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Gene Expression Changes Following Acute Hydrogen Sulfide (H2S)-induced Nasal Respiratory Epithelial InjuryCIIT at The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA Correspondence: David C. Dorman, College of Veterinary, Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA; e-mail:david_dorman{at}ncsu.edu.
Hydrogen sulfide (H2S) is a naturally occurring gas that is also associated with several industries. The potential for widespread human inhalation exposure to this toxic gas is a public health concern. The nasal epithelium is especially susceptible to H2S-induced pathology. Injury to and regeneration of the nasal respiratory mucosa occurred in animals with ongoing H2S exposure, suggesting that the regenerated respiratory epithelium under-goes an adaptive response and becomes resistant to further injury. To better understand this response, ten-week-old male Sprague-Dawley rats were exposed nose-only to either air or 200 ppm H2S for three hours per day for one day or five consecutive days. Nasal respiratory epithelial cells at the site of injury and regeneration were laser capture microdissected, and gene expression profiles were generated at three, six, and twenty-four hours after the initial three-hour exposure and at twenty-four hours after the fifth exposure using the Affymetrix Rat Genome 230 2.0 microarray. Gene ontology enrichment analysis showed that H2S exposure altered gene expression associated with a variety of biological processes, including cell cycle regulation, protein kinase regulation, and cytoskeletal organization and biogenesis. Surprisingly, our results did not show a significant change in cytochrome oxidase gene expression or bioenergetics.
Key Words: gene expression • nasal respiratory epithelium • LCM • rat • H2S • inhalation • DNA microarray
Hydrogen sulfide (H2S) is a toxic gas with a characteristic rotten egg odor. Human exposure to H2S is widespread owing to its association with a variety of industrial processes, high-intensity agricultural practices, and natural sources. It has been estimated that each year over 1,000 human exposures are sufficiently severe to warrant reporting to human poison control centers in the United States (ATSDR 1999). The toxic effects of H2S are characteristically dose related and most notably involve the nervous, cardiovascular, and respiratory systems (ATSDR 1999). Headache, coughing, and throat irritation occur at 2.5–5 ppm, whereas collapse and death have been observed following acute H2S exposure to 1,000 ppm (ACGIH 1991; Reiffenstein et al. 1992; Schiffman et al. 2001). Animal studies have shown that the nose is a particularly sensitive respiratory tract target for inhaled H2S (ACGIH 1998; ACGIH 1991; Deng 1992). The nasal cavity is lined with specialized epithelial cell populations that maintain the normal functions of the nose. These surface epithelial cells have specific roles in conducting airflow and maintaining normal nasal function (Miller 1995) and include squamous, respiratory, transitional, and olfactory epithelium. The nasal respiratory epithelium is pseudo-stratified and ciliated with mucus-secreting cells (Morgan 1995). The olfactory epithelium, located in the more caudal portion of the nasal cavity, consists of three cell types supported by a basal lamina: sustentacular or support cells; neurons, essential for the detection of odorants; and basal cells, which act as progenitor cells for the olfactory neurons (Barrow 1986). Thus, the proximity of the respiratory and olfactory epithelial cells to inspired air makes them a target for toxicant-induced damage (Shusterman 2003).
Acute, repeated inhalation exposure of rats to The present project was conducted to better understand the initial injury and subsequent adaptive changes that result in the rat nasal respiratory epithelium becoming resistant to further H2S cytotoxicity. Inhibition of cytochrome oxidase is believed to be the main mechanism of toxicity for H2S (Beauchamp et al. 1984; Deng 1992), although alternative mechanisms, including activation of ATP-activated potassium channels and alteration in cell signaling pathways, have also been postulated (Szabó 2007). The present project was also intended to improve our understanding of the mode of action of H2S nasal toxicity. We used laser capture microdissection (LCM) to selectively acquire respiratory epithelial cells from affected sites, and we applied microarray technology to identify the gene expression changes that occurred in these cells of interest following H2S inhalation in the Sprague-Dawley rat.
