Involvement of JNK regulation in oxidative stress-mediated murine liver injury by microcystin-LR

Abstract

Microcystin-LR (MC-LR) produced by cyanobacteria in diverse water systems is a potent specific hepatotoxin and has been documented to induce various liver diseases via oxidative stress. However, the underlying mechanisms are largely unknown. In the current study, we investigated the molecular events involved in the oxidative liver injury by MC-LR. Our results demonstrated that MC-LR induced liver injury in mice through a series of steps that began with the production of reactive oxygen species (ROS), which stimulated the sustained activation of JNK and its downstream targets, AP-1 and Bid. Furthermore, the mitochondrial proteomic analysis indicated that JNK activation affected some crucial enzymes of energy metabolism, led to mitochondria dysfunction, which contributed to hepatocyte apoptosis and oxidative liver injury by MC-LR. Our results reveal significant insights into the mechanisms of liver injury induced by microcystins, and serve as a framework for deciphering the role of JNK in oxidative stress-associated liver diseases.

A review of reproductive toxicity of microcystins

“…Zhang et al [34] reported endoplasmic reticulum (ER) stress as an event that occurs downstream of oxidative stress and found that MCs exposure may induce testis apoptosis involving both the mitochondrial and ER pathways. It was also confirmed that MC-LR-induced oxidative stress may stimulate sustained activation of JNK, which in turn induced apoptosis via AP-1 and Bid, two important substrates downstream of JNK [124]. Moreover, MCs could lead to cytoskeleton disruption and the cytoskeleton may also play a key role in regulating apoptosis and necrosis in reproductive system (Fig.…”

Assessing the toxicity of ingested Taihu Lake water on mice via hepatic histopathology and matrix metalloproteinase expression

“…Previous studies have indicated that MCs can exert harmful toxicity on mammals (Clark et al 2009), birds (Peckova et al 2009) and aquatic animals such as cladocerans and fish (Malbrouck and Kestemont 2006;Okumura et al 2007). Wei et al (2008b) revealed that MCs exposure induces adaptive responses to enhance the antioxidant enzymatic activities. MCs also constitute a carcinogenic risk to people via drinking water and food chains (Ueno et al 1996).…”

“…MCs also constitute a carcinogenic risk to people via drinking water and food chains (Ueno et al 1996). Currently, most attention is focused on the carcinogenic mechanism of MCs (Wei et al 2008b;Hernandez et al 2009), but limited information is available about its effects on cellular infiltration and migration, and in turn on tumor metastasis.…”

Cyanobacteria-blooming water samples from Lake Taihu induce endoplasmic reticulum stress in liver and kidney of mice

“…The liver has been described as the most important organ involved in the regulation of redox metabolism (Wei et al 2008), and it is the target organ of many pollutants (Albina et al 2010;Ding and Ong 2003). Consequently, its oxidative status may be affected by such pollutants.…”