Biomarkers Of Early Effects Research Articles

Distinct transcriptional profiles in rat thyroid glands after developmental exposure to three in vitro thyroperoxidase inhibiting chemicals

Thyroperoxidase (TPO) is central in thyroid hormone (TH) synthesis and inhibition can lead to TH deficiency. Many chemicals can inhibit TPO activity in vitro, but how this may manifest in the developing thyroid gland at the molecular level is unclear. Here, we characterized the thyroid gland transcriptome of male rats developmentally exposed to the in vitro TPO-inhibitors amitrole, 2-mercaptobenzimidazole (MBI), or cyanamide by use of Bulk-RNA-Barcoding (BRB) and sequencing. Amitrole exposure caused TH deficiency and 149 differentially expressed genes in the thyroid gland. The effects indicated an activated and growing thyroid gland. MBI caused intermittent changes to serum TH concentrations in a previous study and this was accompanied by 60 differentially expressed genes in the present study. More than half of these were also affected by amitrole, indicating that they could be early effect biomarkers of developmental TH system disruption due to TPO inhibition. Further work to validate the signature is needed, including assessment of substance independency and applicability domain.

Potential Early Effect Biomarkers for Ambient Air Pollution Related Mental Disorders.

Air pollution is one of the greatest environmental risks to health, with 99% of the world's population living where the World Health Organization's air quality guidelines were not met. In addition to the respiratory and cardiovascular systems, the brain is another potential target of air pollution. Population- and experiment-based studies have shown that air pollution may affect mental health through direct or indirect biological pathways. The evidence for mental hazards associated with air pollution has been well documented. However, previous reviews mainly focused on epidemiological associations of air pollution with some specific mental disorders or possible biological mechanisms. A systematic review is absent for early effect biomarkers for characterizing mental health hazards associated with ambient air pollution, which can be used for early warning of related mental disorders and identifying susceptible populations at high risk. This review summarizes possible biomarkers involved in oxidative stress, inflammation, and epigenetic changes linking air pollution and mental disorders, as well as genetic susceptibility biomarkers. These biomarkers may provide a better understanding of air pollution's adverse effects on mental disorders and provide future research direction in this arena.

Extracellular Vesicles in Environmental Toxicological Studies: Association between Urinary Concentrations of Phthalate Metabolites and Exosomal miRNA Expression Profiles.

Phthalates are chemical compounds, mainly used as additives in plastics, which are known to induce harmful impacts to the environment and human health due to their ability to act as hormone-mimics. Few studies have been reported on the relationship between human exposure to phthalates and the level of circulating microRNAs (miRs), especially those miRs encapsulated in extracellular vesicles/exosomes or exosome-like vesicles (ELVs). We examined the relationship of ELV-miR expression patterns and urine of adult men with five phthalate metabolites (i.e., mono isobutyl phthalate, mono-n-butyl phthalate, mono benzyl phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethylhexyl) phthalate) to identify potential biomarkers and relevant pathways. We found significant positive associations which were further confirmed by multivariable analysis. Overall, our analyses showed that the Σ phthalate metabolite concentration was associated with a significant increase in the expression level of two miRs found in ELV: miR-202 and miR-543. Different pathways including cancer and immune-related responses were predicted to be involved in this relationship. Analyzing the specific downstream target genes of miR-202 and miR-543, we identified the phosphatase and tensin homolog (PTEN) as the key gene in several converging pathways. In summary, the obtained results demonstrate that exposure to environmental phthalates could be related to altered expression profiles of specific ELV-miRs in adult men, thereby demonstrating the potential of miRs carried by exosomes to act as early effect biomarkers.

Exposure and Early Effect Biomarkers for Risk Assessment of Occupational Exposure to Formaldehyde: A Systematic Review

The aim of the present review was to identify all the biomarkers used for assessing the internal dose and the related early effects determined by the occupational exposure to formaldehyde. For this purpose, a systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered in PROSPERO (ID: CRD42023416960). An electronic search of Pubmed, Scopus, and Web of Science was performed to collect all the papers concerning the focus of the review and published from the inception of each database until 18 September 2023. Articles were considered eligible if they reported data from observational studies, semi-experimental, and experimental studies on adult workers who were occupationally exposed to formaldehyde, regardless of gender or age. The quality assessment was performed using the adapted Newcastle–Ottawa Quality Assessment Scale. From 1524 articles, 52 were included. Few studies assessed the exposure to formaldehyde in occupational settings through biomarkers, especially by measuring formic acid in urine. The most common approach for evaluating the effects derived from occupational exposure to formaldehyde was the use of the cytogenetic biomarker micronucleus assay in peripheral blood lymphocytes and/or epithelial buccal cells.

