| 1. |
- Arlt, Volker M., et al.
(författare)
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Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone
- 2017
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:4, s. 1957-1975
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to aristolochic acid (AA) causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). Conflicting results have been found for the role of human sulfotransferase 1A1 (SULT1A1) contributing to the metabolic activation of aristolochic acid I (AAI) in vitro. We evaluated the role of human SULT1A1 in AA bioactivation in vivo after treatment of transgenic mice carrying a functional human SULT1A1-SULT1A2 gene cluster (i.e. hSULT1A1/2 mice) and Sult1a1(−/−) mice with AAI and aristolochic acid II (AAII). Both compounds formed characteristic DNA adducts in the intact mouse and in cytosolic incubations in vitro. However, we did not find differences in AAI-/AAII-DNA adduct levels between hSULT1A1/2 and wild-type (WT) mice in all tissues analysed including kidney and liver despite strong enhancement of sulfotransferase activity in both kidney and liver of hSULT1A1/2 mice relative to WT, kidney and liver being major organs involved in AA metabolism. In contrast, DNA adduct formation was strongly increased in hSULT1A1/2 mice compared to WT after treatment with 3-nitrobenzanthrone (3-NBA), another carcinogenic aromatic nitro compound where human SULT1A1/2 is known to contribute to genotoxicity. We found no differences in AAI-/AAII-DNA adduct formation in Sult1a1(−/−) and WT mice in vivo. Using renal and hepatic cytosolic fractions of hSULT1A1/2, Sult1a1(−/−) and WT mice, we investigated AAI-DNA adduct formation in vitro but failed to find a contribution of human SULT1A1/2 or murine Sult1a1 to AAI bioactivation. Our results indicate that sulfo-conjugation catalysed by human SULT1A1 does not play a role in the activation pathways of AAI and AAII in vivo, but is important in 3-NBA bioactivation.
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| 2. |
- Bondarenko, Olesja M., et al.
(författare)
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Current challenges and coming opportunities in nanoparticle risk assessment
- 2020
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Ingår i: Colloids for Nanobiotechnology : Synthesis, Characterization and Potential Applications - Synthesis, Characterization and Potential Applications. - 1876-276X .- 1876-2778. - 9780081028285 ; 16, s. 353-371
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Bokkapitel (refereegranskat)abstract
- This chapter discusses the key aspects of engineered nanomaterial (ENM) toxicity. The individual properties of ENMs affecting their toxic potential are described, with a special focus on size, shape, and surface charge and functionalization. We present empirical evidence from a range of in vitro and in vivo studies showing potential adverse effects induced via inhalation, ingestion, or skin contact with ENMs, as well as a brief overview of human studies and nanoecotoxicology. Finally, a summary of current guidelines and frameworks is provided, together with a collection of the most prominent nanosafety projects and resources available for the assessment of nanotoxicity. This literature review demonstrates that there is a need for the collection of standardized data from human studies to inform epidemiological studies. Moreover, despite the wide usage of ENMs and reported toxic potentials, there is a shortage of policies regulating the exposure and usage of ENMs to protect both the environment and human health.
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| 3. |
- Gorrochategui, Eva, et al.
(författare)
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High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring
- 2023
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Ingår i: Environment International. - 0160-4120. ; 181
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.
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| 4. |
- Gren, Louise, et al.
