Mitochondrial dysfunction induced by Bisphenol A is a factor of its hepatotoxicity in rats

Abstract

Bisphenol A (BPA), an estrogenic and endocrine disrupting agent, is widely used in manufacturing of polycarbonate plastics and epoxy resins. BPA and other endocrine disrupting chemicals (EDCs) act via multiple mechanisms including interference with mitochondrial functions. Mitochondria are the hub of cellular energy pool and hence are the target of many EDCs. We studied perturbation of activities of mitochondrial enzymes by BPA and its possible role in hepatotoxicity in Wistar rats. Rats were exposed to BPA (150 mg/kg, 250 mg/kg, 500 mg/kg per os, for 14 days) and activities of enzymes of mitochondrial electron transport chain (ETC) were measured. Besides, other biochemical parameters such as superoxide generation, protein oxidation, and lipid peroxidation (LPO) were also measured. Our results indicated a significant decrease in the activities of enzymes of mitochondrial ETC complexes, i.e., complex I, II, III, IV, and V along with significant increase in LPO and protein oxidation. Additionally, a significant increase in mitochondrial superoxide generation was also observed. All these findings could be attributed to enhanced oxidative stress, decrease in reduced glutathione level, and decrease in the activity of superoxide dismutase in rat liver mitochondria isolated from BPA-treated rats. BPA treatment also caused a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase indicating its potential hepatotoxicity. Furthermore, histopathological findings revealed marked edema formation, hepatocellular degeneration, and necrosis of liver tissue in BPA-exposed rats. In conclusion, this study provides an evidence of impaired mitochondrial bioenergetics and liver toxicity after high-dose BPA exposure in rats. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1922-1934, 2016.

Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics

“…The methods of action of BPA are that it can bind to the nuclear receptors for ER␣ and ER␤, with differing affinities for each which may lead to differing agonist/antagonist responses, although it is believed that the majority of its action is through other mechanisms, such as through intracellular signal transduction pathways independent of the nuclear hormone receptors, modification of cytochrome P-450 enzyme expression and activity, alterations in the level and activity of sex hormone binding globulin, and epigenetic modulation by the silencing of promoters by methylation [for review, see Wetherill et al (365)]. In addition, BPA is believed to impair mitochondrial function and promote oxidative stress in high doses in rat studies (178). It is reported that more BPA is produced than any other chemical with ϳ15 billion pounds produced in 2013 (125).…”

Bisphenol A aggravates renal ischemia–reperfusion injury by disrupting mitochondrial homeostasis and N‐acetylcysteine mitigates the injurious outcomes

“…This suggestion was based on the findings that the severity of IR‐induced mitochondrial dysfunction and apoptosis (Figure a–f) including disruption of mitochondrial homeostasis (Figure a–d) in rats exposed to BPA were significantly (all p < .001) greater than those received vehicle, which implied an additional impact of BPA that caused the injury worsened. In line with this notion, studies using an isolated mitochondrial model have shown that BPA is capable of acting directly at the mitochondria and resulting in mitochondrial disorder . Investigations both in vitro and in vivo have reported that BPA was able to disrupt electron transport chain, decrease ATP synthesis, increase ROS production with subsequent oxidative injury, impair mitochondrial ultrastructure, induce permeability transition, and release proteins that lead to activation of apoptosis .…”

“…The 5 mg/kg BPA is chosen as a starting dose, since it is a no‐observed‐adverse‐effect level (NOAEL) . In view of the high dose, BPA as high as 250–500 mg/kg were used in several animal studies and BPA detectable level in occupational individuals were reported to be 70 times higher than in general population . In the present study, however, BPA at the maximum of 50 mg/kg is selected as it has been reported to induce oxidative and mitochondrial injury to a certain extent .…”

“…Disruption of mitochondrial homeostasis has recently been acknowledged as the key mechanism underlying AKI pathology, and the novel strategies for treatment AKI also pay particular attention to the regulators of mitochondrial homeostasis. Interestingly, BPA‐induced organs injury has also been reported to be associated with mitochondrial dysfunction . In this case, it is possible that supplement with pharmacological agent that can target the mitochondria and maintain homeostasis within the organelle may alleviate the outcomes of AKI that may be intensified by exposure to BPA.…”

Developmental programming: Interaction between prenatal BPA and postnatal overfeeding on cardiac tissue gene expression in female sheep

“…Our finding of downregulation of pathways involved in mitochondrial function in left ventricular myocardium in prenatal BPA‐treted animals is consistent with earlier findings of such dysfunction in neonatal cardiomyocytes of prenatal BPA‐treated animals (Jiang et al ). Mitochondrial dysfunction, which includes gene sets involved in regulation of mitochondrial inner membrane, respiratory electron chain, and oxidoreductase activity that are vital for cardiac function and cardiac failure over time (Khan et al ), is a known target for EDCs including BPA (Xia et al ). Additional prenatal BPA‐induced disruptions include downregulation of pathways associated with cardiac contractility, such as those associated with actin‐myosin filament sliding and myofilament function, which can lead to disruptions in myocardial mechanical properties and contractile functions (Moss et al ).…”