Diesel exhaust particles exposure induces liver dysfunction: Exploring predictive potential of human circulating microRNAs signature relevant to liver injury risk

Diesel exhaust particles (DEP) pollution should be taken seriously because it is an extensive environmental and occupational health concern. Exploring early effect biomarkers is crucial for monitoring and managing DEP-associated health risk assessment. Here, we found that serum levels of 67 miRNAs were dysregulated in DEP exposure group. Notably, 20 miRNAs were identified as each having a significant dose-response relationship with the internal exposure level of DEP. Further, we revealed that the DEP exposure could affect the liver function of subjects and that 7 miRNAs (including the well-known liver injury indicator, miR-122–5p) could serve as the novel epigenetic-biomarkers (epi-biomarkers) to reflect the liver-specific response to the DEP exposure. Importantly, an unprecedented prediction model using these 7 miRNAs was established for the assessment of DEP-induced liver injury risk. Finally, bioinformatic analysis indicated that the unique set of miRNA panel in serum might also contribute to the molecular mechanism of DEP exposure-induced liver damage. These results broaden our understanding of the adverse health outcomes of DEP exposure. Noteworthy, we believe this study could shed light on roles and functions of epigenetic biomarkers from environmental exposure to health outcomes by revealing the full chain of exposure-miRNAs-molecular pathways-disease evidence.

Metal mixture exposures and multiplexed autoantibody screening in Navajo communities exposed to uranium mine wastes

BackgroundEnvironmental exposures to metals in uranium mining wastes and drinking water were documented in more than half of the 1304 Navajo community members of the Diné Network for Environmental Health (DiNEH) Project, the first comprehensive assessment of exposures to these metals and community health on the Navajo Nation. ObjectiveEvaluate environmental exposures among participants who provided blood and urine samples using multiplexed autoantibody positivity as an early effect biomarker. MethodsSurvey and geospatial location data, well water quality, and metals biomonitoring were used to assess exposures to mixed-metal wastes from 100 abandoned uranium waste sites. ResultsWe observed that the prevalence of multiplexed autoantibody positivity in 239 participants was more than double that reported for the U.S. population (27.2% v. 13.8%) even though the national prevalence was generated using a different assay, the HEp-2 cell-based antinuclear antibody test. Increased risk of multiplexed autoantibody screening positivity (OR = 3.07,95%CI 1.15–8.22) was found among DiNEH study people who lived close to uranium mine and milling wastes and consumed metals in drinking water. Associations for females were even stronger when they lived closed to contaminated uranium mining and milling sites. Anti-U1-RNP antibodies were associated with water consumption of nickel. ConclusionProximity to waste sites and consumption of metals in water even below current drinking water standards were associated with perturbations of immune tolerance. These findings are consistent with previous studies of autoimmunity in the local population and demonstrate that multiplexed autoantibody screening method has a potential as sentinel indicator of exposures to environmental metals. Impact statementThis is the first, community-engaged environmental health study in exposed Navajo communities that applied clinical multiplexed testing in risk assessment of environmental metals associated with abandoned, unremediated uranium mining and milling waste sites. Routine clinical autoimmunity measures could be used as early effect biomarkers of environmental metal exposures.

Next Generation Sequencing for miRNA Detection on the Exhaled Breath Condensate: A Pilot Study.