(författare)
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Effect of renewable fuels and intake O2 concentration on diesel engine emission characteristics and reactive oxygen species (ROS) formation
- 2020
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Ingår i: Atmosphere. - : MDPI AG. - 2073-4433. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Renewable diesel fuels have the potential to reduce net CO2 emissions, and simultaneously decrease particulate matter (PM) emissions. This study characterized engine-out PM emissions and PM-induced reactive oxygen species (ROS) formation potential. Emissions from a modern heavy-duty diesel engine without external aftertreatment devices, and fueled with petroleum diesel, hydrotreated vegetable oil (HVO) or rapeseed methyl ester (RME) biodiesel were studied. Exhaust gas recirculation (EGR) allowed us to probe the effect of air intake O2 concentration, and thereby combustion temperature, on emissions and ROS formation potential. An increasing level of EGR (decreasing O2 concentration) resulted in a general increase of equivalent black carbon (eBC) emissions and decrease of NOx emissions. At a medium level of EGR (13% intake O2), eBC emissions were reduced for HVO and RME by 30 and 54% respectively compared to petroleum diesel. In general, substantially lower emissions of polycyclic aromatic hydrocarbons (PAHs), including nitro and oxy-PAHs, were observed for RME compared to both HVO and diesel. At low-temperature combustion (LTC, O2 < 10%), CO and hydrocarbon gas emissions increased and an increased fraction of refractory organic carbon and PAHs were found in the particle phase. These altered soot properties have implications for the design of aftertreatment systems and diesel PM measurements with optical techniques. The ROS formation potential per mass of particles increased with increasing engine O2 concentration intake. We hypothesize that this is because soot surface properties evolve with the combustion temperature and become more active as the soot matures into refractory BC, and secondly as the soot surface becomes altered by surface oxidation. At 13% intake O2, the ROS-producing ability was high and of similar magnitude per mass for all fuels. When normalizing by energy output, the lowered emissions for the renewable fuels led to a reduced ROS formation potential.
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| 5. |
- Krais, Annette M., et al.
(författare)
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Carcinogen-DNA Adducts
- 2019. - Third Edition
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Ingår i: Encyclopedia of Cancer. - 9780128124857 ; , s. 282-295
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Bokkapitel (refereegranskat)abstract
- Carcinogen-DNA adducts result from the covalent interaction of electrophilic chemical carcinogens with nucleophilic sites in DNA. Some highly reactive genotoxic carcinogens are capable of directly binding to DNA but most carcinogens require metabolic activation. DNA adducts, if not repaired, can lead to mutations, and mutations in critical genes are a characteristic feature of tumors. Thus DNA adduct formation is considered a critical step in the initiation of carcinogenesis. DNA adducts formed in human tissues can be detected by a variety of sensitive techniques including 32P-postlabeling, mass spectrometry, accelerator mass spectrometry, and immunoassays. Their detection and characterization in human tissues can provide clues on the etiology of human cancer.
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| 6. |
- Krais, Annette, et al.
(författare)
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Metabolic activation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine and DNA adduct formation depends on p53: Studies in Trp53(+/+),Trp53(+/-) and Trp53(-/-) mice.
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136.
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Tidskriftsartikel (refereegranskat)abstract
- The expression of the tumor suppressor p53 can influence the bioactivation of, and DNA damage induced by, the environmental carcinogen benzo[a]pyrene, indicating a role for p53 in its cytochrome P450 (CYP)-mediated biotransformation. The carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which is formed during the cooking of food, is also metabolically activated by CYP enzymes, particularly CYP1A2. We investigated the potential role of p53 in PhIP metabolism in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with a single oral dose of 50 mg/kg body weight PhIP. N-(Deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP-C8-dG) levels in DNA, measured by liquid chromatography-tandem mass spectrometry, were significantly lower in liver, colon, forestomach and glandular stomach of Trp53(-/-) mice compared to Trp53(+/+) mice. Lower PhIP-DNA adduct levels in the livers of Trp53(-/-) mice correlated with lower Cyp1a2 enzyme activity (measured by methoxyresorufin-O-demethylase activity) in these animals. Interestingly, PhIP-DNA adduct levels were significantly higher in kidney and bladder of Trp53(-/-) mice compared to Trp53(+/+) mice, which was accompanied by higher sulfotransferase (Sult) 1a1 protein levels and increased Sult1a1 enzyme activity (measured by 2-naphthylsulfate formation from 2-naphthol) in kidneys of these animals. Our study demonstrates a role for p53 in the metabolism of PhIP in vivo, extending previous results on a novel role for p53 in xenobiotic metabolism. Our results also indicate that the impact of p53 on PhIP biotransformation is tissue-dependent and that in addition to Cyp1a enzymes, Sult1a1 can contribute to PhIP-DNA adduct formation.
