Opportunities offered by latent-based multiblock strategies to integrate biomarkers of chemical exposure and biomarkers of effect in environmental health studies.

Modern environmental epidemiology benefits from a new generation of technologies that enable comprehensive profiling of biomarkers, including environmental chemical exposure and omic datasets. The integration and analysis of large and structured datasets to identify functional associations is constrained by computational challenges that cannot be overcome using conventional regression methods. Some extensions of Partial Least Squares (PLS) regression have been developed to efficently integrate multiple datasets, including Multiblock PLS (MB-PLS) and Sequential and Orthogonalized PLS; however, these approaches remain seldom applied in environmental epidemiology. To address that research gap, this study aimed to assess and compare the applicability of PLS-based multiblock models in an observational case study, where biomarkers of exposure to environmental chemicals and endogenous biomarkers of effect were simultaneously integrated to highlight biological links related to a health outcome. The methods were compared with and without sparsity coupling two metrics to support the variable selection: Variable Importance in Projection (VIP) and Selectivity Ratio (SR). The framework was applied to a case-study dataset mimicking the structure of 36 environmental exposure biomarkers (E-block), 61 inflammation biomarkers (M-block), and their relationships with the gestational age at delivery of 161 mother-infant pairs. The results showed an overall consistency in the selected variables across models, although some specific selection patterns were identified. The block-scaled concatenation-based approaches (e.g. MB-PLS) tended to select more variables from the E-block, while these methods were unable to identify certain variables in the M-block. Overall, the number of variables selected using the SR criterion was higher than using the VIP criterion, with lower predictive performances. The multiblock models coupled to VIP, appeared to be the methods of choice for identifying relevant variables with similar statistical performances. Overall, the use of multiblock PLS-based methods appears to be a good strategy to efficiently support the variable selection process in modern environmental epidemiology.

Urinary phthalate/DINCH metabolites associations with kisspeptin and reproductive hormones in teenagers: A cross-sectional study from the HBM4EU aligned studies.

BACKGROUND: Exposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated. OBJECTIVE: To investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies. METHODS: In 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed. RESULTS: The LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): -2.8 (-4.2;-0.4); MEHP: -1.4 (-3.4,0.2)] and higher FSH [∑DINP: 11.8 (-0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [-4.28 (-8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: -12.22 (-21.09;-1.18); oxo-MEHP: -12.73 (-22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males. CONCLUSION: We observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.

Assessing the inhaled dose of nanomaterials by nanoparticle tracking analysis (NTA) of exhaled breath condensate (EBC) and its relationship with lung inflammatory biomarkers.

The widespread and increasing use of nanomaterials has resulted in a higher likelihood of exposure by inhalation for nanotechnology workers. However, tracking the internal dose of nanoparticles deposited at the airways level, is still challenging. To assess the suitability of particle number concentration determination as biomarker of internal dose, we carried out a cross sectional investigation involving 80 workers handling nanomaterials. External exposure was characterized by portable counters of particles DISCminiTM (Testo, DE), allowing to categorize 51 workers as exposed and 29 as non-exposed (NE) to nanoparticles. Each subject filled in a questionnaire reporting working practices and health status. Exhaled breath condensate was collected and analysed for the number of particles/ml as well as for inflammatory biomarkers. A clear-cut relationship between the number of airborne particles in the nano-size range determined by the particle counters and the particle concentration in exhaled breath condensate (EBC) was apparent. Moreover, inflammatory cytokines (IL-1ß, IL-10, and TNF-α) measured in EBC, were significantly higher in the exposed subjects as compared to not exposed. Finally, significant correlations were found between external exposure, the number concentration of particles measured by the nanoparticle tracking analysis (NTA) and inflammatory cytokines. As a whole, the present study, suggests that NTA can be regarded as a reliable tool to assess the inhaled dose of particles and that this dose can effectively elicit inflammatory effects.

Deeper insights into the effects of low dietary levels of polychlorinated biphenyls on pig metabolism using gas chromatography-high resolution mass spectrometry metabolomics.