Exhaled breath condensate (EBC) sampling has been suggested as a less-invasive and cost-effective method to detect biological macromolecules, including miRNA. To explore the feasibility of its use as a biomarker of early effects of asbestos exposure, we conducted a preliminary test on male volunteers by comparing the miRNA profile in the EBC and the plasma using 2 different sequencing platforms. Six male volunteers, all retired and unexposed to dust or fumes, participated in the test. RNA was extracted from 200 μL EBC samples and same-size plasma samples. Sample aliquots were processed in 2 laboratories using 2 different sequencing platforms: a MiSeq Illumina® platform and a more performing HiSeq Illumina® platform. The HiSeq3000® sequencing platform identified twice as many unique molecular indexes (UMI)-validated miRNA as the MiSeq® platform. The Spearman's correlation coefficient between EBC counts and plasma counts was significant in 5/6 subjects with either platform (MiSeq® = 0.128-0.508, P = .026-<.001; HiSeq® = 0.156-0.412, P = .001-<.001). The intraclass correlation coefficient confirmed the consistency of the miRNA profile over the 6 participants with both biospecimens. Exploring the agreement between the EBC and plasma samples with Bland-Altman plots showed that using the HiSeq3000® platform substantially improved the EBC miRNA detection rate. Our preliminary study confirms that, when using the HiSeq® sequencing platform, EBC sampling is a suitable, non-invasive method to detect the miRNA profile in healthy subjects.

Pulmonary effects of exposure to indium and its compounds: cross-sectional survey of exposed workers and experimental findings in rodents

BackgroundMany studies have shown that occupational exposure to indium and its compounds could induce lung disease. Although animal toxicological studies and human epidemiological studies suggest indium exposure may cause lung injury, inflammation, pulmonary fibrosis, emphysema, pulmonary alveolar proteinosis, and even lung cancer, related data collected from humans is currently limited and confined to single workplaces, and the early effects of exposure on the lungs are not well understood.ObjectivesThis study combined population studies and animal experiments to examine the links of indium with pulmonary injury, as well as its mechanism of action. A cross-sectional epidemiological study of indium-exposed workers from China was conducted to evaluate associations between occupational indium exposure and serum biomarkers of early effect. This study also compares and analyzes the causal perspectives of changes in human serum biomarkers induced by indium compound exposure and indium exposure-related rat lung pathobiology, and discusses possible avenues for their recognition and prevention.MethodsThis is a study of 57 exposed (at least 6 h per day for one year) workers from an indium ingot production plant, and 63 controls. Indium concentration in serum, urine, and airborne as exposure indices were measured by inductively coupled plasma-mass spectrometry. Sixteen serum biomarkers of pulmonary injury, inflammation, and oxidative stress were measured using ELISA. The associations between serum indium and 16 serum biomarkers were analyzed to explore the mechanism of action of indium on pulmonary injury in indium-exposed workers. Animal experiments were conducted to measure inflammatory factors levels in bronchoalveolar lavage fluid (BALF) and lung tissue protein expressions in rats. Four different forms of indium compound-exposed rat models were established (intratracheal instillation twice per week, 8 week exposure, 8 week recovery). Model I: 0, 1.2, 3, and 6 mg/kg bw indium tin oxide group; Model II: 0, 1.2, 3, and 6 mg/kg bw indium oxide (In2O3) group; Model III: 0, 0.523, 1.046, and 2.614 mg/kg bw indium sulfate (In2(SO4)3) group; Model IV: 0, 0.065, 0.65, and 1.3 mg/kg bw indium trichloride (InCl3) group. Lung pathological changes were assessed by hematoxylin & eosin, periodic acid Schiff, and Masson’s staining, transmission electron microscopy, and the protein changes were determined by immunohistochemistry.ResultsIn the production workshop, the airborne indium concentration was 78.4 μg/m3. The levels of serum indium and urine indium in indium-exposed workers were 39.3 μg/L and 11.0 ng/g creatinine. Increased lung damage markers, oxidative stress markers, and inflammation markers were found in indium-exposed workers. Serum indium levels were statistically and positively associated with the serum levels of SP-A, IL-1β, IL-6 in indium-exposed workers. Among them, SP-A showed a duration-response pattern. The results of animal experiments showed that, with an increase in dosage, indium exposure significantly increased the levels of serum indium and lung indium, as well as the BALF levels of IL‑1β, IL‑6, IL‑10, and TNF‑α and up-regulated the protein expression of SP-A, SP-D, KL-6, GM-CSF, NF-κB p65, and HO-1 in all rat models groups. TEM revealed that In2(SO4)3 and InCl3 are soluble and that no particles were found in lung tissue, in contrast to the non-soluble compounds (ITO and In2O3). No PAS-staining positive substance was found in the lung tissue of In2(SO4)3 and InCl3 exposure groups, whereas ITO and In2O3 rat models supported findings of pulmonary alveolar proteinosis and interstitial fibrosis seen in human indium lung disease. ITO and InCl3 can accelerate interstitial fibrosis. Findings from our in vivo studies demonstrated that intra-alveolar accumulation of surfactant (immunohistochemistry) and characteristic cholesterol clefts granulomas of indium lung disease (PAS staining) were triggered by a specific form of indium (ITO and In2O3).ConclusionsIn indium-exposed workers, biomarker findings indicated lung damage, oxidative stress and an inflammatory response. In rat models of the four forms of indium encountered in a workplace, the biomarkers response to all compounds overall corresponded to that in humans. In addition, pulmonary alveolar proteinosis was found following exposure to indium tin oxide and indium oxide in the rat models, and interstitial fibrosis was found following exposure to indium tin oxide and indium trichloride, supporting previous report of human disease. Serum SP-A levels were positively associated with indium exposure and may be considered a potential biomarker of exposure and effect in exposed workers.