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| 7. |
- Li, Li, et al.
(författare)
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Characterization of residential household dust from Shanghai by particle size and analysis of organophosphorus flame retardants and metals
- 2019
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Ingår i: Environmental Sciences Europe. - : Springer. - 2190-4707 .- 2190-4715. ; 31:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Physical and biological properties of dust particles might affect the availability and distribution of chemicals associated to indoor dust; however it has not been adequately examined. In this study, household dust from Shanghai was fractionated into five particle sizes and size distribution, morphology, surface area, organic matter, microorganisms, elemental composition, metals and organophosphorus flame retardants (OPFRs) compositions were characterized. Also, household dust samples from Stockholm that has previously been characterized were included in the analysis of OPFRs for comparison.Results: The respirable fraction had a yield of 3.3% in mass percentage, with a particle size of 2.22 +/- 2.04 mu m. As expected, both metals and OPFRs concentrations increased with decreased particle size. Al and Fe dominated (66-87%) followed by the concentrations of Zn (5-14%) and Ga (1.8-5%) of the sum of 16 metals in the dust. The concentrations of OPFRs in Shanghai dust ranged from 5.34 to 13.7 mu g/g (median: 7.21 mu g/g), compared to household dust from Stockholm that ranged from 16.0 to 28.3 mu g/g (median: 26.6 mu g/g). Tris(2-chloroisopropyl) phosphate (TCIPP) and tris(2-chloroethyl) phosphate (TCEP) dominated in Shanghai dust samples while tris(2-butoxyethyl) phosphate (TBOEP) dominated in dust from Stockholm homes.Conclusion: The results showed that mass percentage for each particle size fraction was not evenly distributed. Furthermore, the particle-bound microorganisms and OPFRs increased with decreased particle size, whereas metals had the highest concentrations at specific dust sizes. Therefore, it is essential to select the proper particle size in order to assess any specific human exposure study to indoor pollutants.
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| 8. |
- McCarrick, Sarah, et al.
(författare)
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Toxicity of particles derived from combustion of Ethiopian traditional biomass fuels in human bronchial and macrophage-like cells
- 2024
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Ingår i: Archives of Toxicology. - 0340-5761. ; 98:5, s. 1515-1532
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Tidskriftsartikel (refereegranskat)abstract
- The combustion of traditional fuels in low-income countries, including those in sub-Saharan Africa, leads to extensive indoor particle exposure. Yet, the related health consequences in this context are understudied. This study aimed to evaluate the in vitro toxicity of combustion-derived particles relevant for Sub-Saharan household environments. Particles (< 2.5 µm) were collected using a high-volume sampler during combustion of traditional Ethiopian biomass fuels: cow dung, eucalyptus wood and eucalyptus charcoal. Diesel exhaust particles (DEP, NIST 2975) served as reference particles. The highest levels of particle-bound polycyclic aromatic hydrocarbons (PAHs) were found in wood (3219 ng/mg), followed by dung (618 ng/mg), charcoal (136 ng/mg) and DEP (118 ng/mg) (GC–MS). BEAS-2B bronchial epithelial cells and THP-1 derived macrophages were exposed to particle suspensions (1–150 µg/mL) for 24 h. All particles induced concentration-dependent genotoxicity (comet assay) but no pro-inflammatory cytokine release in epithelial cells, whereas dung and wood particles also induced concentration-dependent cytotoxicity (Alamar Blue). Only wood particles induced concentration-dependent cytotoxicity and genotoxicity in macrophage-like cells, while dung particles were unique at increasing secretion of pro-inflammatory cytokines (IL-6, IL-8, TNF-α). In summary, particles derived from combustion of less energy dense fuels like dung and wood had a higher PAH content and were more cytotoxic in epithelial cells. In addition, the least energy dense and cheapest fuel, dung, also induced pro-inflammatory effects in macrophage-like cells. These findings highlight the influence of fuel type on the toxic profile of the emitted particles and warrant further research to understand and mitigate health effects of indoor air pollution.