Polychlorinated biphenyls (PCBs) are a class of contaminants of great concern, linked to the development of many chronic diseases. Adverse effects of PCBs have been documented in humans after accidental and massive exposure. However, little is known about the effect of chronic exposure to low-dose PCB mixtures, and studies regarding scattered lifetime exposures to non-dioxin-like (NDL)-PCBs are especially missing. In this work, serum samples from pigs chronically exposed through their diet during 22 days to Aroclor 1260 (i.e. a commercially available mixture of NDL-PCBs) underwent a metabolomics analysis using gas chromatography-high resolution mass spectrometry (GC-HRMS), with the objective to investigate the effect of exposure to low doses of NDL-PCBs (few ng/kg body weight (b.w.) per day). The study showed that the serum profiles of 84 metabolites are significantly altered by the administration of Aroclor 1260, of which 40 could be identified at level 1. The aggregate interpretation of the results of this study, together with the outcome of a previous one involving LC-HRMS profiling, provided a substantial and concise overview of the effect of low dose exposure to NDL-PCBs, reflecting the hepatotoxic and neurotoxic effects already reported in literature at higher and longer exposures. These results are intended to contribute to the debate on the current toxicological reference values for these substances.

PFAS association with kisspeptin and sex hormones in teenagers of the HBM4EU aligned studies.

Exposure to Perfluoroalkyl acids (PFAS) can impair human reproductive function, e.g., by delaying or advancing puberty, although their mechanisms of action are not fully understood. We therefore set out to evaluate the relationship between serum PFAS levels, both individually and as a mixture, on the Hypothalamic-Pituitary-Gonadal (HPG) axis by analyzing serum levels of reproductive hormones and also kisspeptin in European teenagers participating in three of the HBM4EU Aligned Studies. For this purpose, PFAS compounds were measured in 733 teenagers from Belgium (FLEHS IV study), Slovakia (PCB cohort follow-up), and Spain (BEA study) by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS) in laboratories under the HBM4EU quality assurance quality control (QA/QC) program. In the same serum samples, kisspeptin 54 (kiss-54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were also measured using immunosorbent assays. Sex-stratified single pollutant linear regression models for separate studies, mixed single pollutant models accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the mixture of the three most available (PFNA, PFOA, and PFOS) were fit. PFAS associations with reproductive markers differed according to sex. Each natural log-unit increase of PFOA, PFNA, and PFOS were associated with higher TT [18.41 (6.18; 32.31), 15.60 (7.25; 24.61), 14.68 (6.18; 24.61), respectively] in girls, in the pooled analysis (all studies together). In males, G-computation showed that PFAS mixture was associated with lower FSH levels [-10.51 (-18.81;-1.36)]. The BKMR showed the same patterns observed in G-computation, including a significant increase on male Kiss-54 and SHBG levels. Overall, effect biomarkers may enhance the current epidemiological knowledge regarding the adverse effect of PFAS in human HPG axis, although further research is warranted.

Effect biomarkers of nanoparticle-exposed workers: A scoping review.

The widespread and increasing use of engineered nanomaterials (i.e., particulate materials measuring 1-100 nanometers (nm) in at least one dimension) poses a potential health and safety risk to exposed workers. The unique properties of nanomaterials have made nanomaterials useful in multiple industries. However, their production and use may compromise worker health, presenting an emerging occupational health hazard, the acute and chronic effects of which have not been fully assessed. In this scoping review, we critically assess the literature on biomarkers of effect from nanoparticles and discuss the utility of biomonitoring as a means of assessing the physiological effects of nanoparticle exposure among nanotechnology workers. Multiple databases were queried based on select inclusion and exclusion criteria according to PRISMA guidelines, and articles were independently screened by two topic experts. Of 286 articles initially retrieved, 28 were included after screening and eligibility. The reviewed articles indicated that sensitive effect biomarkers could reflect early health effects of exposure to nanoparticles in the workplace and may be useful for monitoring toxicological effects and associated risks.

