The thesis is devoted to the investigation of bisphenol A-detoxifying enzymes activities under the conditions of different retinoids supplementation, the prooxidant and obesogenic effect of ВРА and the conduct of preventive correction of BPA-induced oxidative damage of liver by the previous administration of selective bacteria culture genus Lactobacillus, which have highly detoxification potential of this xenobiotics. The results indicate that the normal functioning of the enzymes I and II phases of the cellular detoxification system requires the presence of retinoids. Thus, hepatic BPA-biotransformation is retinoid-dependent. This conclusion is supported by the observation that high oral doses of retinoids allow increasing the enzymatic activities of both phases under the administration of xenobiotic. The detoxification of this xenobiotic occurs both transferase and oxygenase metabolic pathway. Non-toxic glucuronic acid conjugates are formed when phase II detoxification enzymes are involved in ВРА-biotransformation. However, when the high doses of this contaminant are consumed, BPA metabolism occurs with the involvement of the enzymes of the phase I cellular biotransformation system. It was found that the ВРА administration under the conditions of normal retinoid supplementation was accompanied by the development of free radical damage of cellular biopolymers, mainly in the hepatic microsomal fraction as the site of detoxification of this contaminant. Additional supplementation with retinoids aggravates the BPA-induced free radical processes. It was confirmed by obtained results of transgenic animals and application of high dose of vitamin A. The absence of oxidative damage in liver and subcellular fractions in case of insufficiency of hepatic retinyl esters and its appearance at normal or excess amounts of vitamin A indicates that retinoid supplementation is one of the factors determining of the ВРА prooxidant effect.
It was shown, that the activities of enzymatic biotransformation systems induced by the additional administration of retinoids are an additional source of free radicals, which are confirmed by the increased generation of superoxide anion radical and nitric oxide. However, microsomes and cytosol were the main source of free radicals, as recorded in our studies. Additionally, the depletion of the antioxidant system’s enzymes of the liver in BPA-exposure animals is observed. The decrease in catalase, superoxide dismutase and peroxidase activities in the cytosolic fraction leads to increased processes of oxidative damage to cell biopolymers of the subcellular fractions. This conclusion is confirmed by the results of studies in BPA-exposure animals with normal retinoid supplementation after pharmacological supplementation of 3000 IU retinyl acetate. Oral supplementation with retinoids of animals with a lack of retinoids stores also has adverse effects on the liver, aggravation of BPA-induced oxidative damage, by induction activities of microsomal monooxygenase. These results are accompanied by the enhanced generation of non-mitochondrial ROS, reduced activity of the antioxidant enzymes, which leads to the induction of free radical damage of cellular biopolymers, expressed in increasing levels of markers of lipid and protein peroxidation, mainly in the liver microsomal fraction as the site of detoxification of ВРА. In the dissertation, it is established that under the conditions of normal intake of retinoids BPA disrupts the transport of glucose and lipids in the body, which was expressed in the increased content and intolerance to this monosaccharide, and impaired of serum lipid profile. These effects are exacerbated under the conditions of the additional retinoid supplementation, which is primarily due to the enhanced of RA-signaling-mediated action of ВРA. In contrast, the main indicators of the lipid profile of the blood serum, the blood glucose curve and glucose content did not change with the administration of the xenobiotic under the conditions of endogenous retinoid hepatic stores deficiency. However, the administration of pharmacological doses of retinoids leads to the development of BPA-induced hypercholesterolemia, hypertriacylglycerolemia, and impaired glucose transport. As part of this study, a method for preventive correction of bisphenol A-induced oxidative damage by probiotic cultures isolated from fecal samples of BPA-exposed animals with toxic liver damage was developed and patented. It was shown that gastrointestinal tract colonization by probiotics leads to an increasing of the number of beneficial microflora microorganism and decreasing the number of conditionally pathogenic microorganisms. The application of the developed approach for the selection of selective autochthonous probiotic bacteria of animals that have been exposed to ВРА and their subsequent administration to healthy animals provides prevention of hepatic oxidative damage induced by the administration of ВРА.
