Oxidation of retinoic acids in hepatic microsomes of wild bullfrogs Lithobates catesbeianus environmentally-exposed to a gradient of agricultural contamination

Abstract

Agricultural contaminants are suspected of contributing to the increased incidence of deformities and the decline of amphibians populations worldwide. Many authors have further suggested that a retinoid effect could be implicated in teratogenic mechanisms since the reported deformities resemble those caused by abnormal levels of retinoic acid (RA). We previously reported altered retinoid concentrations in male bullfrogs from the Yamaska River basin (Québec, Canada) associated with moderate-to-high agricultural activity, and the findings were consistent with a possible effect on hepatic RA oxidation. An in vitro assay was therefore optimized and hepatic microsomal RA oxidation in bullfrogs was found to be quite different from that of other vertebrates. With either all-transRA (atRA) or 13cisRA as the substrate, the major metabolite generated was at4-oxo-RA. The reaction with 13cisRA as substrate, markedly greater compared with atRA, was enhanced in the presence of a reducing agent and inhibited by cytochrome P450 inhibitors in a dose-dependent manner. Hepatic RA oxidation in male bullfrogs showed significant differences between sites with no clear relationship to a gradient of agricultural activity or 13cis-4-oxo-RA quantified in plasma. In contrast, the in vitro RA oxidation in females increased with the levels of contamination and coincided in vivo with higher plasma 13cis-4-oxo-RA concentration. The levels of circulating 4-oxo-derivatives could be influenced by hepatic RA oxidative metabolism as well as isomerization conditions or RA precursor levels.

Plasma retinoids concentration in Leptodactylus chaquensis (Amphibia: Leptodactylidae) from rice agroecosystems, Santa Fe province, Argentina

“…Plasma RA concentrations in L. chaquensis were significantly higher in frogs from RF than in RS. These ROH metabolites are part of the signaling pathways in embryos, but an increase in their concentrations are involved in teratogenic processes (Thibodeau et al, 2012). At this point, several evidences reinforced the hypothesis that environmental pollutions in both aquatic and terrestrial habitats may interfere with the retinoic signaling pathway (Gardiner et al, 2003;Bérubé et al, 2005;Novák et al 2007).…”

Environmentally friendly stability-indicating HPLC method for the determination of isotretinoin in commercial products and solubility samples

“…Studies on pigmentary diseases [ 7 ], photoaging [ 8 ], in-vitro and in-vivo carcinogenesis [ 9 ], and photoaging have all sparked interest in the preventative and therapeutic effects of ITN. Due to the teratogenicity of these substances, retinoid levels should also be evaluated [ 10 , 11 ]. Recently, a practical method for administering ITN orally to pediatric patient with neuroblastoma has been suggested [ 12 ].…”

Rapid determination of retinoic acid and its main isomers in plasma by second-order high-performance liquid chromatography data modeling

“…Both RA and 13-cis-RA are widely used in the treatment of a variety of dermatological diseases, for example acne, psoriasis, skin cancer, and photo aging, and for regulating growth and differentiation of epithelial cells, sebum production, and collagen synthesis [2][3][4]. However, retinoid levels should be monitored owing to the teratogenicity of these compounds [5,6].…”

“…A literature search reveals that such techniques as gas chromatography (GC), high-performance liquid chromatography (HPLC) column-switching with and without direct injection of plasma, ultra-high-performance liquid chromatography (UHPLC), and capillary electrophoresis (CE), with ultraviolet, fluorescence, and mass spectrometric detection have mostly been used to develop methods for quantification of RA and its isomers [7][8][9][10][11]. In most of these methods, the analytes were separated with retention times close to 30 min by use of C 18 columns (4.6 mm×250 mm, 5.0 μm particle size) [6][7][8][9]. Very recently, an enhanced HPLC method in which the analytes were separated in 12 minutes by use of C 18 (4.6 mm×75 mm, 3.5 μm particle size) has been developed in our laboratory [12].…”