Sex-dependent gene expression after ochratoxin A insult in F344 rat kidney

Area of Science:

• Toxicology
• Genomics
• Molecular Biology

Background:

• Ochratoxin A (OTA) is a known nephrocarcinogen in rodents, with observed sex-based differences in sensitivity.
• Understanding sex-specific molecular responses to OTA is crucial for accurate risk assessment.

Purpose of the Study:

• To investigate sex-specific gene expression and DNA methylation changes in rat kidneys following OTA exposure.
• To compare the transcriptomic and epigenetic responses to OTA between male and female F344 rats.

Main Methods:

• Whole genome transcriptomics (RNA sequencing) was employed to analyze kidney gene expression.
• DNA methylation analysis of selected genes was performed using MALDI-TOF mass spectrometry.
• Rats were treated with two doses of OTA (0.21 or 0.50 mg/kg bw) for 21 days.

Main Results:

• OTA exposure induced dose-dependent responses in both sexes, more pronounced in males.
• Females exhibited a higher number of altered genes, but males showed more significantly enriched toxicity lists at a lower dose.
• Both sexes displayed modulation of damage, signaling, metabolism, inflammation, proliferation, and oxidative stress pathways; however, specific pathways were uniquely affected in each sex.
• No significant biologically relevant changes in DNA methylation were detected.

Conclusions:

• Kidney response to OTA is sex-dependent, with distinct transcriptomic profiles and affected pathways in males and females.
• While OTA impacts common toxicity pathways, sex-biased gene modulation, particularly in phase I/II enzymes, transporters, and nuclear receptors, contributes to differential responses.
• The study underscores the importance of considering sex as a biological variable in toxicological assessments of Ochratoxin A.