Time Course of Renal Transcriptomics after Subchronic Exposure to Ochratoxin A in Fisher Rats

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.

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

“…pathways (Ayed-Boussema et al 2012;Doricakova and Vrzal, 2015), hepatocyte nuclear factor 4 alpha (Hnf4α) (Pastor et al, 2018b;Marin-Kuan et al, 2006) and nuclear factor-erytroid 2-related factor (Nrf2) (Limonciel and Jennings, 2014). In addition, as it was described in Pastor et al, 2018b, several of these signaling pathways showed a clear sex-dependent response.…”

“…pathways (Ayed-Boussema et al 2012;Doricakova and Vrzal, 2015), hepatocyte nuclear factor 4 alpha (Hnf4α) (Pastor et al, 2018b;Marin-Kuan et al, 2006) and nuclear factor-erytroid 2-related factor (Nrf2) (Limonciel and Jennings, 2014). In addition, as it was described in Pastor et al, 2018b, several of these signaling pathways showed a clear sex-dependent response. Finally, these pathways could be relevant in others functions such as cell cycle progression or apoptosis, such as Ahr that has been proposed to be related with to some mechanisms of hepatocarcinogenesis (Souza et al, 2016).…”

“…So, taking into account the high influence of time of exposure previously found in OTA gene expression response (Pastor et al, 2018b) and that little information is available about the impact of the dose in both sexes, the aim of the present study was to evaluate the gene expression response of both sexes F344 rats after daily oral administration of 0.21 and 0.50 mg/kg bw for 21 days.…”

“…In a gene expression analysis of kidney tissues from the same rats, in which time modulation was evaluated, a clear different response was observed in males after 7 days of treatment, not only in relation to females, but also when both timepoints were compared in males (Pastor et al, 2018b).…”

“…It is known that several phase I and II enzymes, as well as transporters show sex-biased expression at basal level and most of the sex-dependent responses observed against toxicants are due to their role in activation or detoxification of these compounds (Trevisan et al, 2012). Short-term toxicogenomics studies in male rats (Arbillaga et al, 2008;Marin-Kuan et al, 2006;Stemmer et al, 2007), as well as results from Pastor et al (2018b), also pointed to that, as some of most altered genes by OTA were related to the modulation of cytochromes (Cyp2c11, Cyp2d1, Cyp2d5, Cyp24a1, in males), aldo-keto reductases (Akr1b7 and Akr1c2 in females), alcohol dehydrogenase (Adh6 in females), and transporters (Slco1a1, Slc51b and Slc22a22 in males). In addition, it is important to remark that most of these genes are regulated by nuclear receptors.…”