Several investigators reported that lead-induced hepatotoxicity decreases HDL significantly and increases their serum cholesterol, triglyceride levels and also serum liver enzyme activities in rats. The increased liver enzyme is a biomarker of liver damage, the destruction of the liver cell membrane, and the induction of lipid peroxidation (Abdelhamid et al., 2020; Abdou and Hassan, 2014; Farida et al., 2012; Laamech et al., 2017). The present findings showed that PbAc-induced toxicity elevates serum cholesterol and LDL levels compared to the controls, but no change was observed in triglycerides and HDL levels in this treatment group, which may be due to the concentration of PbAc (100 mg/ml) used. Lead exposure changes cell surface receptors for lipoprotein or inhibits lipoprotein lipase function in liver, which then reduces removal of lipoproteins (Chajek-Shaul et al., 1989; Kojima et al., 2004; Kojima et al., 2005; Newairy and Abdou, 2009; Tarugi et al., 1982). Moreover, lead alters lipid metabolism enzymes activity in liver, this can limit the bile acids biosynthesis, which is the only route for elimination of body cholesterol (Kojima et al., 2004; Kojima et al., 2005; Mudipalli, 2007; Newairy and Abdou, 2009). So, the balance between biosynthesis and catabolism of cholesterol by the liver is a critical determinant of its concentration in the blood serum. Other studies have also shown that the main mechanism of lead-induced toxicity is the enhancement of cellular oxidative stress due to increased free radical production or antioxidant enzyme reduction (El-Boshy et al., 2019; El-Tantawy, 2016; Laamech et al., 2017; Liu et al., 2011; Winiarska-Mieczan, 2018), which leads to metabolic abnormalities such as abnormal lipid profile (Ohara et al., 1993).
In this study, to determine if CoQ10 affects PbAc-induced toxicity, CoQ10 (10 mg/kg/day by gavage) was added to the PbAc (1g/100 ml) regimen of the rats as well. The results demonstrated for the first time that CoQ10 administration in rats fed with PbAc causes a down-regulation of the cholesterol and LDL in the rats’ blood serum and increases HDL compared to the PbAc-treated and control rats. These results are consistent with previous findings on the antioxidant activity and protective effects of CoQ10 in different tissues (Paunović et al., 2017; Sharma et al., 2018; Tarry-Adkins et al., 2016; Yousef et al., 2019) and the reduction in blood cholesterol following CoQ10 treatment (Xu et al., 2017). Several studies reveal that CoQ10 inhibits lipid peroxidation in mice fed with cadmium and arsenic. The suppression of lipid peroxidation as a result of CoQ10 treatment may be caused by the ability of CoQ10 to inhibit ROS (Paunović et al., 2017; Sharma et al., 2018). Also, Yousef et al. (2019) showed that CoQ10 causes a balance between the oxidants and antioxidants and has beneficial effects against lead-induced neuronal damage. Thus, the present study showed that CoQ10 may be reduced hyperlipidemia induced by PbAc due to its ability to neutralize oxidative damage and inhibiting ROS generation.
Previous studies have demonstrated MT3 protein and mRNA expression in various organs of rats, mainly in the brain, and in a low amount in the liver, kidney pancreas, prostate, testis, and tongue (Clifford and MacDonald, 2000; Hozumi et al., 2008; Juárez-Rebollar et al., 2017; Sabolić et al., 2010; Thirumoorthy et al., 2011; Vašák and Meloni, 2017). Moreover, MT3 mRNA and protein overexpression has been detected in many cases of human bladder, prostate and breast cancers (Sens et al., 2001). MT3 mRNA and protein are also expressed in normal human kidneys, renal carcinoma and the nuclei isolated from rat nephrons (Al-Waeli et al., 2012; Sabolić et al., 2018; Thirumoorthy et al., 2011). Also, MT3 expression was also identified in Broiler’s liver (Zoidis et al., 2019). In present study, MT3 mRNA and protein were expressed in rats’ liver and kidney. These localizations are also confirmed by the studies that showed MT3 protein expression in different peripheral organs of rats and humans (Garrett et al., 1999; Hozumi et al., 2008; Sabolić et al., 2018).
