Synergy Between DNA Replication and Repair Mechanisms

Zannis‐Hadjopoulos, Maria; Rampakakis, Emmanouil

doi:10.5772/24164

Cited by 1 publication

(1 citation statement)

References 139 publications

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“…Due to the fact that many genes active in DNA damage repair are also active during cell replication ( Zannis-Hadjopoulos and Rampakakis, 2011 ), transcriptomic evidence for or against genotoxicity is difficult to parse, and activation of genes and pathways involved in both cell proliferation and DNA damage response in tissues actively undergoing proliferation presents a challenge in interpretation. For example, Rpa1 and Rpa3 (Replication protein A isoforms), which are involved in DNA replication and repair ( Oakley and Patrick, 2010 ) were significantly dose-responsive in the villus at day 91; however, Rpa1 was significantly downregulated, whereas Rpa3 was upregulated, further complicating the clarity of the role of the Cr(VI) effect on these replication proteins in the villus.…”

Section: Discussionmentioning

confidence: 99%

Crypt and Villus Transcriptomic Responses in Mouse Small Intestine Following Oral Exposure to Hexavalent Chromium

Chappell

Wolf

Thompson

2021

Toxicological Sciences

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Oral exposure to hexavalent chromium (Cr(VI)) induces tumors in the mouse duodenum. Previous microarray-based transcriptomic analyses of homogenized mouse duodenal tissue have demonstrated Cr(VI)-induced alterations in various cellular pathways and processes. However, X-ray fluorescence microscopy indicates that chromium localizes primarily to the duodenal villi following exposure to Cr(VI), suggesting that previous transcriptomic analyses of homogenized tissue provide an incomplete picture of transcriptomic responses in the duodenum. Herein, transcriptomic analyses were conducted separately on crypt and villus tissue from formalin-fixed paraffin-embedded transverse duodenal sections from the same study in which microarray-based analyses were previously conducted. A total of 28 groups (7 doses × 2 timepoints × 2 tissue compartments) were analyzed for differential gene expression, dose-response, and gene set enrichment. Tissue compartment isolation was confirmed by differences in expression of typical markers of crypt and villus compartments. Fewer than 21 genes were altered in the crypt compartment of mice exposed to 0.1-5 ppm Cr(VI) for 7 or 90 days, which increased to hundreds or thousands of genes at ≥ 20 ppm Cr(VI). Consistent with histological evidence for crypt proliferation, a significant, dose-dependent increase in genes that regulate mitotic cell cycle was prominent in the crypt, while subtle in the villus, when compared to samples from time-matched controls. Minimal transcriptomic evidence of DNA damage response in either the crypts or the villi is consistent with published in vivo genotoxicity data. These results are also discussed in the context of modes of action that have been proposed for Cr(VI)-induced small intestine tumors in mice.

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Section: Discussionmentioning

confidence: 99%