Citrinin induces apoptosis in mouse embryonic stem cells

Area of Science:

• Toxicology
• Developmental Biology
• Cell Biology

Background:

• Mycotoxin citrinin (CTN) is a food contaminant with known cytotoxic and genotoxic effects.
• CTN's specific mechanisms in stem cells and embryos remain unclear.
• Previous studies indicate CTN's adverse effects on mouse embryonic stem cells and blastocysts.

Purpose of the Study:

• To elucidate the precise regulatory mechanisms of citrinin (CTN)-induced apoptosis in embryonic stem cells.
• To investigate CTN's impact on blastocyst development and associated signaling pathways.
• To propose a model for CTN-induced cell injury signaling cascades.

Main Methods:

• Utilized the mouse embryonic stem cell line, ESC-B5.
• Analyzed CTN-induced apoptosis through various cellular and molecular assays.
• Investigated the role of reactive oxygen species (ROS), calcium signaling, and mitochondrial pathways.
• Examined the involvement of caspase activation and specific protein kinases (PAK2, JNK).
• Assessed the impact of CTN on the HSP90/multi-chaperone complex and Ras-ERK signaling.

Main Results:

• CTN induces apoptosis in ESC-B5 cells via ROS generation, calcium influx, and nitric oxide production.
• CTN disrupts mitochondrial membrane potential, leading to cytochrome c release and caspase activation (caspase-9, caspase-3).
• CTN increases the Bax/Bcl-2 ratio and activates PAK2 and JNK pathways.
• CTN inhibits anti-apoptotic signaling by inactivating the HSP90 complex, degrading Ras and Raf-1, and suppressing the Ras-ERK pathway.

Conclusions:

• CTN triggers apoptosis in embryonic stem cells and blastocysts through multiple interconnected signaling pathways.
• Disruption of mitochondrial function and key signaling cascades like Ras-ERK contribute to CTN's toxicity.
• The findings provide a comprehensive model for understanding CTN-induced developmental toxicity.