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Cadmium: toxic to mammals, harmless to a bacterium, helpful to an alga

Joe Magliocca

Joe MaglioccaI'm on ScienceSeeker-Microscope

Heavy metal poisoning is a major health concern across the world. Heavy metal ions frequently leak into the environment from industrial waste causing multiple health problems in humans, animals, and other organisms. While there is no universally accepted definition of what elements are heavy metals, the definition I find most useful includes the metal rubidium and all metals heavier than it.  These metals have large atomic masses, and aside from molybdenum (and possibly tungsten), have no essential biological function; they only interfere with other biological functions.

One heavy metal of significant concern is element 48, cadmium. This element is mostly found in nature as an impurity in zinc ore, but small amounts are scattered throughout soil, seawater, coal, and other mineral deposits. It first became known as an environmental and medical hazard when a disease known as “itai-itai” (literally “it hurts-it hurts”) appeared around the city of Toyama, Japan between the Russo-Japanese war and World War II (roughly 1905-1945). This city was a major center for zinc mining, and the cadmium waste from this process was found to be the cause of the disease.

Now that cadmium’s toxic effects are well-known, most industries are trying to phase out its use. However, it is still used in Ni-Cd batteries (rechargeable AA and AAA batteries), some solar panels (don’t tell Fox News), and some paint pigments. Most humans are exposed to cadmium through cigarette smoke and industrial processes such as burning coal (although I’m sure only hard-core environmentalists would worry about this cadmium.  Solar panels are much more dangerous.)

What does cadmium do to people? The effects of this metal are severe. Cadmium can cause kidney failure, liver failure, respiratory disease, immunosuppression, bone deformation, type 2 diabetes, disregulated blood pressure, peripheral neuropathy, and multiple types of cancer. (These effects are almost as bad as the side-effects of that transdermal testosterone supplement gel you see advertised on cable!)

Cadmium Pathway

Summary of effects of cadmium on mammalian cells

But what occurs at the cellular level to cause these effects? A review from 2006 by Bertin and Averbeck answers this question. Most of the damage done by cadmium to cells results from the metal binding to the thiol group in cysteine residues in proteins and peptides. These effects compliment and reinforce each other in a sort of positive feedback loop. For example, cadmium binds to two cellular antioxidants, glutathione and metallothioneins. This binding is likely a natural defensive mechanism that helps the cells rid themselves of low concentrations of cadmium and some other heavy metals.  Problems occur at higher heavy metal concentration. The cell can only make a limited amount of these antioxidants, and chelating heavy metals is not their only job. The main job of these antioxidants is to protect cells from reactive oxygen species (ROS), small toxic chemicals produced by reactions involving oxygen. When all the antioxidants are used up chelating heavy metals, there are none left to help protect the cells from ROS.

Reactive oxygen species damage nucleic acids and lipids. All of the cell’s membranes will be damaged, but the mitochondria will be especially damaged because they are composed of so much membrane. It’s in mitochondria that oxygen reacts during the electron transport chain to produce ATP. Mitochondria always give off some ROS, but when the organelle is damaged, more ROS than normal are released.

ROS also damage DNA. A small amount of DNA damage can be repaired by the cell, but DNA binding proteins are required for this to occur. Unfortunately, DNA binding proteins are especially damaged by cadmium due to the “zinc finger” (ZnF) motif. This motif is a very common structure in DNA binding proteins. A DNA binding domain is held in place by a zinc ion bound to cysteine and histidine residues in the protein. Cadmium however, can replace zinc in the structure so that the DNA binding domain is altered. Usually the altered DNA binding domain cannot bind to DNA, so the protein will cease to function.  This results in a build-up of mutations in the cadmium-poisoned cells, which leads to cell death and cancer.

Cadmium is detrimental to the growth and vitality of most cells, but some organisms can tolerate it. Recent research has shown how some species can avoid the heavy metal’s toxicity. One such species is the soil bacterium Burkholderia cenocepacia. This species is often the only bacteria present in cadmium-contaminated soil. In 2012, Schwager and Lumjiktase conducted the first investigations into the mechanism of this resistance.

To locate the gene responsible for the resistance to cadmium, Schwager and Lumjiktase created 5000 mutant strains of the culture using a transposon gene that randomly inserted itself into the genome of B. cenocepacia. Each of these 5000 strains were grown in media that contained 1 mM cadmium sulfate. Of these 5000, all but seven grew in this media. They then identified the genes that were disrupted by the transposon and found four distinct disrupted genes (there were a few repeats). Of these genes, only one, which they named CadA, was thought to be likely to be involved in cadmium resistance specifically. After examining the sequence of the CadA protein and comparing it to the sequence of other proteins found in related bacteria, they predicted it would be an ATPase ion pump that would pump heavy metal ions out of the cell.

Burkholderia cenocepacia

Burkholderia cenocepacia

To test this prediction, they studied a total of four strains of B. cenocepacia.  A wild-type strain was developed with its CadA gene deleted. Also, they reinserted the CadA gene into the mutant with the transposon. They grew these four strains in the presence of cadmium, and also lead, zinc, and cobalt. They found that their hypothesis was confirmed; the strains with functioning CadA genes grew better in cadmium than the strains without it in. Also, they grew better in zinc and lead, but not in cobalt.

They then decided to study whether or not cadmium exposure causes B. cenocepacia to express more of the CadA protein. To accomplish this, they made a new strain of the species that had the green fluorescence protein (GFP) gene attached to the CadA gene.  This allowed the amount of CadA produced to be measured; the more CadA produced, the more visible GFP produced. They found that not only was more CadA produced when cadmium is present, but that this upregulation is significant enough to allow the GFP strain to be used to detect the presence of cadmium in soil.

B. cenocepacia is a metallotolerant organism. These organisms can survive in heavy metal concentrations much higher than those in which most organism can survive, but they still grow better when there is no heavy metal present. Is there a true “cadmium-philic” organism?

As it turns out, there is one organism that is known to use cadmium as a nutrient. In 1995, the organism, a marine diatom called Thalassiosira weissflogii, was proven to be able to use cadmium as a nutrient. Specifically, this species has an advantage over other algal species because it can incorporate cadmium in place of zinc in its carbonic anhydrase enzyme. Because it regulates the conversion of carbon dioxide to carbonic acid, this (normally) zinc-containing enzyme is essential for a cell to keep its pH buffered at the right level. Most algae species require zinc for this enzyme, but T. wessflogii can use either zinc or cadmium. High concentrations of cadmium will still kill T. wessflogii cells, but at low concentrations, it is helpful for this organism.

Cadmium is harmful to most organism, but some organisms, like B. cenocepaci, can tolerate high cadmium concentrations by pumping out the ions. Alternatively, T. wessflogii can use cadmium as a nutrient. Because T. wessflogii does not absolutely require cadmium, some people would argue that it is still not a “cadmium-philic” organism, but it is certainly the most “cadmium–loving” organism now known.

References:
Bertin G. & Averbeck D. (2006). Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review), Biochimie, 88 (11) 1549-1559. DOI:

Schwager S., Lumjiaktase P., Stöckli M., Weisskopf L. & Eberl L. (2012). The genetic basis of cadmium resistance of Burkholderia cenocepacia, Environmental Microbiology Reports, 4 (5) 562-568. DOI:

LEE J.G., ROBERTS S.B. & MOREL F.M.M. (1995). Cadmium: A nutrient for the marine diatom Thalassiosira weissflogii, Limnology and Oceanography, 40 (6) 1056-1063. DOI:

Photo credit:
Burkholderia cenocepacia

http://www.microbeworld.org/component/jlibrary/?view=article&id=8118