Animals Following a two-week acclimation period, twenty-four male Sprague-Dawley rats (Charles River Laboratories, Inc., Raleigh, NC, USA) were assigned to six weight-matched exposure groups (n = 3 or 4 rats/time point). Animals were housed two to a cage in polycarbonate cages with cellulose fiber chip bedding (ALPHI-driTM, Shepherd Specialty Papers, Kalamazoo, MI, USA). Animal rooms were ventilated with HEPA-filtered air and maintained at 18.5–21.5°C with a relative humidity of 40–70% on a twelve-hour light/dark cycle. Animals were fed a certified NIH-07 pelleted rodent chow (Zeigler Brothers, Gardners, PA) and had access to reverse-osmosis water (Hydro Picosystem and Supplies, Research Triangle Park, NC, USA) ad libitum except during exposures. The study was reviewed by the CIIT Institutional Animal Care and Use Committee and conducted under federal guidelines for the care and use of laboratory animals (NRC 1996).
Atmospheric Generation and Exposure System Rats were held in individual nose-only, polycarbonate tubes and exposed for three hours per day for either one day or five consecutive days to a target concentration of 200 ppm H2S. The average analytical concentrations (± SD) of H2S for each three-hour exposure was 205 ± 5 ppm. The average temperatures and relative humidities during the exposures ranged from 20.5°C to 21.2°C and 42% to 45%, respectively.
Euthanasia
Tissue Processing for Gene Microarray Frozen OCT-embedded nasal tissue blocks were serially cut with a cryostat transversely perpendicular to the bridge of the nose sectioning rostrally at level 3, as defined by Méry et al. (1994). Ten-micron tissue sections were placed onto plain, uncharged microscope slides (Esco SuperFrost slides, Sigma, St. Louis, MO, USA), allowed to rapidly thaw onto the microscope slide for adhesion, and processed immediately for LCM. During the staining procedure, the slide-mounted tissue sections were maintained on dry ice and processed for LCM four slides at a time to minimize RNA degradation and ensure efficient laser capture. Frozen sections were submerged sequentially in 75% ethanol; deionized water; HistoGene Staining Solution; and 75%, 95%, and 100% ethanol for thirty seconds each, with final dehydration in xylene for five minutes (HistoGeneTM LCM Frozen Section Staining Kit, Arcturus, Mountain View, CA, USA). To avoid cross-contamination, all solutions were changed after each batch of four slides. The slides were then allowed to air dry for five minutes before proceeding to LCM. Proper RNA technique consisting of the use of clean, disposable gloves and RNase-free instruments was maintained throughout.
Tissue Processing for Histopathology
Laser Capture Microdissection
RNA Isolation, Extraction, and Amplification RNA isolation and extraction was completed using the PicoPure RNA Isolation Kit (Arcturus Engineering, Mountain View, CA, USA). Briefly, the captured cells of interest were incubated for thirty minutes at 42°C in RNA extraction buffer. The RNA extract was centrifuged (800 x g for two minutes), and the cell extract was loaded onto a preconditioned purification column. The column with the cell extract was centrifuged to ensure binding of the RNA to the column, the column was washed, and DNA was removed using Qiagen’s DNase treatment (Qiagen, Valencia, CA, USA). The isolated total cellular RNA was then eluted in a low ionic strength buffer, and the quality of the RNA was verified with standard spectrophotometric analysis and gel electrophoresis using the Agilent 2100 Bioanalyzer (Agilent, Foster City, CA, USA). The samples were kept frozen at –80°C until amplification. Two rounds of amplification were carried out using the RiboAmp OA RNA Amplification Kit (Arcturus). Briefly, in the first round of amplification, approximately 7 ng of total cellular RNA was reverse-transcribed using a polyT-T7 primer. Double-stranded cDNA was synthesized in the second reaction and then purified using MiraCol purification columns contained within the kit. In vitro transcription was performed using T7 RNA polymerase and the aRNA was column purified. After the first round of amplification, purified aRNA was converted to double-stranded cDNA and column-purified. This double-stranded cDNA was the template for the second round of amplification with simultaneous overnight labeling using the GeneChip Expression 3' Amplification Reagents for IVT Labeling (Affymetrix, Santa Clara, CA, USA). As a final step, the labeled aRNA was column-purified, and yield was determined by measuring the optical density (OD) of the product at A260 and A280. Average yield was 117 ± 15 µg frozen at –80°C until processing for microarray analysis.