Metabolomic Study of Urine from Workers Exposed to Low Concentrations of Benzene by UHPLC-ESI-QToF-MS Reveals Potential Biomarkers Associated with Oxidative Stress and Genotoxicity.

Benzene is a human carcinogen whose exposure to concentrations below 1 ppm (3.19 mg·m−3) is associated with myelotoxic effects. The determination of biomarkers such as trans-trans muconic acid (AttM) and S-phenylmercapturic acid (SPMA) show exposure without reflecting the toxic effects of benzene. For this reason, in this study, the urinary metabolome of individuals exposed to low concentrations of benzene was investigated, with the aim of understanding the biological response to exposure to this xenobiotic and identifying metabolites correlated with the toxic effects induced by it. Ultra-efficient liquid chromatography coupled to a quadrupole-time-of-flight mass spectrometer (UHPLC-ESI-Q-ToF-MS) was used to identify metabolites in the urine of environmentally (n = 28) and occupationally exposed (n = 32) to benzene (mean of 22.1 μg·m−3 and 31.8 μg·m−3, respectively). Non-targeted metabolomics analysis by PLS-DA revealed nine urinary metabolites discriminating between groups and statistically correlated with oxidative damage (MDA, thiol) and genetic material (chromosomal aberrations) induced by the hydrocarbon. The analysis of metabolic pathways revealed important alterations in lipid metabolism. These results point to the involvement of alterations in lipid metabolism in the mechanisms of cytotoxic and genotoxic action of benzene. Furthermore, this study proves the potential of metabolomics to provide relevant information to understand the biological response to exposure to xenobiotics and identify early effect biomarkers.

Exposure to engineered nanomaterials and early biological effects measured in the exhaled breath condensate: First results from the NanoExplore cohort

BACKGROUND AND AIM Activities involving engineered nanomaterials (ENM) may raise concerns of occupational exposure and subsequent health effects. We aimed to build a multicenter prospective cohort to assess the potential effects of ENM exposure using biomarkers of early effects measured in exhaled breath condensate (EBC). METHODS We recruited seven centers in three countries (Switzerland, Spain, and Italy), where we conducted a 4-day exposure monitoring campaign and two EBC samplings, at the beginning (T1) and end (T2) of working week. The recruited workers were split in three groups depending on their exposure and compared in terms of their baseline individual and professional characteristics, and health status. EBC biomarkers of oxidative and nitrosative stress (malondialdehyde, 8-isoprostane, nitrotyrosine), systemic inflammation (High-Sensitivity C-Reactive Protein (hsCRP)), activation of pro-fibrotic cascade and interstitial lung disease (Krebs von den Lungen glycoprotein 6 (KL6)) and inflammatory cytokines (Interleukins (IL-10, IL-1β), Tumor necrosis factor (TNF-α)) were analyzed using multilevel mixed interval regression models. RESULTS The cohort included 140 participants: 43 non-exposed, 55 with negligible to low exposure, and 43 with medium to high exposure. The latter were gradually more often men, older, and in overweight than lowly exposed and non-exposed workers. A statistically significant change between T1 and T2 average concentrations was observed for malondialdehyde and KL6. Between-group differences were observed for all biomarkers but KL6 and nitrotyrosine. In multivariate models adjusted for age, sex and body mass index, a linear exposure-response relationship was observed for malondialdehyde, 8-isoprostane, IL-10, IL-1β, and TNF-α. ENM exposure was also associated with higher hs-CRP and KL6 levels, but not monotonically. CONCLUSION These first results suggest that ENM exposure might lead to early biological effects in workers’ airways. These findings need confirmation and a caution interpretation of their clinical significance, as most effects are non-specific and likely reversible.

