Re: IBD & Dioxins Link?

> Persistent activation of the AhR is probably responsible for toxic
> responses in experimental animals and humans.

Dioxin-mediated tumor progression through activation of mitochondria-
to-nucleus stress signaling.
The environmental toxin 2,3,7,8-tetrachlorodibenzodioxin (TCDD) is a
known human carcinogen; however, its precise mechanism of action
remains unclear. Here we show that TCDD induces mitochondrial
dysfunction, stress signaling, and tumor invasion by a mechanism
similar to that described for mtDNA-depleted cells. Treatment of C2C12
cells with TCDD disrupted mitochondrial transmembrane potential in a
time-dependent fa****on and inhibited mitochondrial transcription and
translation. TCDD also increased cytosolic [Ca(2+)](c) and RyR1-
specific Ca(2+) release. These changes were associated with increased
calcineurin (CnA) levels and activation of CnA-sensitive NF-kappaB/Rel
(IkappaBbeta-dependent) factors. Cells treated with TCDD displayed
resistance to apoptosis, increased expression of the tumor marker
cathepsin L, and a high degree of invasiveness as tested by the
Matrigel membrane invasion assay. These effects were reversed by the
CnA inhibitor FK506, and CnA mRNA silencing suggesting that TCDD
triggers a signaling pathway similar to mtDNA depletion. Taken
together, these results reveal that TCDD may promote tumor progression
in vivo by directly targeting mitochondrial transcription and
induction of mitochondrial stress signaling. PMID: 18172213