Gene Expression Profiling by Microarray
Real-time PCR
Gene Ontology Assessment
Statistical Analyses
Nasal Respiratory Epithelial Lesions following Acute H2S Exposure A highly localized, bilaterally symmetrical, mild respiratory epithelial injury occurred in all animals after a single three-hour exposure to 200 ppm H2S. This lesion was localized to the lateral wall of the ventral meatus (Figure 3B), and at three hours postexposure it was characterized by infiltration with inflammatory cells (primarily neutrophils). By six hours post-exposure, there was epithelial sloughing and loss of the basal cellular structure (Figure 3C). Respiratory epithelial regeneration occurred by twenty-four hours postexposure. The regeneration consisted of replacement of the respiratory epithelium by a squamous to low cuboidal, sparsely ciliated, and poorly differentiated epithelium (Figure 3D). Complete recovery from this initial respiratory epithelial injury was noted in all animals after five consecutive days of exposure to H2S (Figure 3E).
Gene Expression Profiling by Microarray Figure 4 is a cluster analysis depicting significant changes in gene expression in the nasal respiratory epithelium of rats exposed to H2S. Early (three hours) H2S-induced changes in gene expression consistent with cellular defense/inflammation included alterations in expression of activating transcription factor 3 (Atf3), heme oxygenase-1 (Hmox1), tumor necrosis factor 12a (Tnfrsf12a), heat shock protein 1b (Hsp1b), toll-like receptor 4 (Tlr4), and initial matrix remodeling (matrix metal-lopeptidase 3 [Mmp3], annexin, cathespin, microtubule-associated protein 6 [Map6]). By twenty-four hours after the three-hour H2S exposure, genes involved in cellular proliferation and microtubule-based movement with significantly increased expression included genes encoding for cell division cycle associated proteins, cyclins, beta 5 tubulin (Tubb5), and high mobility group protein 2 (Hmg-2). Three-hour inhalation exposure to H2S for five consecutive days resulted in an up-regulation in gene expression of myosin, serine protease inhibitor, lipidosin, kinesin, and 15-hydroxyprostaglandin dehydrogenase (15-Pgdh).
Gene Ontology Analysis Table 1 shows an ontological analysis of significant gene expression changes in the respiratory epithelium following H2S exposure. Gene ontology enrichment analysis showed that H2S exposure altered gene expression associated with a variety of biological processes including cell cycle regulation, cellular division, DNA metabolism and repair, protein kinase regulation, and cytoskeletal organization and biogenesis.