On-Site Deployment of an Air-Liquid-Interphase Device to Assess Health Hazard Potency of Airborne Workplace Contaminants: The Case of 3-D Printers.

Biomonitoring of workers is an approach of evaluating workers’ exposure to chemicals and particulate matter by measuring biomarkers of parent chemicals, their metabolites, and reaction products in workers’ biospecimens. Prerequisites for biological monitoring in the workplace include permission to enter the workplace, approval of the study plan from the IRB (Institutional Review Board), and obtaining consent from workers. Because of the complex legal process involved in biomonitoring, few studies have been conducted so far on biomonitoring of workers’ exposures to nanoparticles and other hazards from emerging materials and advanced nanotechnologies. We have developed a cell-based biomonitoring device that can evaluate acute cytotoxicity and various other effect biomakers, such as inflammation, at realistic workplace exposure. This device is based on air–liquid interphase (ALI) and can be used to evaluate cell toxicity and early effect biomarkers along adverse outcome pathways. Following exposure of A549 lung epithelial cells in ALI to workplace air for 1–2 h, the cells were processed to assess the induction of inflammatory and cell damage biomarkers. Initially, we estimated the deposition rate of nanoparticles in the transwell by exposing the cell-free ALI device to silver nanoparticle aerosols (AgNP 20–30 nm) for 2 h in the laboratory. Then A549 lung epithelial cells cultured on the transwell in the ALI device were exposed to AgNP nanoaerosols for 2 h and evaluated for cytotoxicity and induction of mRNAs of pro-inflammatory cytokines IL-1b, IL-6, and TNF-α. Then the cells in the ALI device were exposed to 3-D printer emissions at the workplace and evaluated for the same matched endpoints. The mRNA levels for IL-1b, IL-6, and TNF-α increased significantly at the end of 2-h exposure of A549 cells to the positive control AgNP aerosols. These mRNAs, as well as LDH and microprotein concentrations, increased even more after 24-h post-exposure incubation (p < 0.05). Cytotoxicity evaluation of 3-D printer emissions at 810 and 957 μg/m3, which was more than 80 times higher than the airborne total suspended particulate concentrations in the workplace air (9–12.5 μg/m3), suggested no significant acute cytotoxicity at the end of 2-h exposure to 3-D-printing emission, as well as at 24-h post-exposure incubation. Hyperspectral microscopic observation showed that 3-D printers emitted particles to be attached to A549 cells after 2-h exposure, and many particles were internalized by A549 cells after 24 h of post-exposure incubation. The mRNA expression of pro-inflammatory cytokine IL-1b and IL-6 increased significantly after 2-h exposure to 3-D printer emissions and after 24-h incubation (only IL-6). In contrast, the expression of TNF-α mRNA decreased significantly after 2 h of exposure to 3-D printers and decreased even more after 24-h post-exposure incubation. These results support the use of cell-based ALI devices for direct assessment of airborne hazards in the workplace, for probing toxicological properties of airborne contaminants using adverse molecular pathways, and for guiding study design for workplace biomonitoring. ALI devices can bridge conventional exposure assessment with cellular toxicity testing platforms for hazard and risk assessment.

Long term mortality and morbidity of Italian soldiers after deployment in Iraq as related to biomarkers assessment: Results of the SIGNUM study