MT3 expression was highly increased in the liver after exposure to cadmium (Al-Waeli et al., 2012), which shows that MT3 mediates the mechanism of cytotoxicity in different mammalian organs. Tsui et al. (2019) have shown that MT3 is a tumorigenesis factor and increasing invasiveness and cell growth of bladder carcinoma, which is upregulated by hypoxia and arsenic in vivo. Also, the overexpression of the mRNA or protein of MT3 has been observed in many human bladder, prostate and breast cancers (Sens et al., 2001). Moreover, the MT3 gene is involved in cellular growth and heavy metals’ metabolism during oxidative stress situations in the human brain (Bonaventura et al., 2018), and the MT3 gene expression also decreases with oxidative stress (Tahmasbpour et al., 2016). Thus, the present findings suggest that MT3 expression can decrease after acute exposure to PbAc during oxidative stress conditions (Bonaventura et al., 2018).
The reduction of MT3 levels is indicated in metal-associated neurodegenerative diseases, and this function is due to the diminution of cellular capacity to neutralize ROS (Tsuji et al., 1992; Uchida et al., 1991; Vašák and Meloni, 2017; Yu et al., 2001). Many studies demonstrated that cadmium exposure increased the cells’ resistance against cell apoptosis with elevated MT3 levels (Garrett et al., 2002; Zoidis et al., 2019). On the other hand, Somji et al. (2004) showed that when the cells are in proliferation/regeneration, MT3 expression decreases and occurs cell destruction through cell apoptosis. In the present study, the expression of MT3 mRNA and protein decreased in the liver and kidney of the PbAc-treated rats. Thus, the present findings suggest that PbAc exposure may decrease the cellular capacity for the neutralization of ROS and cause cellular apoptosis by inducing oxidative stress (Somji et al., 2004; Tsuji et al., 1992; Yu et al., 2001). The reduction of MT3 levels may be indicative of PbAc-induced apoptosis due to toxicity in the liver and kidney of rats.
The mechanism of reduction of MT3 expression by Pb toxicity in the liver and kidney is not known. Mammalian MT3 is an unusual protein with a puzzling role (Bousleiman et al., 2017). However, the proposed mechanism may be operative here. The binding Affinity of Pb to MT3 is more compared to its binding with Zn (Carpenter et al., 2016; Wong et al., 2017) and thus during Pb-induced toxicity, Zn may be replaced by Pb and affecting liver and kidney function. Furthermore, Bonaventura et al. (2018) has shown that expression level of MT3 gene is dependent on toxic conditions. However, the mechanisms that show in the PbAc-induced reduction of MT-3 in the liver and kidney remain to be investigated.
Several studies have shown that the mechanism of toxicity of Pb occurs through the production of free radicals and generation of ROS, which result in cellar apoptosis generation (HERRERA et al., 2001). During apoptotic stimuli, Cyt c is released into the cytosol, and mediates the activation of the adaptor molecule apoptosis-protease activating factor 1 (Apaf-1), which is required for the activation of effector caspases (caspases 3, 6, and 7) and induces apoptosis (Dua et al., 2016; Garrido et al., 2006). Also, El-Tantawy et al. (2016) showed a markedly increase of hepatic caspase-3 levels in PbAc-treated rats. Thus, the upregulation of Cyt-c mRNA expression in the liver and kidney of the PbAc-treated rats may explain cell apoptosis production in the present study.
Several researches showed that CoQ10 has been implicated in the metabolic pathways that are associated with protecting organisms against oxidative damage (Lee et al., 2012a; Miyamae et al., 2013; Paunović et al., 2017; Rivara et al., 2017; Sharma et al., 2018; Tarry-Adkins et al., 2016). CoQ10 is a potent antioxidant that protects against the production of mitochondrial ROS generated by oxidative stress (La Guardia et al., 2013; Tian et al., 2014). One study has shown the ability of CoQ10 to protect against PbAc-induced neurotoxicity in rats by restoring the balance between the antioxidants and oxidants through its antioxidant and anti-apoptotic activities (Yousef et al., 2019). The present study also showed that CoQ10 can increase MT3 protein and mRNA levels in rats’ liver and kidney after PbAc exposure. CoQ10 also reduced the upregulation of Cyt c mRNA levels. This effect of CoQ10 has modulated the upregulation of anti-apoptotic mitochondrial-related proteins through its antioxidant activity and the inhibition of ROS generation by CoQ10 by neutralizing ROS through protective effects against free radicals (Yousef et al., 2019).