry has become an upcoming marker of various other inflammatory kidney diseases. As recent studies have illuminated the emerging role of T regulatory (Treg) and Th17 cells in the pathogenesis of AAV, these could represent a viable non-invasive biomarker more closely displaying the underlying pathogenic processes than metabolites or epiphenomena of inflammation.Objectives:To quantify urinary T cells in active renal AAV and asses their biomarker characteristics.Methods:Using flow cytometry, T-lymphocytes and their subsets were quantified in peripheral blood and urine samples from patients with active AAV with or without NCGN, in stable remission with previous NCGN and healthy controls. Concentrations of urinary soluble metabolites and cytokines (Monocyte-attracting protein 1 (MCP-1), sCD163, sCD25 and C5a) were measured using Multiplex analysis. Results were verified in a separate validation cohort.Results:Patients with renal active AAV (n = 30) showed significantly higher urinary cell counts of total T cells, CD4+, CD8+, Treg and Th17 subsets than disease (n = 21) and healthy controls (n = 8). Patients with active renal AAV also showed a significantly higher percentage of Tregs in urine than in blood. While Tregs allowed a robust discrimination between active renal AAV and disease controls (receiver operator characteristics (ROC): area under the curve (AUC) 0.93, sensitivity 79%, specificity 95%) quantification of all T cells proved to be slightly more accurate (ROC: AUC 0.95, sensitivity 92%, specificity 95%). Soluble markers showed a slightly inferior discrimination (MCP-1 ROC: AUC 0.90, sensitivity 60%, specificity 100%, sCD163 ROC: AUC 0.92, sensitivity 96%, specificity 85%) while sCD25 and C5a were far less accurate.Conclusion:Urinary T cells are significantly elevated in active renal AAV and the increased frequency of Tregs in urine suggests active migration into inflamed glomeruli and thereby the urine rather than mere bleeding of ruptured capillaries. These cells show great potential for a non-invasive biomarker close to the local inflammatory milieu. Particularly the total count of urinary T cells showed slightly superior biomarker characteristics than previously established soluble markers. Further studies are needed to confirm these results and show potential prognostic value of these cellular markers.Disclosure of Interests:None declared

Acrylamide induces a thyroid allostasis–adaptive response in prepubertal exposed rats

Some endocrine-disrupting chemicals (EDCs) can affect the endocrine system through covalent interactions with specific sites, leading to deregulation of physiological homeostasis. The acrylamide (AA) present in some fried or baked foods is an example of an electrophile molecule that is able to form adducts with nucleophilic regions of nervous system proteins leading to neurological defects. A positive correlation between increased urinary AA metabolite concentration and reduced levels of thyroid hormones (TH) was described in adolescents and young adults. Thus, this study aimed to evaluate whether AA affects the physiology of the hypothalamus-pituitary-thyroid (HPT) axis and the possible repercussions in peripheral TH-target systems. For this, male Wistar rats were exposed to doses of 2.5 or 5.0 mg AA/Kg/day, based on the LOAEL (Lowest Observed Adverse Effect Level) during prepubertal development. The expression of molecular markers of HPT functionality was investigated in the hypothalamus, pituitary, thyroid, heart and liver, as well as the hormonal and lipid profiles in blood samples. Herein, we showed that AA acts as EDCs for thyroid gland function, increasing the transcript expression of several proteins related to TH synthesis and altering hypothalamus-pituitary-thyroid axis homeostasis, an effect evidenced by the higher levels of THs in the serum. Compensatory mechanisms were observed in TH-target tissues, such as an increase in Dio3 mRNA expression in the liver and a reduction in Mct8 transcript content in the hearts of AA-treated rats. Together, these results pointed out an allostatic regulation of the HPT axis induced by AA and suggest that chronic exposure to it, mainly associated with food consumption, might be related to the higher prevalence of thyroid dysfunctions.

