Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-4 (of 4 Records) |
Query Trace: Mustafa GM[original query] |
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Pulmonary toxicity and gene expression changes in response to whole-body inhalation exposure to multi-walled carbon nanotubes in rats
Sager TM , Umbright CM , Mustafa GM , Roberts JR , Orandle MS , Cumpston JL , McKinney WG , Boots T , Kashon ML , Joseph P . Inhal Toxicol 2022 34 1-19 Purpose: To investigate the molecular mechanisms underlying the pulmonary toxicity induced by exposure to one form of multi-walled carbon nanotubes (MWCNT-7).Materials and methods: Rats were exposed, by whole-body inhalation, to air or an aerosol containing MWCNT-7 particles at target cumulative doses (concentration x time) ranging from 22.5 to 180 (mg/m(3))h over a three-day (6 hours/day) period and toxicity and global gene expression profiles were determined in the lungs.Results: MWCNT-7 particles, associated with alveolar macrophages (AMs), were detected in rat lungs following the exposure. Mild to moderate lung pathological changes consisting of increased cellularity, thickening of the alveolar wall, alveolitis, fibrosis, and granuloma formation were detected. Bronchoalveolar lavage (BAL) toxicity parameters such as lactate dehydrogenase activity, number of AMs and polymorphonuclear leukocytes (PMNs), intracellular oxidant generation by phagocytes, and levels of cytokines were significantly (p < 0.05) increased in response to exposure to MWCNT-7. Global gene expression profiling identified several significantly differentially expressed genes (fold change >1.5 and FDR p value <0.05) in all the MWCNT-7 exposed rats. Bioinformatic analysis of the gene expression data identified significant enrichment of several diseases/biological function categories (for example, cancer, leukocyte migration, inflammatory response, mitosis, and movement of phagocytes) and canonical pathways (for example, kinetochore metaphase signaling pathway, granulocyte and agranulocyte adhesion and diapedesis, acute phase response, and LXR/RXR activation). The alterations in the lung toxicity parameters and gene expression changes exhibited a dose-response to the MWCNT exposure.Conclusions: Taken together, the data provided insights into the molecular mechanisms underlying the pulmonary toxicity induced by inhalation exposure of rats to MWCNT-7. |
Tobacco smoke exposure exacerbated crystalline silica-induced lung toxicity in rats
Sager TM , Umbright CM , Mustafa GM , Yanamala N , Leonard HD , McKinney WG , Kashon ML , Joseph P . Toxicol Sci 2020 178 (2) 375-390 Smoking may modify the lung response to silica exposure including cancer and silicosis. Nevertheless, the precise role of exposure to tobacco smoke (TS) on the lung response to crystalline silica (CS) exposure and the underlying mechanisms need further clarification. The objectives of the present study were to determine the role of TS on lung response to CS exposure and the underlying mechanism(s). Male Fischer 344 rats were exposed by inhalation to air, CS (15 mg/m3, 6 hrs/day, 5 days), TS (80 mg/m3, 3 hrs/day, twice weekly, 6 months), or CS (15 mg/m3, 6 hrs/day, 5 days) followed by TS (80 mg/m3, 3 hrs/day, twice weekly, 6 months). The rats were euthanized 6 months and 3 weeks following initiation of the first exposure and the lung response was assessed. Silica exposure resulted in significant lung toxicity as evidenced by lung histological changes, enhanced neutrophil infiltration, increased LDH levels, enhanced oxidant production, and increased cytokine levels. The TS exposure alone had only a minimal effect on these toxicity parameters. However, the combined exposure to TS and CS exacerbated the lung response, compared to TS or CS exposure alone. Global gene expression changes in the lungs correlated with the lung toxicity severity. Bioinformatic analysis of the gene expression data demonstrated significant enrichment in functions, pathways, and networks relevant to the response to CS exposure which correlated with the lung toxicity detected. Collectively our data demonstrated an exacerbation of CS-induced lung toxicity by TS exposure and the molecular mechanisms underlying the exacerbated toxicity. |
A possible relationship between telomere length and markers of neurodegeneration in rat brain after welding fume inhalation exposure
Shoeb M , Mustafa GM , Kodali VK , Smith K , Roach KA , Boyce G , Meighan T , Roberts JR , Erdely A , Antonini JM . Environ Res 2019 180 108900 Inhalation of welding fume (WF) can result in the deposition of toxic metals, such as manganese (Mn), in the brain and may cause neurological changes in exposed workers. Alterations in telomere length are indicative of cellular aging and, possibly, neurodegeneration. Here, we investigated the effect of WF inhalation on telomere length and markers of neurodegeneration in whole brain tissue in rats. Male Fischer-344 (F-344) rats were exposed by inhalation to stainless steel WF (20mg/m(3) x 3h/d x 4d/wk x 5wk) or filtered air (control). Telomere length, DNA-methylation, gene expression of Trf1, Trf2, ATM, and APP, protein expression of p-Tau, alpha-synuclein, and presenilin 1 and 2 were assessed in whole brain tissue at 12wk after WF exposure ended. Results suggest that WF inhalation increased telomere length without affecting telomerase in whole brain. Moreover, we observed that components of the shelterin complex, Trf1 and Trf2, play an important role in telomere end protection, and their regulation may be responsible for the increase in telomere length. In addition, expression of different neurodegeneration markers, such as p-Tau, presenilin 1-2 and alpha-synuclein proteins, were increased in brain tissue from the WF-exposed rats as compared to control. These findings suggest a possible correlation between epigenetic modifications, telomere length alteration, and neurodegeneration because of the presence of factors in serum after WF exposure that may cause extra-pulmonary effects as well as the translocation of potentially neurotoxic metals associated with WF to the central nervous system (CNS). Further studies are needed to investigate the brain region specificity and temporal response of these effects. |
Initiation of Pulmonary Fibrosis after Silica Inhalation in Rats is linked with Dysfunctional Shelterin Complex and DNA Damage Response.
Shoeb M , Mustafa GM , Joseph P , Umbright C , Kodali V , Roach KA , Meighan T , Roberts JR , Erdely A , Antonini JM . Sci Rep 2019 9 (1) 471 ![]() Occupational exposure to silica has been observed to cause pulmonary fibrosis and lung cancer through complex mechanisms. Telomeres, the nucleoprotein structures with repetitive (TTAGGG) sequences at the end of chromosomes, are a molecular "clock of life", and alterations are associated with chronic disease. The shelterin complex (POT1, TRF1, TRF2, Tin2, Rap1, and POT1 and TPP1) plays an important role in maintaining telomere length and integrity, and any alteration in telomeres may activate DNA damage response (DDR) machinery resulting in telomere attrition. The goal of this study was to assess the effect of silica exposure on the regulation of the shelterin complex in an animal model. Male Fisher 344 rats were exposed by inhalation to Min-U-Sil 5 silica for 3, 6, or 12 wk at a concentration of 15 mg/m(3) for 6 hr/d for 5 consecutive d/wk. Expression of shelterin complex genes was assessed in the lungs at 16 hr after the end of each exposure. Also, the relationship between increased DNA damage protein (gammaH2AX) and expression of silica-induced fibrotic marker, alphaSMA, was evaluated. Our findings reveal new information about the dysregulation of shelterin complex after silica inhalation in rats, and how this pathway may lead to the initiation of silica-induced pulmonary fibrosis. |
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