Oxidative Signaling Response to Cadmium Exposure

For those interested in reactive oxygen species (ROS) formation and subsequent downstream activation of redox-signaling pathways, the attached review is an excellent update/summary. The author elegantly reviews and updates changes in the intracellular thiol–disulfide balance –– which are considered major determinants in the redox status/signaling of the cell. Cellular signaling is very sensitive to both exogenous and intracellular redox status and respond to many exogenous pro-oxidative or oxidative stress signals.

Redox status has dual effects on upstream signaling systems and downstream transcription factors. Redox signaling pathways use ROS to transfer signals from different sources to the nucleus to regulate such functions as growth, differentiation, proliferation, and apoptosis (i.e. programmed cell death). Mitogen-activated protein kinases (MAPKs) are activated by numerous cellular stress and ligand-receptor binding signals.

Any imbalance in the oxidant/antioxidant system, either resulting from excessive ROS/reactive nitrogen species production and/or antioxidant system impairment, leads to oxidative stress. Reduced glutathione (GSH) is known to play a critical role in the cellular defense against unregulated oxidative stress in mammalian cells. Involvement of large molecular antioxidants (i.e. downstream targets) include classical antioxidant enzymes –– such as superoxide dismutases (SODs), catalase (CAT), glutathione peroxidases (GPXs), and glutathione reductases (GRs).

The author has chosen to combine the biological effects of ROS formation with the highly toxic heavy metal cadmium (Cd), which is a widespread environmental contaminant. Cd is known to cause renal dysfunction, hepatic toxicity, testicular necrosis, genotoxicity, and apoptotic effects –– depending on the dose, route, and duration of exposure. It is well known that Cd induces ROS formation and activates the cascade of ROS-signaling pathways. What is missing in the question I’ve had in my mind for the past 40+ years: WHY does Cd cause ROS formation? As we all know, the element Cd has 48 electrons in the 2-8-18-18-2 configuration, meaning that the Cd2+ cation has its 1s-2s-2p-3s-3p-3d-4s-4p-4d orbitals all filled.

 Image result for cadmium atom    Image result for cadmium atom


If ANYONE can explain to me WHY the (very stable) Cd2+ cation should cause ROS formation, I would be eternally grateful..!!  I’ve asked a number of colleagues over the years, and there’s been a lot of handwaving and smoke and mirrors –– but I have yet to hear a reasonable mechanism.

Toxicol Sci 2o17; 156: 4–10


This is important information to share –– information perhaps unknown in the entire field of animal heavy-metal toxicology. Therefore, the 2o17 Toxicol Sci review [attached] is an elegant update, describing the various oxidative stress-signaling pathways in mammals, but combining this topic with the topic of Cd toxicity is a bit of a nonsequitor.


Gonçalves 2007 Cd toxicity


Maybe Cd2+, itself, isn’t that strong as a direct ROS inducer –– especially in a low-temperature, slow-metabolizing cell (such as cucumber seedlings). In a 37 oC rapid-metabolizing animal cell, such an insult cannot be ignored; all the defense mechanisms (useful as well as not useful) might be energized to fight this heavy metal.  And, during this “fighting” process in response to this adverse signal, ROS formation might occur at 37 oC, but not at 5-15 oC.

To test this hypothesis, one should treat bacteria, yeast, plant cells, (poikilothermic) amphibian cells, and mammalian cells with (same series of doses of) Cd2+ –– and compare the Cd2+ response, to see if ROS formation occurs, and what downstream pathways are affected as a function of heavy-metal concentration.  Such an experiment might directly define the pattern of ROS-inducing mechanism.


Lei, good point .The TEMPERATURE of the organism might lead to different types of response to the Cd2+ stressor signal.

THIS (email chat group) discussion is a great example of the REASON why we should include a VERY heterogeneous bunch of participants.

The same “story” or “stimulus” put forth ––> invokes widely-differing responses and interpretations, which are related to the individual experiences and expertise of each participant..!!


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