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Transcriptional response of porcine skin to sulfur mustard

ABSTRACT: Sulfur mustard (HD) is a potent alkylating agent that induces cutaneous injury. The molecular mechanisms of cutaneous injury are not completely understood, and the molecular pathways involved in post-exposure wound healing are not well characterized. To elucidate these molecular pathways for the purpose of identifying potential therapeutic targets, we used oligonucleotide microarrays to identify gene expression profile changes induced by HD in porcine skin, an established animal model of HD injury and wound healing. Female Yorkshire crossbred pigs were exposed to neat HD to generate a superficial dermal (second degree) injury. Skin punch biopsies were collected at 1 h, 2 h, 4 h, 24 h, 48 h, 72 h, 7 d, 14 d or 21 d post-exposure. Biopsies were scored for histopathology, and RNA extracted from biopsies was used for microarray analysis. Gene expression profiles were analyzed for significant temporal response to HD by analysis of variance (false discovery corrected p<0.05). Gene expression profiles were also correlated (Pearson linear correlation |r|>0.7, false discovery corrected p<0.05) to histopathology scores to identify molecular pathways significantly correlated with specific clinical endpoints of injury and repair. Several pathways linked to aspects of inflammatory response and cell cycle checkpoint regulation were altered by HD exposure through 72 h. Several of these inflammatory pathways were highly correlated with clinical endpoints assessed through 72 h, including epidermal necrosis and vesicle formation. Pathways linked to inflammation were also highly correlated with 7-21 d total histopathology scores, suggesting that inflammation is continual through the course of injury and healing. Specific therapeutic targets were identified within these inflammatory pathways, and potential therapeutics were also identified for future drug screening efforts.

ORGANISM(S): Sus scrofa

PROVIDER: GSE29588 | GEO | 2018/06/15

REPOSITORIES: GEO

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Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers. AKI biopsies sample names and CEL files are from GSE21374. All consenting renal transplant patients undergoing biopsies for cause as standard of care between 09/2004 and 10/2007 at the university of Alberta or between 11/2006 and 02/2007 at the University of Illinois were included in the analysis. In addition to the cores required for standard histopathology, we collected one core for gene expression studies. the relationship between gene expression in the biopsy and subsequent graft loss was analyzed. This dataset is part of the TransQST collection.

Project description:Current human reproductive risk assessment methods rely on semen and serum hormone analyses, which are not easily comparable to the histopathological endpoints and mating studies used in animal testing. Because of these limitations, there is a need to develop universal evaluations that reliably reflect male reproductive function. We hypothesized that toxicant-induced testicular injury can be detected in sperm using mRNA transcripts as indicators of insult. To test this, we exposed adult male Fischer 344 rats to low doses of model testicular toxicants and classically characterized the testicular injury while simultaneously evaluating sperm mRNA transcripts from the same animals. Overall, this study aimed to: 1) identify sperm transcripts altered after exposure to the model testicular toxicant, 2,5-hexanedione (HD) using microarrays; 2) expand on the HD-induced transcript changes in a comprehensive time course experiment using qRT-PCR arrays; and 3) test these injury indicators after exposure to another model testicular toxicant, carbendazim (CBZ). Microarray analysis of HD-treated adult Fischer 344 rats identified 128 altered sperm mRNA transcripts when compared to control using linear models of microarray analysis (q < 0.05). All transcript alterations disappeared after 3 months of post-exposure recovery. In the time course experiment, time-dependent alterations were observed for 12 candidate transcripts selected from the microarray data based upon fold change and biological relevance, and 8 of these transcripts remained significantly altered after the 3-month recovery period (p < 0.05). In the last experiment, 8 candidate transcripts changed after exposure to CBZ (p < 0.05). The two testicular toxicants produced distinct molecular signatures with only 4 overlapping transcripts between them, each occurring in opposite directions. Overall, these results suggest that sperm mRNA transcripts are indicators of low dose toxicant-induced testicular injury in the rat. Rats were exposed to sub-chronic low doses of the Sertoli cell toxicant 2,5-hexanedione (HD) or water (control for HD) for 3 months. Some rats in each group underwent 3 months of post-exposure recovery.

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Transcriptional response of porcine skin to sulfur mustard

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