IntroductionThe health profile of military veterans deployed in foreign operative theatres was assessed by several international studies because of potential exposure to depleted uranium and other pollutants. Here we reported results of 15-year epidemiological surveillance assessing long-term health effects in a cohort of Italian soldiers deployed in Iraq in 2004–2005 and participating in a biomonitoring campaign to identify potential genotoxic exposure to environmental xenobiotics before and after deployment (n = 981, SIGNUM cohort). MethodsWe evaluated mortality and hospitalization risks of the SIGNUM cohort retrospectively until 2016 and 2018 respectively. A wide cohort of military personnel never deployed abroad (n = 114,260) and the general Italian population were used as control populations in risk assessment. Causes of death and diagnoses of hospitalization were derived through deterministic record linkage with official national databases of mortality and hospital discharge. Standardized Mortality Ratio (SMR) and Standardized Hospitalization Ratio (SHR) were computed adjusting according to sex, age, area of birth, and calendar year. Differential pre-post deployment in xenobiotics concentrations and early effect biomarkers (oxidative DNA alterations and micronuclei) measured in blood serum were analysed in relation to cancer hospitalization. ResultsMortality risk due to pathologies was more than halved compared to the general population (SMR = 0.41, 95% CI 0.11–1.05) and not significantly different compared to soldiers never deployed abroad (SMR = 0.69, 95% CI 0.19–1.68).Similarly overall hospitalization risk due to pathologies was decreased with respect to the general population (SHR = 0.86, 95% CI 0.80–0.92) and comparable to the control military group (SHR = 0.99, 95% CI: 0.93–1.06). For haematological cancers a decreased hospitalization risk compared to the Italian general population was observed (SHR = 0.38, 95% CI 0–0.92). No statistically significant differences emerged in the patterns of biomarkers in association with cancer hospitalization. ConclusionThe study confirms the so called ‘healthy warrior’ effect for the SIGNUM veterans and showed no correlation between cancer occurrence and biomonitoring markers measured on field.

Organophosphate and Organohalogen Flame-Retardant Exposure and Thyroid Hormone Disruption in a Cross-Sectional Study of Female Firefighters and Office Workers from San Francisco.

Occupational exposures to flame retardants (FRs), a class of suspected endocrine-disrupting compounds, are of health concern for firefighters. We sought to characterize exposure to FR compounds and evaluate their association with thyroid hormone levels, a biomarker of early effect, in female firefighters and office workers in San Francisco. In a cross-sectional study, we measured replacement organophosphate and organohalogen FRs in spot urine samples from firefighters (N = 86) and office workers (N = 84), as well as total thyroxine (T4) and thyroid-stimulating hormone in plasma for 84 firefighters and 81 office workers. Median bis(1,3-dichloro-2-propyl)phosphate (BDCPP) levels were 5 times higher in firefighters than office workers. Among firefighters, a doubling of BDCPP was associated with a 2.88% decrease (95% confidence interval −5.28, −0.42) in T4. We did not observe significant associations between FRs and T4 among office workers. In the full group, intermediate body mass index and a college education were associated with higher FR levels. The inverse association observed between FRs and T4 coupled with the lack of studies on women workers and evidence of adverse health effects from FR exposure—including endocrine disruption and breast cancer risk—warrant further research on occupational exposures and identification of opportunities for exposure reduction.

Assessing effects of chronic heavy metal exposure through a multibiomarker approach: the case of Liomys irroratus (Rodentia: Heteromyidae)

Wild animals that inhabit inside mine tailings which contain heavy metals are an excellent study model to conduct ecotoxicological studies that analyze chronic metal exposures at low doses (realistic exposures). This study was conducted in Huautla, Morelos, Mexico, in a mining district where 780,000 tons of wastes were deposited in open air. Liomys irroratus is a small mammal species that lives inside these mine tailings. A multibiomarker approach study was performed to analyze metal bioaccumulation levels (biomarker of exposure) by inductively coupled plasma mass spectrometry, DNA damage levels (biomarker of early effects) through the alkaline comet assay, and population genetic structure and diversity (biomarker of permanent effects), using seven microsatellite loci, in 75 L. irroratus individuals, from two mine tailings and one reference site. Concentrations of aluminum, copper, iron, nickel, lead, and zinc were statistically higher in the liver of exposed individuals. Significant DNA damage levels were registered in the mine tailings groups. Aluminum, lead, and nickel had the highest contribution to the genetic damage levels observed, while aluminum and nickel had the highest contribution to genetic diversity effects. A positive and significant relationship was detected between individual genetic diversity (internal relatedness) and genetic damage (DNA single-strand breaks). Genetic structure of L. irroratus populations revealed that the main source of genetic variation was located within populations. We consider that multibiomarker studies in environmental settings using sentinel species are valuable for environmental risk assessment and ecological responses in chronic exposed populations.

Renal impairment assessment on adults living nearby a landfill: Early kidney dysfunction biomarkers linked to the environmental exposure to heavy metals.