A review of statistical strategies to integrate biomarkers of chemical exposure with biomarkers of effect applied in omic-scale environmental epidemiology.

Humans are exposed to a growing list of synthetic chemicals, some of them becoming a major public health concern due to their capacity to impact multiple biological endpoints and contribute to a range of chronic diseases. The integration of endogenous (omic) biomarkers of effect in environmental health studies has been growing during the last decade, aiming to gain insight into potential mechanisms linking the exposures and the clinical conditions. The emergence of high-throughput omic platforms has raised a list of statistical challenges posed by the large dimension and complexity of data generated. Thus, the aim of the present study was to critically review the current state-of-the-science about statistical approaches used to integrate endogenous biomarkers in environmental-health studies linking chemical exposures with health outcomes. The present review specifically focused on internal exposure to environmental chemical pollutants, involving both persistent organic pollutants (POPs) and non-persistent pollutants like phthalates or bisphenols, and metals. We identified 42 eligible articles published since 2016, reporting 48 different statistical workflows, mostly focused on POPs and using metabolomic profiling in the intermediate layer. The outcomes were mainly binary and focused on metabolic disorders. A large diversity of statistical strategies were reported to integrate chemical mixtures and endogenous biomarkers to characterize their associations with health conditions. Multivariate regression models were the most predominant statistical method reported in the published workflows, however some studies applied latent based methods or multipollutant models to overcome the specific constraints of omic or exposure data. A minority of studies used formal mediation analysis to characterize the indirect effects mediated by the endogenous biomarkers. The principles of each specific statistical method and overall workflow set-up are summarized in the light of highlighting their applicability, strengths and weaknesses or interpretability to gain insight into the causal structures underlying the triad: exposure, effect-biomarker and outcome.

A harmonized protocol for an international multicenter prospective study of nanotechnology workers: the NanoExplore cohort.

Nanotechnology applications are fast-growing in many industrial fields. Consequently, health effects of engineered nanomaterials (ENMs) should be investigated. Within the EU-Life project NanoExplore, we developed a harmonized protocol of an international multicenter prospective cohort study of workers in ENM-producing companies. This article describes the development of the protocol, sample size calculation, data collection and management procedures and discusses its relevance with respect to research needs. Within this protocol, workers' ENM exposure will be assessed over four consecutive working days during the initial recruitment campaign and the subsequent follow-up campaigns. Biomonitoring using noninvasive sampling of exhaled breath condensate (EBC), exhaled air, and urine will be collected before and after 4-day exposure monitoring. Both exposure and effect biomarkers, will be quantified along with pulmonary function tests and diagnosed diseases reported using a standardized epidemiological questionnaire available in four languages. Until now, this protocol was implemented at seven companies in Switzerland, Spain and Italy. The protocol is well standardized, though sufficiently flexible to include company-specific conditions and occupational hygiene measures. The recruitment, to date, of 140 participants and collection of all data and samples, enabled us launching the first international cohort of nanotechnology workers. All companies dealing with ENMs could join the NanoExplore Consortium, apply this harmonized protocol and enter in the cohort, concieved as an open cohort. Its protocol meets all requirements of a hypotheses-driven prospective study, which will assess and reassess effects of ENM exposure on workers' health by updating the follow-up of the cohort. New hypothesis could be also considered.

Implementation of effect biomarkers in human biomonitoring studies: A systematic approach synergizing toxicological and epidemiological knowledge.

Human biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of validated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxicological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2'-deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU confirms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better understand the public health implications of human exposure to environmental chemicals.

Brain-derived neurotrophic factor (BDNF): an effect biomarker of neurodevelopment in human biomonitoring programs.

