| 1. |
- Ameer, Syeda Shegufta, et al.
(författare)
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Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood
- 2017
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 321, s. 57-66
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Tidskriftsartikel (refereegranskat)abstract
- Background Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. Objectives To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. Methods The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N = 80 women) and DNA methylation (N = 93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. Results U-As concentrations, ranging 10–1251 μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000 CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. Conclusions Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap.
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| 2. |
- Andersson, Marie, 1974-, et al.
(författare)
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Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding : Predictions from human cell lines
- 2017
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier. - 0041-008X .- 1096-0333. ; 320, s. 40-50
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Tidskriftsartikel (refereegranskat)abstract
- β-N-methylamino-alanine (BMAA) is a non-protein amino acid produced by cyanobacteria, diatoms and dinoflagellates. BMAA has potential to biomagnify in a terrestrial food chain, and to bioaccumulate in fish and shellfish. We have reported that administration of [14C]l-BMAA to lactating mice and rats results in a mother to off-spring transfer via the milk. A preferential enantiomer-specific uptake of [14C]l-BMAA has also been demonstrated in differentiated murine mammary epithelium HC11 cells. These findings, together with neurotoxic effects of BMAA demonstrated both in vitro and in vivo, highlight the need to determine whether such transfer could also occur in humans. Here, we used four cell lines of human origin to examine and compare the transport of the two BMAA enantiomers in vitro. The uptake patterns of [14C]l- and [14C]d-BMAA in the human mammary MCF7 cell line were in agreement with the results in murine HC11 cells, suggesting a potential secretion of BMAA into human breast milk. The permeability coefficients for both [14C]l- and [14C]d-BMAA over monolayers of human intestinal Caco2 cells supported an efficient absorption from the human intestine. As a final step, transport experiments confirmed that [14C]l-and [14C]d-BMAA can be taken up by human SHSY5Y neuroblastoma cells and even more efficiently by human U343 glioblastoma cells. In competition experiments with various amino acids, the ASCT2 specific inhibitor benzylserine was the most effective inhibitor of [14C]l-BMAA uptake tested here. Altogether, our results suggest that BMAA can be transferred from an exposed mother, via the milk, to the brain of the nursed infant.
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| 3. |
- Broström, Julia M., et al.
(författare)
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Toluene diisocyanate exposure and autotaxin–lysophosphatidic acid signalling
- 2018
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 355, s. 43-51
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Tidskriftsartikel (refereegranskat)abstract
- Toluene diisocyanate (TDI) is a reactive chemical used in manufacturing plastics. TDI exposure adversely affects workers' health, causing occupational asthma, but individuals differ in susceptibility. We recently suggested a role for signalling mediated by the enzyme autotaxin (ATX) and its product, lysophosphatidic acid (LPA), in TDI toxicity. Here we genotyped 118 TDI-exposed workers for six single-nucleotide polymorphisms (SNPs) in genes encoding proteins implicated in ATX–LPA signalling: purinergic receptor P2X7 (P2RX7), C–C motif chemokine ligand 2 (CCL2), interleukin 1β (IL1B), and caveolin 1 (CAV1). Two P2RX7 SNPs (rs208294 and rs2230911) significantly modified the associations between a biomarker of TDI exposure (urinary 2,4-toluene diamine) and plasma LPA; two IL1B SNPs (rs16944 and rs1143634) did not. CAV1 rs3807989 modified the associations, but the effect was not statistically significant (p = 0.05–0.09). In vitro, TDI-exposed bronchial epithelial cells (16HBE14o-) rapidly released ATX and IL-1β. P2X7 inhibitors attenuated both responses, but confocal microscopy showed non-overlapping localizations of ATX and IL-1β, and down-regulation of CAV1 inhibited the ATX response but not the IL-1β response. This study indicates that P2X7 is pivotal for TDI-induced ATX–LPA signalling, which was modified by genetic variation in P2RX7. Furthermore, our data suggest that the TDI-induced ATX and IL-1β responses occur independently.
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| 4. |
- Broström, Julia, et al.
(författare)
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Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms.
- 2015
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 1096-0333 .- 0041-008X. ; 287:3, s. 222-231
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Tidskriftsartikel (refereegranskat)abstract
- Diisocyanates are industrial chemicals which have a wide range of applications in developed and developing countries. They are notorious lung toxicants and respiratory sensitizers. However, the mechanisms behind their adverse effects are not adequately characterized. Autotaxin (ATX) is an enzyme producing lysophosphatidic acid (LPA), and the ATX-LPA axis has been implicated in lung related inflammatory conditions and diseases, including allergic asthma, but not to toxicity of environmental low-molecular-weight chemicals. We investigated effects of toluene diisocyanate (TDI) on ATX induction in human lung epithelial cell models, and we correlated LPA-levels in plasma to biomarkers of TDI exposure in urine collected from workers exposed to <5ppb (parts per billion). Information on workers' symptoms was collected through interviews. One nanomolar TDI robustly induced ATX release within 10min in vitro. A P2X7- and P2X4-dependent microvesicle formation was implicated in a rapid ATX release and a subsequent protein synthesis. Co-localization between purinergic receptors and ATX was documented by immunofluorescence and confocal microscopy. The release was modulated by monocyte chemoattractant protein-1 (MCP-1) and by extracellular ATP. In workers, we found a dose-response relationship between TDI exposure biomarkers in urine and LPA levels in plasma. Among symptomatic workers reporting "sneezing", the LPA levels were higher than among non-symptomatic workers. This is the first report indicating induction of the ATX-LPA axis by an environmental low-molecular-weight chemical, and our data suggest a role for the ATX-LPA axis in TDI toxicity.
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| 7. |
- Ganapathy, Suthakar, et al.
(författare)
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Low doses of arsenic, via perturbing p53, promotes tumorigenesis.
- 2016
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Ingår i: Toxicology and applied pharmacology. - : Elsevier BV. - 1096-0333 .- 0041-008X. ; 306, s. 98-104
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Tidskriftsartikel (refereegranskat)abstract
- In drinking water and in workplace or living environments, low doses of arsenic can exist and operate as a potent carcinogen. Due to insufficient understanding and information on the pervasiveness of environmental exposures to arsenic, there is an urgent need to elucidate the underlying molecular mechanisms of arsenic regarding its carcinogenic effect on human health. In this study, we demonstrate that low doses of arsenic exposure mitigate or mask p53 function and further perturb intracellular redox state, which triggers persistent endoplasmic reticulum (ER) stress and activates UPR (unfolded protein response), leading to transformation or tumorigenesis. Thus, the results suggest that low doses of arsenic exposure, through attenuating p53-regulated tumor suppressive function, change the state of intracellular redox and create a microenvironment for tumorigenesis. Our study also provides the information for designing more effective strategies to prevent or treat human cancers initiated by arsenic exposure.
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| 8. |
- Gustafsson, Åsa, et al.
(författare)
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Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles
- 2015
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 288:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials.
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| 9. |
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| 10. |
- Kharlyngdoh, Joubert Banjop, 1982-, et al.
(författare)
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TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer
- 2016
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier. - 0041-008X .- 1096-0333. ; 307, s. 91-101
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Tidskriftsartikel (refereegranskat)abstract
- Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The ART877A mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters.
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