The aim of this study was to assess the integrity and kidney overall functional capacity of subjects exposed to landfill emissions. Urine and blood levels of Pb and Cd, and several of the newly biomarkers of nephrotoxicity (Kim Injury Molecule 1 (KIM-1), alpha-1 Microglobulin (α1 M), beta-2 Microglobulin (β2 M), Cystatin-C (Cyst C), Clusterin, alpha-glutathione S-transferase (GSTα), pi-glutathione S-transferase (GSTπ), Tissue Inhibitor of Metalloproteinase-1 (TIMP1), Calbindin, Neutrophil Gelatinase-Associated Lipocalin (NGAL), Osteopontin (OPN), (Retinol Binding Protein(RBP), Liver-type Fatty Acid-Binding Protein (FABP-1), Trefoil Factor 3 (TFF3), Collagen VI) were measured in order to assess glomerular and tubule damage in adults living near a landfill. Our results indicate glomerular dysfunction in exposed subjects, and supported evidence of necrosis of proximal and distal tubule epithelial cells as specific biomarkers began to appear in the urine. Positive correlation by Pearson test were obtained between : blood Pb and B-OPN, B-Cyst C, Calbindin, U-KIM-1, TIMP1, U-OPN, and U-Clusterin; and also, between urinary Cd and TIMP1, B-Clusterin, U-OPN, FABP-1, Albumin, and U-Clusterin. The relation between biomarkers of Cd/Pb exposure and early effect biomarkers in this study clearly predicts the future risk of severe kidney injury in subjects living close to the landfill.

1H NMR-based metabolomics study of the dynamic effect of Xue-Fu-Zhu-Yu capsules on coronary heart disease rats induced by high-fat diet, coronary artery ligation

An 1H NMR-based metabolomics approach was conducted to holisticly explore the effect of Xue Fu Zhu Yu (XFZY) capsule (a well-known Chinese herbal medicine) on high-fat diets combined with coronary artery ligation induced coronary heart disease (CHD) model rats. 1H NMR-based metabolomics approach combined with multivariate analysis was performed to explore potential biomarkers, a total of 20 metabolites were confirmed as contributors to the discrimination of model group and sham group. We investigated the dynamic metabolic characteristics of XFZY capsule on CHD rats, lactate, glutamine, pyruvate, citrate, choline and taurine were potential biomarkers of early effect. More potential biomarkers changed after 28 days of medication, XFZY capsules primarily influenced the taurine and hypotaurine metabolism, glycine, serine and threonine metabolism, glyoxylate and dicarboxylate metabolism, purine metabolism, glycolysis/gluconeogenesis, amino sugar and nucleotide sugar metabolism, primary bile acid biosynthesis.

First baseline for bioenergetic biomarkers in Cnesterodon decemmaculatus as test organism in ecotoxicological studies

Cnesterodon decemmaculatus is a Neotropical teleost fish frequently used in ecotoxicological evaluations, whose biology has been thoroughly studied. Although there is considerable information on its response to different toxicants, no range of reference values has been so far established for the different biological parameters proposed as biomarkers of effect or exposure. Moreover, no study has yet examined the possible influence of the metabolic status of the exposed animals on their response to toxic stress. Therefore, the aim of this work was to provide a first baseline for a set of bioenergetic biomarkers in C. decemmaculatus adults exposed to a control medium under previously standardized conditions, and to assess their possible intrinsic seasonal variability. The responses of the biomarkers obtained from the controls were contrasted with those from the reference toxicant (Cadmio-Cd) and receiving waters (surface waters of the Reconquista River RR, Buenos Aires Province, Argentina). We conducted four 12-day assays (one in each season) of exposure to control media, (reconstituted moderate hard water, MHW) and two assays of exposure to Cd in MHW and surface river water (RR) in both summer and autumn. The variables recorded were: Food intake (In), fecal production (F), specific assimilation (A) and cumulative mortality, oxygen extraction efficiency (OEE), specific metabolic rate (SMR), ammonia excretion (N), ammonia quotient (AQ) and scope for growth (SFG). The seasonal variation shown by some physiological parameters, points to the need for establishing a baseline obtained from standardized media, preferably on a seasonal basis. Moreover, SFG and A appeared as the most sensitive biomarkers, emphasizing the importance to consider the metabolic status of the test organisms for the appropriate interpretation of results from ecotoxicological studies performed under controlled experimental conditions. The obtained results provide useful information on C. decemmaculatus as model species in ecotoxicological bioassays involving biomarkers of early effect.

