Abstract
Humans are exposed to multiple exogenous environmental pollutants. Many of these compounds are parts of mixtures that can exacerbate harmful effects of the individual mixture components. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is primarily produced via industrial processes including incineration and the manufacture of herbicides. Both endosulfan and TCDD are persistent organic pollutants which elicit cytotoxic effects by inducing reactive oxygen species generation. Sublethal concentrations of mixtures of TCDD and endosulfan increase oxidative stress, as well as mitochondrial homeostasis disruption, which is preceded by a calcium rise and, in fine, induce cell death. TCDD+Endosulfan elicit a complex signaling sequence involving reticulum endoplasmic destalilization which leads to Ca2+ rise, superoxide anion production, ATP drop and late NADP(H) depletion associated with a mitochondrial induced apoptosis concomitant early autophagic processes. The ROS scavenger, N-acetyl-cysteine, blocks both the mixture-induced autophagy and death. Calcium chelators act similarly and mitochondrially targeted anti-oxidants also abrogate these effects. Inhibition of the autophagic fluxes with 3-methyladenine, increases mixture-induced cell death. These findings show that subchronic doses of pollutants may act synergistically. They also reveal that the onset of autophagy might serve as a protective mechanism against ROS-triggered cytotoxic effects of a cocktail of pollutants in Caco-2 cells and increase their tumorigenicity.
Highlights
Oncogenetics remains a critical component of cancer biology and therapeutic research, the environmental features of tumor development and progression, such as cancer cell metabolism, have recently been reconsidered with much interest
A huge controversy has arisen on this subject, since multiple authors agree with a TCDD induction of apoptosis[22,23,24,25,26], while others argue that an inhibition/delay of apoptosis is at hand[27,28,29]
Since autophagy may mask the reality of mitochondrial apoptosis induced by TCDD and may play an essential role in the increased susceptibility to tumorigenesis, we believe that the cross-link between autophagy and cell death is the primary point to be investigated
Summary
Subtle effects of TCDD and Endosulfan on plasma membrane and cell death. A primary assertion made here is that both TCDD and α-E could interfere with the plasma membrane and modify the. Compared with the controls, TCDD alone (at 10, 25 and 50 nM) does not induce a very significant amount of cell death (no more than 30%) and neither does the endosulfan alone (Fig. 1B) whereas the association of the two products acts synergistically to provoke elevated levels of death (up to 60%at TCDD 25 + E 10 and as high as 75% of cells for TCDD 50 + E 20 for 48 h incubation) It seems that TCDD and α-E mixtures deeply change the plasma membrane permeability of the cells exposed to such treatments. The production of MDA was significantly increased with increasing cocktail concentrations, compared to the DMSO + nonane-treated control cells (Fig. 2A) These results suggest that the different mixtures increase the production of peroxidized lipids in a concentration-dependent manner even with a sub-lethal combination of cocktail (i.e. TCDD 10 nM and α-E 1 μM).
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