Linking long-term toxicity of xeno-chemicals with short-term biological adaptation

Understanding the mechanisms of long-term toxicities of chemicals is challenging. The present review discusses evidence suggesting that the biological adaptation to acute xenobiotic exposure could lead in the long run to toxic side effects. Upon acute exposure, hydrophobic xenobiotics are sequestered in the adipose tissue, which consequently protects other organs. However, this could also lead to the persistence of these xenochemicals and to a chronic low level internal exposure. The intrinsic properties of the xenobiotic detection and metabolism systems could also account for long-term toxicity. Indeed, hydrophobic xenochemicals are metabolized into more hydrophilic compounds; the first step of this pathway consists in the “activation” of the parent compound into a more reactive intermediate by cytochromes P450 activity. Those intermediates can be extremely reactive with DNA and proteins and thus could lead to toxic side effects that may become significant over time. Furthermore, recent evidence suggests that xenobiotic receptors also display endogenous functions. It is likely that repeated exposure to xenobiotics disrupts those endogenous functions with possibly dire cellular consequences. Altogether, The hypothesis presented here proposes that one mechanism for long-term toxicity stems from cumulative side effects due to the repeated activity of adaptive pathways triggered by acute intoxication.