| ObjectiveOxidative stress mechanisms are involved in hepatotoxicity. The liver is reported to be affected by endocrine disrupting chemicals (EDCs) such as bisphenol A (BPA) and4-nonylphenol (4-NP) in mammalians. BPA and4-NP can exert estrogenic properties and have been also reported to possess hepatic toxicity. This study aimed to investigate association between liver health status and the effects of BPA and4-NP on liver biomarkers and the antioxidant defense systems, and their involvement in liver damage.MethodsBPA and4-NP (0,2,10,50mg/kg) body weight was mixed respectively in corn oil and intra-peritoneally administered every forty-eight hours for30days in dose dependent manner.48males Sprague-Dawley rats were chosen and then were firstly divided en two groups24rats for each chemical. The rats were randomly divided into four groups, each group containing six rats. In this current study, we investigated the effects of BPA and4-NP on the antioxidants enzymes and liver markers activities such as (SGOT, SGPT, LDH and y-GT) in serum and histopathological study. We also investigated the effects of BPA and4-NP on the expression of up-regulated genes involved in apoptosis, hepatotoxicity genes and other oxidative stress related genes. Incidence and severity of liver injury was scored and taken into consideration according to modified Batts&Ludwig scoring system (necrosis) and grading and staging system for NASH according Brunt et al.(steatosis, ballooning and lobular inflammation).ResultsThe study is shown no significant difference between the body weight and weight of rat liver in BPA-treated groups and control groups. However, significant changes between rat liver absolute and relative weight of4-NP-treated groups were observed. The study results show that the levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) increased after exposure to BPA and4-NP However, the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were significantly decreased (P<0.05, P<0.01) in response to BPA-treatment. While in the4-NP treatment groups the activities of antioxidants CAT and GSH-Px were significantly decreased at dose2mg/kg b.wt.(P<0.01) and extremely decreased at dose10and50mg/kg b.wt.(P<0.001). The elevation of serum SGOT, SGPT, LDH and γ-GT activities were also observed in the4-Np treatment. Furthermore, in the BPA treatment groups the levels of SGOT, SGPT, LDH activities were also elevated, but γ-GT was reduced.The revealed up-regulated genes were involved in apoptosis, hepatotoxity and oxidative stress (OS) genes were observed in the both EDCs treatment. Moreover, BPA-treated group significantly decrease expression of OS related genes (SOD1, GPx and Txnrd1)(P<0.05, P<0.01). The results also revealed significantly decreased expression of Bcl-2gene and increase of iNOS, TNF-a, Casp-3and Casp-9which are the key executioners in apoptosis. Furthermore,4-NP treatment also significantly promoted the reduction of expression of OS related genes such as (SOD1and GPx)(P<0.05, P<0.01) except for the expression of HSP70which was increased significantly at dose50mg/kg b.wt.(P<0.05). Hepatocyte apoptosis would promote NAFLD progression; Fas/FasL, TNF-a and Caspase-9mRNA activation were important contributing factors to hepatic steatosis. Moreover,4-NP treatment also revealed, significantly decreased expression of Bcl-2gene and increase of the expression of Bax.ConclusionOur results provided key evidence of liver damage through apoptosis, necrosis and progression NAFLD. Furthermore, BPA may lead to induced toxic response of liver oxidative system, which may contribute to long-term hepatotoxicity through apoptosis and necrosis. Whereas, our present research provide the first evidence that4-NP affects the gene expression related to liver hepatotoxicity, which is correlated with hepatic steatosis. |
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