Genotoxic damage in workers exposed to pigment-grade titanium dioxide (TiO2) during paint production

Abstract TiO2 is broadly used in a wide range of applications such as photocatalysis, pigments and additives. Despite the promising commercial opportunities, different studies have shown that TiO2 can induce oxidative stress, inflammatory and genotoxic effects. The European Union has classified certain titanium dioxide powders and powder mixtures containing TiO2 as a suspected carcinogen (Category 2) via inhalation. Considering that the information about the potential adverse health effects of TiO2 in occupational environment are still scarce and controversial, the purpose of the study was to investigate the genotoxic effects and oxidative stress in workers exposed to TiO2 during paint production. Biomarkers of early effect (DNA damage and micronuclei) were evaluated in the buccal cells and salivary leucocytes of 30 workers (15 production workers and 15 controls). To collect information about personal details, occupational history, medication, smoking, diet, physical activity, a questionnaire was administered to all workers. Personal and area monitoring have been carried out to determine airborne inhalable and respirable fraction of TiO2; a NanoTracer was used to monitor the presence of ultrafine particles. In spite of the low mass concentration and a mild percentage of nanoparticles, filter deposited TiO2 was in sub-micron size, thus accounting for its respirability. Preliminary results on salivary leucocytes show a slight higher DNA damage in the exposed workers as compared to the controls. Whereas biomarker assessment is still in progress, these preliminary findings show that workers are exposed to low but measurable levels of TiO2 able to induce a mild genotoxic damage. A combined approach using both personal exposure assessment and biomonitoring can improve the risk assessment in occupational settings in which TiO2 is handled. Moreover, this also suggest to take precautionary measure during specific activities and operational phases thus decreasing the risks for worker. Key messages The results of the present study may promote effective risk management practices in occupational environments that uses TiO2. The results obtained suggest the introduction of activities and operational phases with lower risks for the worker.

Increased micronucleus frequencies in reticulocytes of children exposed to industrial pollution: oxidative stress and the OGG1 S326C polymorphism

We examined possible early-effect biomarkers and polymorphisms of susceptibility in primary school children living near the Atoyac River in central México, which receives waste from multiple industries. We observed a significant increase in micronucleated reticulocytes associated with the oxidative stress index (OSI) and the OGG1 GG (S326C) genotype, and a significant decrease of reticulocytes carrying the transferrin receptor, inversely correlated with OSI.

Urinary prostaglandin E2 is a biomarker of early adaptive hyperfiltration in solitary functioning kidney

IntroductionHyperfiltration is a major contributor to progression of chronic kidney disease (CKD) in diabetes, obesity and in individuals with solitary functioning kidney (SFK). We have proposed hyperfiltration-induced injury as a continuum of overlapping glomerular changes caused by increased biomechanical forces namely, fluid flow shear stress (FFSS) and tensile stress. We have shown that FFSS is elevated in animals with SFK and, it upregulates prostaglandin E2 (PGE2), cyclooxygenase-2 and PGE2 receptor EP2 in cultured podocytes and in uninephrectomized mice. We conceptualized urinary PGE2 as a biomarker of early effects of hyperfiltration-induced injury preceding microalbuminuria in individuals with SFK. We studied children with SFK to validate our hypothesis. MethodsUrine samples from children with SFK and controls were analyzed for PGE2, albumin (glomerular injury biomarker) and epidermal growth factor (EGF, tubular injury biomarker). Age, gender, and Z-scores for height, weight, BMI, and blood pressure were obtained. ResultsChildren with SFK were comparable to controls except for lower BMI Z-scores. The median values were elevated in SFK compared to control for urine PGE2 [9.1 (n = 57) vs. 5.7 (n = 72), p = 0.009] ng/mgCr and albumin [7.6 (n = 40) vs. 7.0 (n = 41), p = 0.085] μg/mgCr, but not for EGF [20098 (n = 44) vs. 18637 (n = 44), p = 0.746] pg/mgCr. Significant increase in urinary PGE2 (p = 0.024) and albumin (p = 0.019) but not EGF (p = 0.412) was observed using additional regression modeling. These three urinary analytes were independent of each other. ConclusionIncreased urinary PGE2 from elevated SNGFR and consequently increased FFSS during early stage of CKD precedes overt microalbuminuria and is a biomarker for early hyperfiltration-induced injury in individuals with SFK.