Citrinin induces apoptosis in mouse embryonic stem cells

Abstract

The mycotoxin citrinin (CTN) is a natural contaminant in foodstuffs and animal feeds, and exerts cytotoxic and genotoxic effects on various mammalian cells. CTN causes cell injury, including apoptosis. However, its precise regulatory mechanisms of action, particularly in stem cells and embryos, are currently unclear. Recent studies show that CTN has cytotoxic effects on mouse embryonic stem cells and blastocysts, and is associated with defects in their subsequent development, both in vitro and in vivo. Experiments with the embryonic stem cell line, ESC-B5, disclose that CTN induces apoptosis via several mechanisms, including ROS generation, increased cytoplasmic free calcium levels, intracellular nitric oxide production, enhanced Bax/Bcl-2 ratio, loss of mitochondrial membrane potential, cytochrome c release, activation of caspase-9 and caspase-3, and p21-activated protein kinase 2 and c-Jun N-terminal protein kinase activation. Additional studies show that CTN promotes cell death via inactivation of the HSP90/multi-chaperone complex and subsequent degradation of Ras and Raf-1, further inhibiting anti-apoptotic processes such as the Ras-->ERK signal transduction pathway. On the basis of these findings, we propose a model for CTN-induced cell injury signalling cascades in embryonic stem cells and blastocysts.