Predictors and reproducibility of urinary organophosphate ester metabolite concentrations during pregnancy and associations with birth outcomes in an urban population

BackgroundOrganophosphate esters (OPEs) are synthetic chemicals used as flame retardants and plasticizers in a variety of goods. Despite ubiquitous human exposures and laboratory evidence that prenatal OPE exposures may disrupt offspring metabolism, perinatal studies of OPE health effects are limited. The objectives of this study were to: 1) Determine predictors and reproducibility of urinary OPE biomarker concentrations during pregnancy, and 2) Estimate the relation of prenatal OPE exposures with birth outcomes and cord blood adipokine and insulin concentrations.MethodsWe analyzed five OPE metabolites in urine samples collected at up to three visits during pregnancy from 90 women enrolled in the ORigins of Child Health And Resilience in Development (ORCHARD) pregnancy cohort in Baltimore, MD from 2017 to 2019. To quantify the variability of metabolite concentrations during pregnancy, we calculated intraclass correlation coefficients (ICCs) for each metabolite using mixed effects regression models. Using self-reported questionnaire data collected during gestation, we assessed possible sociodemographic and environmental/behavioral predictors of each OPE metabolite using generalized estimating equations to account for repeated exposure measures. We ascertained birth outcomes of 76 offspring from medical records, including weight-for-gestational age, length, ponderal index, and gestational age. In a subset of 37 infants, we measured cord blood concentrations of leptin, adiponectin, and insulin. To account for repeated exposure measures, we used linear structural equation models to assess the relations of standard deviation (SD) increases in prenatal OPE metabolite factor scores with continuous birth outcomes and cord blood biomarker concentrations.ResultsICCs ranged from 0.09 for isopropylphenyl-phenyl phosphate (ip-PPP) to 0.59 for bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We observed little consistency in environmental or behavioral predictors of OPE exposures, although concentrations were generally lower for samples collected in the afternoon compared to morning and winter compared to other seasons. In adjusted analyses, a SD increase in BDCIPP concentration was associated with a 0.06 g/cm3 (95% CI: 0.00, 0.12) greater ponderal index. A SD increase in BDCIPP was associated with a 0.37 (95% CI: − 0.62, − 0.13) SD lower insulin concentration and 0.24 (95% CI: − 0.39, − 0.08) SD lower leptin concentration. Other OPEs were not associated with infant outcomes.ConclusionsThese findings suggest some OPEs may be metabolic disruptors warranting investigation in larger studies.

Genetic Determinants of Reduced Arsenic Metabolism Efficiency in the 10q24.32 Region Are Associated With Reduced AS3MT Expression in Multiple Human Tissue Types.

Approximately 140 million people worldwide are exposed to inorganic arsenic through contaminated drinking water. Chronic exposure increases risk for cancers as well as cardiovascular, respiratory, and neurologic diseases. Arsenic metabolism involves the AS3MT (arsenic methyltransferase) gene, and arsenic metabolism efficiency (AME, measured as relative concentrations of arsenic metabolites in urine) varies among individuals. Inherited genetic variation in the 10q24.32 region, containing AS3MT, influences AME, but the mechanisms remain unclear. To better understand these mechanisms, we use tissue-specific expression data from GTEx (Genotype-tissue Expression project) to identify cis-eQTLs (expression quantitative trait loci) for AS3MT and other nearby genes. We combined these data with results from a genome-wide association study of AME using "colocalization analysis," to determine if 10q24.32 SNPs (single nucleotide polymorphisms) that affect AME also affect expression of AS3MT or nearby genes. These analyses identified cis-eQTLs for AS3MT in 38 tissue types. Colocalization results suggest that the casual variant represented by AME lead SNP rs4919690 impacts expression of AS3MT in 13 tissue types (> 80% probability). Our results suggest this causal SNP also regulates/coregulates expression of nearby genes: BORCS7 (43 tissues), NT5C2 (2 tissues), CYP17A1-AS1 (1 tissue), and RP11-724N1.1 (1 tissue). The rs4919690 allele associated with decreased AME is associated with decreased expression of AS3MT (and other coregulated genes). Our study provides a potential biological mechanism for the association between 10q24.32 variation and AME and suggests that the causal variant, represented by rs4919690, may impact AME (as measured in urine) through its effects on arsenic metabolism occurring in multiple tissue types.