Our laboratory has previously shown that at concentrations reported with acute accidental human poisoning, exposure to H2S is associated with nasal cell injury in rodents (ATSDR 1999; Brenneman et al. 2000; Brenneman et al. 2002; Dorman et al. 2002). Acute, repeated exposure of rats to concentrations of 80 ppm resulted in nasal pathology characterized by H2S  respiratory epithelial metaplasia and full thickness necrosis of the olfactory mucosa (Brenneman et al. 2002). The present study used LCM to selectively acquire H2S-injured nasal respiratory epithelium and applied microarray technology to identify the gene changes that occur with H2S-induced nasal pathology, thereby providing a more complete assessment of tissue injury (Knezevic et al. 2001). LCM-procured cells have been used by others and examined by genomic and proteomic approaches, creating the unique ability to ascertain patterns of gene expression in specific targeted cell types (Coco et al. 2005; Jones et al. 2002). Our genomic results are in agreement with the observed pathology induced by H2S exposure. Nasal respiratory epithelial injury occurred in the lateral wall of the ventral meatus and was present shortly after a single three-hour exposure to 200 ppm H2S. The initial tissue response was characterized by infiltration of the respiratory epithelium with inflammatory cells. Trevisani and coworkers (2005) showed that intratracheal instillation of the H2S donor, sodium hydrogen sulfide (NaHS), to guinea pigs resulted in increased airway inflammation, as evidenced by increased extravasation of Evans blue dye. This inflammatory response was ameliorated by pretreatment with capsaicin and the tachykinin NK1 receptor antagonist SR140333, suggesting that this response is mediated by sensory nerve terminals. It remains unknown whether the early lesions seen in the respiratory epithelium represent a neurogenic inflammatory response. There was a concomitant early up-regulation of expression of genes involved in defense and inflammation that tracked closely with the observed pathology. Exposure to H2S was associated with an up-regulation of activating transcription factor (Atf3), heme oxygenase 1 (Hmox1), heat shock protein 1b (Hsp1b), and toll-like receptor 4 (Tlr4). Atf3 is a member of the activating transcription factor/cAMP-responsive element binding protein (ATF/CREB) family of transcription factors. Atf3 is induced in a variety of stressed tissues (Chen et al. 1996), apparently through a p38-mediated pathway (Lu et al. 2007). Its expression is also induced by signals that promote cell proliferation and motility. Thus, the Atf3 gene has been characterized as an early-phase gene needed for cellular adaptation to a variety of extra- and/or intracellular changes (Lu et al. 2007). In addition, the initial inflammatory respiratory tissue injury also resulted in an up-regulation of Hmox1 and Hsp1b. Heat shock protein and Hmox1 are stress response molecules that are induced by exposure to oxidative stress (Creagh et al. 2000; Keyse and Tyrrell 1989), and Hmox1 induction, in particular, is widely regarded as a major protective mechanism against oxidative tissue injury (Ryter and Choi 2005). Intraperitoneal administration of NaHS increased gene and protein expression of Hmox1 in the rat pulmonary vascular smooth muscles under hypoxic conditions (Qingyou et al. 2004). Administration of NaHS also resulted in Hmox1 up-regulation in the central nervous system (Han et al. 2006). Acute exposure to H2S was also associated with increased expression of toll-like receptor 4 (Tlr4). Tlr4 belongs to a family of genes that code for toll-like receptors that activate intracellular signaling, resulting in the induction of a variety of effector genes and the production of inflammatory cytokines. Tlr4 has been shown to play a role in modulating responses to ozone (Kleeberger et al. 2000), residual oil fly ash (Cho et al. 2005), and butylated hydroxytoluene in mice (Bauer et al. 2005). Metallothionein expression was also increased following H2S exposure. In addition to being a metal-binding protein, metallothionein also acts as an antioxidant by neutralizing reactive oxygen species (Bauman et al. 1991). Interestingly, by three hours following H2S exposure, not only was there an initial inflammatory/defense response, but this response was coupled with an increase in expression of genes involved in matrix remodeling (e.g., laminin gamma 2, microtubule-associated protein 6, fibrinogen-like 2). This response became more pronounced by twenty-four hours after the three-hour when the epithelial phenotype H2S exposure, was characterized by replacement of the respiratory epithelium with a squamous to low-cuboidal, sparsely ciliated, and poorly differentiated epithelium. In our experiment, at the genomic level at