The present narrative review summarizes recent findings focusing on the role of brain-derived neurotrophic factor (BDNF) as a biomarker of effect for neurodevelopmental alterations during adolescence, based on health effects of exposure to environmental chemical pollutants. To this end, information was gathered from the PubMed database and the results obtained in the European project Human Biomonitoring for Europe (HBM4EU), in which BDNF was measured at two levels of biological organization: total BDNF protein (serum) and BDNF gene DNA methylation (whole blood) levels. The obtained information is organized as follows. First, human biomonitoring, biomarkers of effect and the current state of the art on neurodevelopmental alterations in the population are presented. Second, BDNF secretion and mechanisms of action are briefly explained. Third, previous studies using BDNF as an effect biomarker were consulted in PubMed database and summarized. Finally, the impact of bisphenol A (BPA), metals, and non-persistent pesticide metabolites on BDNF secretion patterns and its mediation role with behavioral outcomes are addressed and discussed. These findings were obtained from three pilot studies conducted in HBM4EU project. Published findings suggested that exposure to some chemical pollutants such as fine particle matter (PM), PFAS, heavy metals, bisphenols, and non-persistent pesticides may alter circulating BDNF levels in healthy population. Therefore, BDNF could be used as a valuable effect biomarker to investigate developmental neurotoxicity of some chemical pollutants.

Research progress on biomarkers of endemic arsenic poisoning / 中华地方病学杂志

The accumulation effect of arsenic and low arsenic exposure can cause sustained health damage to people in arsenic poisoning areas. Early diagnosis and prevention of arsenic poisoning have become the focus of current prevention and control, and biomarkers have important application value in early diagnosis and prevention of diseases. Therefore, the screening and application of sensitive and specific biomarkers of arsenic poisoning are of great significance for the continuous elimination of arsenic poisoning. In this paper, the research progress of biomarkers of endemic arsenic poisoning is reviewed, in order to provide reference for the continuous prevention and control, early monitoring and early warning of endemic arsenic poisoning.

HBM4EU Chromates Study-Genotoxicity and Oxidative Stress Biomarkers in Workers Exposed to Hexavalent Chromium.

A study was conducted within the European Human Biomonitoring Initiative (HBM4EU) to characterize occupational exposure to Cr(VI). Herein we present the results of biomarkers of genotoxicity and oxidative stress, including micronucleus analysis in lymphocytes and reticulocytes, the comet assay in whole blood, and malondialdehyde and 8-oxo-2'-deoxyguanosine in urine. Workers from several Cr(VI)-related industrial activities and controls from industrial (within company) and non-industrial (outwith company) environments were included. The significantly increased genotoxicity (p = 0.03 for MN in lymphocytes and reticulocytes; p < 0.001 for comet assay data) and oxidative stress levels (p = 0.007 and p < 0.001 for MDA and 8-OHdG levels in pre-shift urine samples, respectively) that were detected in the exposed workers over the outwith company controls suggest that Cr(VI) exposure might still represent a health risk, particularly, for chrome painters and electrolytic bath platers, despite the low Cr exposure. The within-company controls displayed DNA and chromosomal damage levels that were comparable to those of the exposed group, highlighting the relevance of considering all industry workers as potentially exposed. The use of effect biomarkers proved their capacity to detect the early biological effects from low Cr(VI) exposure, and to contribute to identifying subgroups that are at higher risk. Overall, this study reinforces the need for further re-evaluation of the occupational exposure limit and better application of protection measures. However, it also raised some additional questions and unexplained inconsistencies that need follow-up studies to be clarified.

Exposure to non-persistent pesticides, BDNF, and behavioral function in adolescent males: Exploring a novel effect biomarker approach.

