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Time Course of Renal Transcriptomics after Subchronic Exposure to Ochratoxin A in Fisher Rats
Laura Pastor1,2, Ariane Vettorazzi1,2, Elizabeth Guruceaga2,3
1Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, CIFA Building, c/Irunlarrea 1, E-31008 Pamplona, Spain.
Abstract:
The mycotoxin ochratoxin A (OTA) is a potent nephrocarcinogen, mainly in male rats. The aim of this study was to determine the time course of gene expression (GeneChip® Rat Gene 2.0 ST Array, Affymetrix) in kidney samples from male and female F344 rats, treated daily (p.o) with 0.50 mg/kg b.w. (body weight) of OTA for 7 or 21 days, and evaluate if there were differences between both sexes. After OTA treatment, there was an evolution of gene expression in the kidney over time, with more differentially expressed genes (DEG) at 21 days. The gene expression time course was different between sexes with respect to the number of DEG and the direction of expression (up or down): the female response was progressive and consistent over time, whereas males had a different early response with more DEG, most of them up-regulated. The statistically most significant DEG corresponded to metabolism enzymes (Akr1b7, Akr1c2, Adh6 down-regulated in females; Cyp2c11, Dhrs7, Cyp2d1, Cyp2d5 down-regulated in males) or transporters (Slc17a9 down-regulated in females; Slco1a1 (OATP-1) and Slc51b and Slc22a22 (OAT) down-regulated in males). Some of these genes had also a basal sex difference and were over-expressed in males or females with respect to the other sex.
Insights
Ochratoxin A (OTA) exposure alters kidney gene expression differently in male and female rats over time. Males show an early, robust response with more up-regulated genes, while females exhibit a progressive, consistent change.
Area of Science:
- Toxicology
- Molecular Biology
- Genomics
Background:
- Ochratoxin A (OTA) is a mycotoxin with known nephrocarcinogenic properties, primarily observed in male rats.
- Understanding sex-specific toxicological responses is crucial for accurate risk assessment.
Purpose of the Study:
- To investigate the temporal gene expression profile in rat kidneys following OTA exposure.
- To identify and compare sex-specific differences in gene expression patterns induced by OTA.
Main Methods:
- Gene expression analysis using Affymetrix GeneChip® Rat Gene 2.0 ST Array.
- Treatment of male and female F344 rats with OTA (0.50 mg/kg b.w.) for 7 and 21 days.
- Statistical analysis to identify differentially expressed genes (DEGs) and assess sex-based variations.
Main Results:
- OTA exposure induced time-dependent changes in kidney gene expression, with a greater number of DEGs observed at 21 days.
- Significant sex-specific differences in gene expression were noted: males displayed an early, pronounced response with more up-regulated genes, while females showed a progressive, consistent pattern.
- Key DEGs included metabolism enzymes (e.g., Akr1b7, Cyp2c11) and transporters (e.g., Slc17a9, Slco1a1), with some exhibiting basal sex differences.
Conclusions:
- Kidney gene expression response to OTA is dynamic and sex-dependent.
- Males and females exhibit distinct temporal patterns and magnitudes of gene regulation following OTA exposure.
- These findings highlight the importance of considering sex in toxicological evaluations of mycotoxins like OTA.
