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Chan WH.
Citrinin
induces apoptosis via a mitochondria-dependent pathway and
inhibition of survival signals in embryonic stem cells, and
causes developmental injury in blastocysts.
Biochem J. 2007 Jun 1;404(2):317-26.
The mycotoxin Citrinin, a natural contaminant in foodstuffs and animal
feeds, has cytotoxic and genotoxic effects on various mammalian cells. Citrinin
is known to cause cell injury, including apoptosis, but the precise regulatory
mechanisms of Citrinin action, particularly in stem cells and embryos, are
currently unclear. In the present paper, I report that Citrinin 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 in embryonic stem cells (ESC-B5) showed that Citrinin
induces apoptosis via ROS (reactive oxygen species) generation, increased
Bax/Bcl-2 ratio, loss of MMP (mitochondrial membrane potential), induction of
cytochrome c release, and activation of caspase 3. In this model, Citrinin
triggers cell death via inactivation of the HSP90 [a 90 kDa isoform of the HSP
(heat-shock protein) family proteins]/multichaperone complex and subsequent
degradation of Ras and Raf-1, further inhibiting anti-apoptotic processes, such
as the Ras-->ERK (extracellular-signal-regulated kinase) signal transduction
pathway. In addition, Citrinin causes early developmental injury in mouse
ESCs and blastocysts in vitro. Lastly, using an in vivo mouse model, I show that
consumption of drinking water containing 10 muM Citrinin results in
blastocyst apoptosis and early embryonic developmental injury. Collectively,
these findings show for the first time that Citrinin induces ROS and
mitochondria-dependent apoptotic processes, inhibits Ras-->ERK survival
signalling via inactivation of the HSP90/multichaperone complex, and causes
developmental injury in vivo.
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