BACKGROUND: Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological function that could help to understand the biological responses of some environmental exposures. OBJECTIVES: To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents. METHODS: The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide carbaryl 1-naphthol (1-N), and the metabolite of ethylene-bis-dithiocarbamate fungicides ethylene thiourea (ETU) were measured in spot urine samples, as well as serum BDNF protein levels and blood DNA methylation of Exon IV of BDNF gene in 15-17-year-old boys from the INMA-Granada cohort in Spain. Adolescents' behavior was reported by parents using the Child Behavior Check List (CBCL/6-18). This study included 140 adolescents of whom 118 had data on BDNF gene DNA methylation. Multivariable linear regression, weighted quantile sum (WQS) for mixture effects, and mediation models were fit. RESULTS: IMPy, MDA, DCCA, and ETU were detected in more than 70% of urine samples, DETP in 53%, and TCPy, 3-PBA, and 1-N in less than 50% of samples. Higher levels of IMPy, TCPy, and ETU were significantly associated with more behavioral problems as social, thought problems, and rule-breaking symptoms. IMPy, MDA, DETP, and 1-N were significantly associated with decreased serum BDNF levels, while MDA, 3-PBA, and ETU were associated with higher DNA methylation percentages at several CpGs. WQS models suggest a mixture effect on more behavioral problems and BDNF DNA methylation at several CpGs. A mediated effect of serum BDNF within IMPy-thought and IMPy-rule breaking associations was suggested. CONCLUSION: BDNF biomarkers measured at different levels of biological complexity provided novel information regarding the potential disruption of behavioral function due to contemporary pesticides, highlighting exposure to diazinon (IMPy) and the combined effect of IMPy, MDA, DCCA, and ETU. However, further research is warranted.

Discovery of Urinary Biomarkers of Spinach Consumption Using Untargeted LC-MS Metabolomics in a Human Intervention Trial.

SCOPE: Biomarkers for intake of green leafy vegetables such as spinach can help investigate their health effects. However, only few potential intake markers have been reported in the literature so far. METHODS AND RESULTS: Based on a cross-over study on whole leaf and minced spinach, we investigate changes in metabolites before and after spinach intake and differences between the two treatments and health status. Nineteen volunteers (12 healthy subjects and 7 short bowel patients) completed the study within 48 days. Urine samples (24-h intervals before and after spinach intake) and serum samples (baseline, post 8 d, and post 15 d) are collected and analyzed by ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). The acquired data is analyzed by multivariate and univariate analyses. Three candidate biomarkers are observed in urine only after the spinach intake, including des-amino arginine pentenol ester, D/L-malic acid ester of cis-p-coumarate, D/L-malic acid ester of trans-p-coumarate, and 69 metabolites are present before spinach intake but showing an altered level after treatment. These metabolites are related to dietary habits or meal structure, and some changes are possibly affected by spinach intake. The candidate biomarkers are independent of spinach pre-processing and healthy status. No markers are discovered in serum samples. CONCLUSION: We propose structures for three candidate spinach intake biomarkers; these markers will need further validation in independent studies.

Lead (Pb) and neurodevelopment: A review on exposure and biomarkers of effect (BDNF, HDL) and susceptibility.

Lead (Pb) is a ubiquitous environmental pollutant and a potent toxic compound. Humans are exposed to Pb through inhalation, ingestion, and skin contact via food, water, tobacco smoke, air, dust, and soil. Pb accumulates in bones, brain, liver and kidney. Fetal exposure occurs via transplacental transmission. The most critical health effects are developmental neurotoxicity in infants and cardiovascular effects and nephrotoxicity in adults. Pb exposure has been steadily decreasing over the past decades, but there are few recent exposure data from the general European population; moreover, no safe Pb limit has been set. Sensitive biomarkers of exposure, effect and susceptibility, that reliably and timely indicate Pb-associated toxicity are required to assess human exposure-health relationships in a situation of low to moderate exposure. Therefore, a systematic literature review based on PubMed entries published before July 2019 that addressed Pb exposure and biomarkers of effect and susceptibility, neurodevelopmental toxicity, epigenetic modifications, and transcriptomics was conducted. Finally included were 58 original papers on Pb exposure and 17 studies on biomarkers. The biomarkers that are linked to Pb exposure and neurodevelopment were grouped into effect biomarkers (serum brain-derived neurotrophic factor (BDNF) and serum/saliva cortisol), susceptibility markers (epigenetic markers and gene sequence variants) and other biomarkers (serum high-density lipoprotein (HDL), maternal iron (Fe) and calcium (Ca) status). Serum BDNF and plasma HDL are potential candidates to be further validated as effect markers for routine use in HBM studies of Pb, complemented by markers of Fe and Ca status to also address nutritional interactions related to neurodevelopmental disorders. For several markers, a causal relationship with Pb-induced neurodevelopmental toxicity is likely. Results on BDNF are discussed in relation to Adverse Outcome Pathway (AOP) 13 ("Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities") of the AOP-Wiki. Further studies are needed to validate sensitive, reliable, and timely effect biomarkers, especially for low to moderate Pb exposure scenarios.

