Citrinin-Induced Hepatotoxicity in Mice Is Regulated by the Ca2+/Endoplasmic Reticulum Stress Signaling Pathway

Abstract

Citrinin (CTN) is a mycotoxin found in crops and agricultural products and poses a serious threat to human and animal health. The aim of this study is to investigate the hepatotoxicity of CTN in mice and analyze its mechanisms from Ca2+-dependent endoplasmic reticulum (ER) stress perspective. We showed that CTN induced histopathological damage, caused ultrastructural changes in liver cells, and induced abnormal values of biochemical laboratory tests of some liver functions in mice. Treatment with CTN could induce nitric oxide (NO), malondialdehyde (MDA), and reactive oxygen species (ROS) accumulation in mice, accompanied with losses of activities of superoxide dismutase (SOD) and catalase (CAT), levels of glutathione (GSH), and capacities of total antioxidant (T-AOC), resulting in oxidative stress in mice. Furthermore, CTN treatment significantly increased Ca2+ accumulation, upregulated protein expressions of ER stress-mediated apoptosis signal protein (glucose regulated protein 78 (GRP78/BIP), C/EBP-homologous protein (CHOP), Caspase-12, and Caspase-3), and induced hepatocyte apoptosis. These adverse effects were counteracted by 4-phenylbutyric acid (4-PBA), an ER stress inhibitor. In summary, our results showed a possible underlying molecular mechanism for CTN that induced hepatocyte apoptosis in mice by the regulation of the Ca2+/ER stress signaling pathway.

Study on the Mechanism of Mesaconitine-Induced Hepatotoxicity in Rats Based on Metabonomics and Toxicology Network

“…Mitochondrial pathway and endoplasmic reticulum stress belong to the endogenous pathway, and death receptor pathway belongs to the exogenous pathway. The endogenous pathway is mainly regulated by Bcl-2 family proteins, while the exogenous pathway is mainly regulated by caspase [ 62 ]. Caspase is a key mediator of programmed cell death or apoptosis, and it plays an important role in mediating apoptosis [ 63 , 64 ].…”

Detoxication of Citrinin with Kojic Acid by the Formation of the Citrinin-Kojic Acid Adduct, and the Enhancement of Kojic Acid Production by Citrinin via Oxidative Stress in Aspergillus parasiticus

“…A mechanism other than oxidative stress may be involved in these phenomena. Wu et al recently reported that CTN-induced hepatotoxicity in mice was regulated mainly via Ca 2+ /endoplasmic reticulum (ER) stress, which is caused by alterations in Ca 2+ homeostasis and an accumulation of misfolded proteins in the ER [ 5 , 34 ]. We suspect that Ca 2+ /ER stress might be involved in the inhibitions of AF production and fungal growth with CTN ( Figure 9 ), but the mechanisms underlying these inhibitions remain to be clarified.…”

“…CTN contamination has been widely detected in cereals, feed, and supplements [ 4 ]. CTN is a nephrotoxic and hepatotoxic substance to animals and is an antibiotic, antifungal, anti-bacteriophage, anti-sarcoma, anti-protozoa and anti-animal cells substance [ 5 ]. Much research has been conducted to develop strategies to combat and control AF and CTN contamination, and the inhibition of the production of these mycotoxins with various types of microorganisms such as bacteria, yeasts, and fungi [ 6 , 7 , 8 ] and plant extracts [ 9 ] has been suggested.…”

Lycopene Alleviates Chronic Stress-Induced Liver Injury by Inhibiting Oxidative Stress-Mediated Endoplasmic Reticulum Stress Pathway Apoptosis in Rats

“…13 Prolonged or intense ERS further induces apoptosis, leading to liver damage. 14 Therefore, maintaining the normal function of the ER is critical for the prevention and treatment of chronic liver diseases. Preliminary research has shown that CRS induces spleen ERS in rats.…”

“…ERS plays an important role in the occurrence and development of various liver diseases . Prolonged or intense ERS further induces apoptosis, leading to liver damage . Therefore, maintaining the normal function of the ER is critical for the prevention and treatment of chronic liver diseases.…”