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| 9. |
- Weiss, Jana M., et al.
(författare)
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Daily intake of phthalates, MEHP, and DINCH by ingestion and inhalation
- 2018
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Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 208, s. 40-49
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Tidskriftsartikel (refereegranskat)abstract
- Phthalate esters, suspected endocrine disrupting chemicals, are used in a wide range of applications. Because phthalate esters are not covalently bound, they can easily leach into the indoor environment and associate to dust particles. Thus, exposure may occur through inhalation, ingestion, or contact with the skin. However, it is unclear to what degree indoor dust contributes to the daily intake of phthalate esters.This study investigates household dust as an exposure pathway for seven phthalate esters, the monoester MEHP, and the plasticizer DINCH. Household dust collected from children's sleeping rooms and from living rooms were analysed using gas and liquid chromatography tandem mass spectrometry. To compare two exposure pathways, different dust particle sizes were generated: a respirable fraction (<5 mu m) and an ingested particle fraction in the anticipated size range of skin adherence (<75 mu m). Modelling of dust inhalation and ingestion showed that the daily intake of dust-bound phthalate esters was likely to be 2 times (inhalation) to 12 times (ingestion) higher for 21-month-old children than for adults. These children's daily uptake of phthalate esters was 40-140 times higher through ingestion than inhalation. Furthermore, dust may be an exposure pathway for phthalate esters as well as for MEHP. Therefore, phthalate monoesters could be environmental contaminants of their own and need to be considered in health risk assessments. (C) 2018 Elsevier Ltd. All rights reserved.
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| 10. |
- Alhamdow, Ayman, et al.
(författare)
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DNA-methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons
- 2018
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 39:7, s. 869-878
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Tidskriftsartikel (refereegranskat)abstract
- Some polycyclic aromatic hydrocarbons (PAH) are known carcinogens and workplace PAH exposure may increase the risk of cancer. Monitoring early cancer-related changes can indicate whether the exposure is carcinogenic. Here, we enrolled 151 chimney sweeps, 152 controls, and 19 creosote-exposed male workers from Sweden. We measured urinary PAH metabolites using LC/MS/MS, the cancer-related markers telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) using qPCR, and DNA methylation of lung cancer-related genes F2RL3 and AHRR using pyrosequencing. The median 1-hydroxypyrene (PAH metabolite) concentrations were highest in creosote-exposed workers (8.0 μg/g creatinine) followed by chimney sweeps (0.34 μg/g creatinine) and controls (0.05 μg/g creatinine). TL and mtDNAcn did not differ between study groups. Chimney sweeps and creosote-exposed workers had significantly lower methylation of AHRR CpG site cg05575921 (88.1% and 84.9%, respectively) than controls (90%). Creosote-exposed workers (73.3%), but not chimney sweeps (76.6%) had lower methylation of F2RL3 cg03636183 than controls (76.7%). Linear regression analyses showed that chimney sweeps had lower AHRR cg05575921 methylation (B=-2.04; P<0.057, adjusted for smoking and age) and lower average AHRR methylation (B=-2.05; P<0.035), and non-smoking chimney sweeps had lower average F2RL3 methylation (B=-0.81; P<0.042, adjusted for age) compared with controls. These cancer-related markers were not associated with urinary concentrations of PAH metabolites. In conclusion, although we found no associations with PAH metabolites in urine (short-term exposure), our results suggest dose-response relationship between PAH exposure and DNA hypomethylation of lung cancer-related loci. These findings indicate that further protective measures should be taken to reduce PAH exposure.
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