twenty-four hours after exposure, genes associated with cell proliferation, cell cycle control, cytoskeleton organization, and biogenesis were the most highly expressed. These findings are remarkably similar to the results of several in vitro and in vivo studies, despite the significant inherent differences between the two types of studies. A reduced redox environment, as may be created in the nasal cavity by H2S inhalation, may act as a proliferative stimulus (Kirlin et al. 1999). Direct evidence comes from experiments conducted by Deplancke and Gaskins (2003) in which nontransformed rat intestinal epithelial cells (IEC-18) were exposed to 1 mM NaHS, a sulfide concentration sufficient to decrease the cellular redox environment. The NaHS-exposed IEC-18 cells underwent rapid proliferation as the result of enhanced cell cycle entry (Deplancke and Gaskins 2003). Microarray analysis of the NaHS-exposed IEC-18 cells also showed increased expression of genes involved in cell growth and proliferation, transcriptional regulation, and stress responses. Therefore, our findings provide a further link between observed metaplastic lesions and the genetic changes necessary for such a metaplastic tissue response. By the end of the repeated five-day exposure regime, there was no notable nasal pathology. Our results are consistent with Brenneman et al. (2002), who suggested that the respiratory epithelium was rapidly repaired following H2S exposure and became resistant to further damage despite ongoing exposure to H2S. Our gene expression analysis showed that after five daily exposures to 200 ppm H2S (three hours/day) there was an up-regulation of expression in very few genes, including those coding for myosin 5B, serine protease inhibitor B3, lipidosin, a benzodiazepine receptor, 15-hydroxyprostaglandin dehydrogenase, and c-myc binding protein. Lipidosin (also known as acyl-CoA synthetase bubblegum family member 1) plays a role in activating long-chain and very-long-chain fatty acids and influences the biosynthesis of steroid hormone precursors (Pei et al. 2003). Interestingly, rat and human colonocytes exposed in vitro to NaHS show impaired beta-oxidation of short-chain fatty acid (Babidge et al. 1998; Moore et al. 1997). Therefore, responses seen in the respiratory epithelium may represent a compensatory mechanism to overcome this bioenergetics response. Direct inhibition of cellular enzymes is postulated to be the primary mechanism of toxicity for H2S (Beauchamp et al. 1984; Deng 1992). In particular, the inhibition of cytochrome oxidase is believed to disrupt the electron transport chain and significantly impair oxidative metabolism, leading to anaerobic metabolism, and severely decreased ATP production with curtailed cellular energy generation. Surprisingly, our results did not show a significant change in cytochrome oxidase gene expression or bioenergetics. However, there is growing evidence that like nitric oxide and carbon monoxide, H2S also functions as a gaseous mediator/neurotransmitter and may influence a variety of biological responses (Fiorucci et al 2005; Leffler et al. 2006; O’Sullivan 2006; Wang 2002). In conclusion, using the combination of LCM and gene microarray technologies allowed us to selectively isolate and examine specific sites of cellular injury and repair following H2S inhalation exposure. Furthermore, by linking genomic changes with resultant pathology, we have increased our understanding of how H2S may cause acute injury to the nasal respiratory epithelium, allowing researchers to establish more accurate risk assessment measures for this chemical. Surprisingly, our results suggest that gene expression changes in cytochrome oxidase did not occur following H2S exposure, suggesting that alternative mechanisms occur. The results of our study suggest that alterations in signal transduction, inflammatory/defense response, cell cycle regulation, and response to oxidative stress are more likely involved in the early pathogenesis of this lesion. Whether other irritant gases that induce similar change in the respiratory epithelium produce comparable changes in epithelial gene expression is unknown and warrants further study.
The authors would like to especially thank CIIT at the Hamner Institutes for Health Sciences’ inhalation, necropsy-histology, and gene expression core personnel for their hardworking endeavors to ensure the success of this manuscript. We also wish to thank Dr. Gabrielle Willson and Dr. Melvin Andersen for their critical reviews. This project was funded in part by the American Petroleum Institute (API) and the American Chemistry Council (ACC).
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1, 2008 Toxicologic Pathology, Vol. 36, No. 4,
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Abstract
Introduction