Study on the relationship between urinary polycyclic aromatic hydrocarbons metabolites and pulmonary function in community population

Objective: To investigate the relationship between urinary polycyclic aromatic hydrocarbons(PAHs) metabolites and pulmonary function in community population. Methods: A total of 4 812 participants were recruited from two communities in Wuhan city from April to May 2011 and two communities in Zhuhai city in May 2012. Information of demographic characteristics and life style was collected by semi-structural questionnaire. Physical examination was performed and pulmonary function was measured. Morning urine was also collected. The concentration of 12 urinary PAHs metabolites was tested and classified into four types by chemical structure, including hydroxynaphthalene, hydroxyfluorene, hydroxyphenanthrene and hydroxypyrene. The level of pulmonary function in different group of urinary PAHs metabolites was compared by using covariance analysis. The association of the urinary PAHs metabolites and pulmonary function was analyzed by using generalized linear model, and the interaction of different population characteristics and life style on the association was analyzed. Results: The age of participants was(51.99±13.64) years old, and 67.66% (n=2 565) of the population were women. The M (P(25), P(75)) of concentration of total urinary PAHs metabolites was 5.72 (3.91,8.72) μg/mmol Cr. After controlling for variables including age, gender, city, Waist-to-Hip Ratio, smoking status, drinking situation, physical activity, cooking meals at home or not, kitchen ventilation and exposure to dust as confounding factors, generalized linear model showed that each 1-unit increase in log-transformed levels of hydroxynaphthalene, hydroxyfluorene, hydroxyphenanthrene, hydroxypyrene and total PAHs was associated with 26.83 (95%CI: -48.18, -5.48) , 21.86 (95%CI: -40.49, -3.23), 26.18(95%CI: -48.27, -4.09), 34.95 (95%CI: -55.95, -13.94), and 35.23 (95%CI: -58.93, -11.54) ml reduction of FVC and 29.36 (95%CI: -47.23, -11.48), 20.79 (95%CI: -36.39, -5.19), 22.65 (95%CI: -41.15, -4.15), 31.44(95%CI: -49.03, -13.85), and 33.20 (95%CI: -53.04, -13.36) ml reduction of FEV(1) respectively (all P values<0.05). Compared to non-alcohol users and participants with home cooking, the association was more evident in alcohol users and participants without home cooking(P for interaction<0.05). Conclusion: The exposure to PAHs was associated with decreased pulmonary function, and the association was more evident in alcohol users and participants without home cooking.

Elevated expression of AhR and NLRP3 link polycyclic aromatic hydrocarbon exposure to cytokine storm in preschool children

BackgroundPolycyclic aromatic hydrocarbons (PAHs), as a group of persistent organic pollutants, are linked to impaired immune function and low-grade inflammation in adults and children. However, the potential of PAHs to lead to a cytokine storm associated with AhR (aryl hydrocarbon receptor) and NLRP3 (NLR family pyrin domain containing 3) in humans has been poorly studied. ObjectivesWe aimed to investigate the associations between PAH exposure, AhR and NLRP3 expression, and cytokines associated with a cytokine storm in healthy preschoolers. MethodsBasic demographic surveys and physical examinations were conducted on 248 preschoolers from an electronic waste (e-waste) recycling area (Guiyu, n = 121) and a reference area (Haojiang, n = 127). Ten urinary PAH metabolite (OH-PAH) concentrations were measured. We also measured the expression levels of AhR and NLRP3 and seventeen serum cytokine levels. ResultsThe concentrations of multiple OH-PAHs were significantly higher in the exposed group than those in the reference group, especially 1-hydroxynaphthalene (1-OH-Nap) and 2-hydroxynaphthalene (2-OH-Nap). PAH exposure was closely related to a child's living environment and hygiene habits. Expression levels of AhR and NLRP3 were significantly higher in the exposed group than in the reference group. Similarly, serum IL-1β, IL-4, IL-5, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-22, IL-23, and IFN-γ levels were notably higher in the e-waste-exposed children than in the reference children. After adjusting for age, gender, BMI, family income, parental education level, and second-hand smoke exposure, we found that increased PAH exposure was associated with higher AhR and NLRP3 expression and elevated IL-4, IL-10, IL-12p70, IL-18, IL-22, IL-23, TNF-α, and IFN-γ levels. The associations between PAH exposure and IL-1β, IL-18, IFN-γ, and TNF-β were mediated by NLRP3 expression, and the relationships between PAH exposure and IL-4, IL-10, IL-12p70, IL-22, IL-23, and TNF-α were mediated by AhR expression. ConclusionsOur findings suggest that the association between PAH exposure and a cytokine storm may be mediated by AhR and NLRP3 expression among preschoolers.

