Alteración del sistema retinoide por exposición a xenobióticos

Abstract

The retinoid system is a cellular regulation system with a crucial role in many aspects of life, development and reproduction. Hundreds of retinoids have been identified, including retinyl esters, the storage form in the liver; retinol, the most representative retinoid in blood; retinal, involved in vision; and retinoic acids, which activate the retinoid receptors. Also can be found functional retinoids, as 9-cis-4-oxo-13,14-dihydro-retinoic acid, which activates RAR, and 9- cis-13,14-dihydro-retinoic acid, which activates RXR; and also biotransformation products found in urine, as retinoyl-β-glucuronides. All of them are present in a very wide concentration range depending on species, sex or tissue, and that is the reason why the election of the extraction and analysis method is a critic step, depending on the case. The homeostasis of the retinoid system can be altered after the exposure to several xenobiotics. This alteration was associated with serious outcomes, as neurologic development and metabolic impairments and fertility problems. The present work is focused on the effects on the retinoid system, driven by four xenobiotics, specifically to the retinoid concentrations and expression of genes involved in their regulation. Two flame retardants were assayed: hexabromocyclododecane (HBCD) and decabromodiphenyl ether (decaBDE), administered for 28 days to Wistar rats of both sexes with doses from 0.3 to 200 mg/kg bw/d for HBCD and from 1.87 to 30 mg/kg bw/d for decaBDE. Also laquinimod and tasquinimod metabolites precursors, IMA-08401 and IMA-07101, respectively, were assayed. Those two drugs act as immunomodulators and potential activators of aryl hydrocarbon receptor. Male Sprague- Dawley rats were exposed to IMA-08401 and IMA-07101 at repeated doses of 100 and 75 mg/kg bw/d, respectively, for 5 days. Exposure to HBCD was associated with induction of retinoid mobilization, as reflected by the reduction in the levels of retinyl palmitate and 9-cis-4-oxo-13,14-dihydro-retinoic acid in liver of both sexes. No changes of all-trans-retinoic acid were observed in females, probably due to the simultaneous induction of the expression of genes of enzymes involved in biosynthesis, as Adh1, Aox1 or Aldh1a1, and biotransformation, as Cyp26a1 or Ugts. In males, however, induction of biosynthesis was less potent than in females, which was associated with a decrease in the hepatic concentration of all-trans-retinoic acid. After exposure to decaBDE, no mobilization of retinyl esters was observed, and there was even a slight increase in retinyl palmitate concentrations in females, together with an induction of the enzyme lecithin-retinol acyltransferase, which mediates retinol esterification. Neither retinol nor 9-cis-4-oxo-13,14-dihydro-retinoic acid were altered, whereas hepatic expression of Crabp1 and Cyp26a1 was induced, genes associated with biotransformation of all-trans retinoic acid and, therefore, with the decrease of its hepatic concentrations, a more pronounced effect in males than in females.