Transcriptome analysis reveals the role of the PCP pathway in fipronil and endotoxin-induced lung damage

Abstract Background Pesticide residues in food and environment along with airborne contaminants like endotoxins pose a tangible threat to living beings. Fipronil, a broad-spectrum insecticide at acute doses in combination with endotoxin has been linked to airway inflammation. Wnt/PCP pathway plays important role in the pathogenesis of chronic inflammatory conditions by contributing to the release of downstream cytokines. However, there is no data on the PCP signaling pathway during fipronil-induced lung damage. This study aims to understand the molecular mechanisms underlying the pulmonary toxicity induced by fipronil alone or in combination with endotoxin. Methods We used a microarray approach to obtain a global view of the transcriptional responses of the lungs exposed to fipronil and endotoxin in a mice model. Lung tissues were harvested from male Swiss albino mice (n=42) following long term oral exposure to high and low doses of fipronil alone or in combination with endotoxin. The differentially expressed genes were analyzed by Ingenuity pathway analysis software to predict the top canonical pathways. The microarray data for selected genes was validated using quantitative PCR and immunohistochemistry. Results Both BAL fluid and histopathology analysis suggested lung damage and altered transcriptomic profile of lung following exposure to high and low dose of fipronil with or without endotoxin. PCP pathway was among the top upregulated canonical pathways following exposure to both doses of fipronil individually or with LPS. Low dose of fipronil increased the expression of WNT-6, MAPK-8, IL-4 and IL-17C while higher dose decreased the expression of MAPK-8 and IL-17C. The expression data verified by realtime PCR was in concordance with microarray data. Conclusion Long-term exposure to low (4.75 mg kg-1) and high (9.50 mg kg-1) dose of fipronil alone or in combination with endotoxins alters the histoarchitecture and transcriptome profile of lungs with the involvement of the PCP pathway. PCP pathway showed higher enrichment in low dose group of fipronil alone or in combination with LPS. The data from the study provides the insights of the potential damage on lungs caused by fipronil and endotoxin interaction and helps to better understand the mechanism of this complex relation