Absence of lung tumor promotion with reduced tumor size in mice after inhalation of copper welding fumes.

Welding fumes are a Group 1 (carcinogenic to humans) carcinogen as classified by the International Agency for Research on Cancer. The process of welding creates inhalable fumes rich in iron (Fe) that may also contain known carcinogenic metals such as chromium (Cr) and nickel (Ni). Epidemiological evidence has shown that both mild-steel (Fe-rich) and stainless steel (Fe-rich + Cr + Ni) welding fume exposure increase lung cancer risk, and experimental animal data support these findings. Copper-nickel (CuNi) welding processes have not been investigated in the context of lung cancer. Cu is intriguing, however, given the role of Cu in carcinogenesis and cancer therapeutics. This study examines the potential for a CuNi fume to induce mechanistic key characteristics of carcinogenesis in vitro and to promote lung tumorigenesis, using a two-stage mouse bioassay, in vivo. Male A/J mice, initiated with 3-methylcholanthrene (MCA; 10 µg/g), were exposed to CuNi fumes or air by whole-body inhalation for nine weeks (low-deposition-LD and high deposition-HD) then sacrificed at 30 weeks. In BEAS-2B cells, the CuNi fume induced micronuclei and caused DNA damage as measured by γ-H2AX. The fume exhibited high reactivity and a dose response in cytotoxicity and oxidative stress. In vivo, MCA/CuNi HD and LD significantly decreased lung tumor size and adenomas. MCA/CuNi HD exposure significantly decreased gross-evaluated tumor number. In summary, the CuNi fume in vitro exhibited characteristics of a carcinogen, but in vivo the exposure resulted in smaller tumors, fewer adenomas, less hyperplasia severity, and with the HD exposure, less overall lung lesion/tumors.

The NCBI Comparative Genome Viewer (CGV) is an interactive visualization tool for the analysis of whole-genome eukaryotic alignments.

We report a new visualization tool for analysis of whole-genome assembly-assembly alignments, the Comparative Genome Viewer (CGV) (https://ncbi.nlm.nih.gov/genome/cgv/). CGV visualizes pairwise same-species and cross-species alignments provided by National Center for Biotechnology Information (NCBI) using assembly alignment algorithms developed by us and others. Researchers can examine large structural differences spanning chromosomes, such as inversions or translocations. Users can also navigate to regions of interest, where they can detect and analyze smaller-scale deletions and rearrangements within specific chromosome or gene regions. RefSeq or user-provided gene annotation is displayed where available. CGV currently provides approximately 800 alignments from over 350 animal, plant, and fungal species. CGV and related NCBI viewers are undergoing active development to further meet needs of the research community in comparative genome visualization.

TERT-independent telomere elongation and shelterin dysregulation after pulmonary exposure to stainless-steel welding fume in-vivo.

Telomeres are inert DNA sequences (TTAGGG) at the end of chromosomes that protect genetic information and maintain DNA integrity. Emerging evidence has demonstrated that telomere alteration can be closely related to occupational exposure and the development of various disease conditions, including cancer. However, the functions and underlying molecular mechanisms of telomere alteration and shelterin dysregulation after welding fume exposures have not been broadly defined. In this study, we analyzed telomere length and shelterin complex proteins in peripheral blood mononuclear cells (PBMCs) and in lung tissue recovered from male Sprague-Dawley rats following exposure by intratracheal instillation (ITI) to 2 mg/rat of manual metal arc-stainless steel (MMA-SS) welding fume particulate or saline (vehicle control). PBMCs and lung tissue were harvested at 30 d after instillation. Our study identified telomere elongation and shelterin dysregulation in PBMCs and lung tissue after welding fume exposure. Mechanistically, telomere elongation was independent of telomerase reverse transcriptase (TERT) activation. Collectively, our findings demonstrated that welding fume-induced telomere elongation was (a) TERT-independent and (b) associated with shelterin complex dysregulation. It is possible that an alteration of telomere length and its regulatory proteins may be utilized as predictive biomarkers for various disease conditions after welding fume exposure. This needs further investigation.

Lung toxicity, deposition, and clearance of thermal spray coating particles with different metal profiles after inhalation in rats.

Thermal spray coating is a process in which molten metal is sprayed onto a surface. Little is known about the health effects associated with these aerosols. Sprague-Dawley rats were exposed to aerosols (25 mg/m3 × 4 hr/d × 4 d) generated during thermal spray coating using different consumables [i.e. stainless-steel wire (PMET731), Ni-based wire (PMET885), Zn-based wire (PMET540)]. Control animals received air. Bronchoalveolar lavage was performed at 4 and 30 d post-exposure to assess lung toxicity. The particles were chain-like agglomerates and similar in size (310-378 nm). Inhalation of PMET885 aerosol caused a significant increase in lung injury and inflammation at both time points. Inhalation of PMET540 aerosol caused a slight but significant increase in lung toxicity at 4 but not 30 d. Exposure to PMET731 aerosol had no effect on lung toxicity. Overall, the lung responses were in the order: PMET885≫PMET540 >PMT731. Following a shorter exposure (25 mg/m3 × 4 h/d × 1d), lung burdens of metals from the different aerosols were determined by ICP-AES at 0, 1, 4 and 30 d post-exposure. Zn was cleared from the lungs at the fastest rate with complete clearance by 4 d post-exposure. Ni, Cr, and Mn had similar rates of clearance as nearly half of the deposited metal was cleared by 4 d. A small but significant percentage of each of these metals persisted in the lungs at 30 d. The pulmonary clearance of Fe was difficult to assess because of inherently high levels of Fe in control lungs.