Bone toxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the retinoid system: A causality analysis anchored in osteoblast gene expression and mouse data.

Dioxin exposures impact on bone quality and osteoblast differentiation, as well as retinoic acid metabolism and signaling. In this study we analyzed associations between increased circulating retinol concentrations and altered bone mineral density in a mouse model following oral exposure to 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD). Additionally, effects of TCDD on differentiation marker genes and genes involved with retinoic acid metabolism were analysed in an osteoblast cell model followed by benchmark dose-response analyses of the gene expression data. Study results show that the increased trabecular and decreased cortical bone mineral density in the mouse model following TCDD exposure are associated with increased circulating retinol concentrations. Also, TCDD disrupted the expression of genes involved in osteoblast differentiation and retinoic acid synthesis, degradation, and nuclear translocation in directions compatible with increasing cellular retinoic acid levels. Further evaluation of the obtained results in relation to previously published data by the use of mode-of-action and weight-of-evidence inspired analytical approaches strengthened the evidence that TCDD-induced bone and retinoid system changes are causally related and compatible with an endocrine disruption mode of action.

Oxidative Stress Biomarkers in Urine of Metal Carpentry Workers Can Be Diagnostic for Occupational Exposure to Low Level of Welding Fumes from Associated Metals.

Urinary concentrations of 16 different exposure biomarkers to metals were determined at the beginning and at the end of a working shift on a group of workers in the metal carpentry industry. Five different oxidative stress biomarkers were also measured, such as the oxidation products of RNA and DNA metabolized and excreted in the urine. The results of workers exposed to metals were compared to those of a control group. The metal concentrations found in these workers were well below the occupational exposure limit values and exceeded the mean concentrations of the same metals in the urine of the control group by a factor of four at maximum. Barium (Ba), mercury (Hg), lead (Pb) and strontium (Sr) were correlated with the RNA oxidative stress biomarker, 8-oxo-7, 8-dihydroguanosine (8-oxoGuo), which was found able to discriminate exposed workers from controls with a high level of specificity and sensitivity. The power of this early diagnostic technique was assessed by means of the ROC curve. Ba, rubidium (Rb), Sr, tellurium (Te), and vanadium (V) were correlated with the level of the protein oxidation biomarker 3-Nitrotyrosine (3-NO2Tyr), and Ba, beryllium (Be), copper (Cu), and Rb with 5-methylcytidine (5-MeCyt), an epigenetic marker of RNA damage. These effect biomarkers can help in identifying those workers that can be defined as "occupationally exposed" even at low exposure levels, and they can provide information about the impact that such doses have on their health.

Dose-response evaluation of urinary cadmium and kidney injury biomarkers in Chinese residents and dietary limit standards.