Association of Parental Preconception Exposure to Phthalates and Phthalate Substitutes With Preterm Birth

Although phthalate exposure during pregnancy has been associated with preterm birth, the association of preconception exposure in either parent with preterm birth constitutes a knowledge gap. To examine the association of paternal and maternal preconception urinary concentrations of biomarkers of phthalates and phthalate substitutes with singleton preterm birth. This study, conducted at an academic fertility center in Boston, Massachusetts, included a prospective preconception cohort of subfertile couples comprising 419 mothers and 229 fathers and their 420 live-born singleton offspring born between January 1, 2005, and December 31, 2018. Statistical analysis was performed from August 1 to October 31, 2019. Urinary concentrations of metabolites of phthalates and phthalate substitutes obtained before conception. Gestational age was abstracted from delivery records and validated using the American College of Obstetricians and Gynecologists guidelines for births after medically assisted reproduction. The risk ratio (RR) of preterm birth (live birth before 37 completed weeks' gestation) was estimated in association with urinary concentrations of 11 individual phthalate metabolites, the molar sum of 4 di-(2-ethylhexyl) phthalate (ΣDEHP) metabolites, and 2 metabolites of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH, a nonphthalate plasticizer substitute) using modified Poisson regression models adjusted for covariates. The mean (SD) age of the 419 mothers was 34.7 (4.0) years, the mean (SD) age of the 229 fathers was 36.0 (4.5) years, and the mean (SD) gestational age of the 420 singleton children (217 boys) was 39.3 (1.7) weeks, with 34 (8%) born preterm. In adjusted models, maternal preconception ΣDEHP concentrations (RR, 1.50; 95% CI, 1.09-2.06; P = .01) and cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH, a metabolite of DINCH) concentrations (RR, 1.70; 95% CI, 0.89-3.24; P = .11) were associated with an increased risk of preterm birth. After additional adjustment for prenatal ΣDEHP or MHiNCH concentrations, the association of maternal preconception exposure to ΣDEHP and preterm birth remained robust (RR, 1.69; 95% CI, 1.17-2.44; P = .006), while the association of maternal preconception exposure to MHiNCH and preterm birth was attenuated (RR, 1.17; 95% CI, 0.49-2.81; P = .72). The remaining urinary metabolites examined in either parent showed no association with preterm birth. In this prospective cohort of subfertile couples, maternal preconception exposure to ΣDEHP metabolites was associated with an increased risk of preterm birth. The results suggest that female exposure to select phthalate plasticizers during the preconception period may be a potential risk factor for adverse pregnancy outcomes, which may need to be considered in preconception care strategies.

Sex and dose-dependent responses of urinary and faecal glucocorticoid metabolite concentrations following an ACTH challenge in eastern rock sengis (Elephantulus myurus)

Non-invasive methods for measuring glucocorticoids and their metabolites are frequently used in ecological, behavioural and physiological studies of mammals. Using faeces, urine and other matrices for such a measurement has considerable advantages in comparison to more traditional methods, but also requires thorough validation of the methods used. Eastern rock sengis (Elephantulus myurus) are fascinating African mammals and the non-invasive monitoring of the adrenocortical activity opens up new opportunities to study their biology. We were able to validate two assays for measuring urinary (uGCM) and faecal glucocorticoid metabolite (fGCM) concentrations in this species using a dose-dependent challenge with adrenocorticotropic hormone (ACTH). A higher concentration of ACTH elicited higher uGCM and fGCM concentrations in both males and females. Interestingly, uGCM and fGCM concentrations and the responses to ACTH were higher in females than in males and small changes in faecal glucocorticoid metabolites could not be reliably detected in males. In contrast to ACTH, a saline injection did not result in an increase in uGCM or fGCM concentrations. The study also provided insight into when responses to a stressor are likely to be detected in the urine and faeces of sengis and opens up new opportunities to study the stress physiology of this and other sengi species. It further emphasises the importance of thoroughly validating non-invasive methods for measuring hormones in both sexes of a species and for incorporating dose-dependent approaches.