BACKGROUND: Cadmium (Cd) is a common heavy metal that mainly causes renal damage. There is a lack of research on the large-scale and systematic evaluation of the association between urinary Cd (U-Cd) and various effect biomarkers among Chinese residents. METHODS: Based on the establishment process of dietary Cd limit standards by European Food Safety Authority (EFSA), the dose-response relationships between U-Cd and four biomarkers, ß2-microglobulin (ß2-MG), N-acetyl-ß-glucosidase (NAG), microalbumin (mALB), and retinol binding Protein (RBP) were explored, respectively. Toxicokinetic model was used to derive the dietary Cd exposure limit for Chinese residents after critical U-Cd concentration was calculated. RESULTS: As the sensitive biomarkers of renal injury, ß2-MG and NAG were selected to estimate the 95% confidence interval lower limit of the U-Cd benchmark dose (BMDL5) to be 3.07 and 2.98 µg/g Cr, respectively. Dietary Cd exposure limit was calculated to be 0.28 µg/kg bw/day (16.8 µg/day, based on the body weight of 60 kg), which was lower than the average Chinese Cd exposure (30.6 µg/day) by the China National Nutrient and Health Survey. CONCLUSION: This study established an overall association between U-Cd and renal injury biomarkers, and explored the Chinese dietary Cd exposure limits, which helps improve Chinese Cd exposure risk assessment and provides a reference basis for formulating reasonable exposure standards.

Urinary biomarkers of nucleic acid oxidation and methylation in workers exposed to low concentrations of benzene.

The study aims to investigate the influence of exposure to low concentrations of benzene on urinary biomarkers of nucleic acid oxidative damage and methylation. Benzene exposure was characterized for 93 coke production workers by measuring both airborne benzene and S-phenylmercapturic acid (SPMA) and unmodified benzene (U-B) in urine samples, collected at the end of the shift (ES) and at the next morning before shift (next BS). In the same urinary samples, biomarkers of nucleic acid oxidative damage and methylation were determined. Urinary concentrations of cotinine and creatinine were also determined to evaluate the smoking effect and to normalize urinary concentrations of analytes, respectively. The biomarkers of benzene internal dose, of oxidative damage (8-hydroxyy-7,8-dihydroguanine, 8-hydroxy-7,8-dihydroguanosine and 8-hydroxy-7,8-2'deoxyguanosine) and some of the biomarkers of nucleic acid methylation (5-Methyl-Cytosine, 1-Methyl-Guanine and 7-Methyl-Guanine) were higher in the ES than the next BS samples. Positive associations between ES 5-Methyl-Cytosine and both SPMA and U-B were found. In conclusion, occupational exposure to low levels of benzene seems to be related to urinary ES 5-Methyl-Cytosine that could be a possible biomarker to evaluate the changes of the nucleic acid methylation status.

Greater tree cover near residence is associated with reduced allostatic load in residents of central North Carolina.

BACKGROUND: Among urban residents, increased contacts with nature are associated with reduced morbidity and mortality. The concept of allostatic load, a biomarker-based composite measure of physiological dysregulation, can be applied to study subclinical benefits of exposure, and to elucidate pathways leading to improved health. OBJECTIVE: This research explored associations between residential vegetated land cover and an allostatic load index calculated using the statistical distance measure known as Mahalanobis distance. METHODS: This cross-sectional population-based study involved 186 adult residents of the Durham-Chapel Hill, North Carolina metropolitan area. Measures of tree and grass cover within 500 m of residence were derived from the U.S. Environmental Protection Agency's EnviroAtlas land cover database. Fifteen biomarkers of immune, neuroendocrine, and metabolic functions were analyzed in serum samples. Regression analysis was conducted using generalized additive models with thin-plate spline functions of geographic coordinates, adjusting for modelled traffic air pollution from local sources and sociodemographic covariates. RESULTS: The second and third tertiles of distance-weighted tree cover were associated with 14% (95% Confidence Limits 20%; 8%) and 15% (21%; 8%) reduction in adjusted median allostatic load, respectively, compared to the first tertile. The same tertiles of tree cover were also associated with 0.16 (0.03; 0.76) and 0.04 (0.01; 0.35) adjusted odds ratios of having allostatic load index above the 90th percentile of the sample distribution. Grass cover was inversely correlated with tree cover and was not associated with reduced allostatic load. CONCLUSIONS: Subclinical beneficial health effects of green spaces demonstrated in this study are consistent with reduced susceptibility to acute environmental and social stressors, and reduced risks of morbidity and mortality.