Elemental biomapping of human tissues suggests toxic metals such as mercury play a role in the pathogenesis of cancer

Abstract

Toxic metals such as mercury, lead, and cadmium have multiple carcinogenic capacities, including the ability to damage DNA and incite inflammation. Environmental toxic metals have long been suspected to play a role in the pathogenesis of cancer, but convincing evidence from epidemiological studies that toxic metals are risk factors for common neoplasms has been difficult to gain. Another approach is to map the location of potentially toxic elements in normal human cells where common cancers originate, as well as in the cancers themselves. In this Perspective, studies are summarized that have used elemental biomapping to detect toxic metals such as mercury in human cells. Two elemental biomapping techniques, autometallography and laser ablation-inductively coupled-mass spectrometry imaging, have shown that multiple toxic metals exist in normal human cells that are particularly prone to developing cancer, and are also seen in neoplastic cells of breast and pancreatic tumors. Biomapping studies of animals exposed to toxic metals show that these animals take up toxic metals in the same cells as humans. The finding of toxic metals such as mercury in human cells prone to cancer could explain the increasing global incidence of many cancers since toxic metals continue to accumulate in the environment. The role of toxic metals in cancer remains to be confirmed experimentally, but to decrease cancer risk a precautionary approach would be to reduce emissions of mercury and other toxic metals into the environment from industrial and mining activities and from the burning of fossil fuels.

Keywords: cancer; carcinogenesis; elemental biomapping; human tissue; mercury; neoplasia; pathogenesis; toxic metals.

Figure 1

Proposed pathway of toxic metal exposure leading to cancer. Upper section: Toxic metal exposure arises from repeated episodes or from a constant source, with the cellular burden of toxic metals increasing during aging. Major consequences are somatic mutations, inflammation, and epigenetic changes, while toxic metal-induced alterations to intracellular processes and organelles (in white italics) can also promote carcinogenesis. Lower section: Examples of toxic metal exposures resulting in two of these mechanisms, somatic mutations and inflammation. (1) Toxic metals enter a progenitor cell and produce (2) a cancer-initiating mutation. (3) Daughter cells carrying the initiating mutation take up further toxic metals which produce driver mutations (4). (5) Circulating toxic metals initiate tumor-promoting inflammation. (6) Toxic metals within tumor cells produce subclone mutations.

Figure 2

Toxic metals in the human kidney, pancreas, and breast. (A) A normal kidney has abundant ^AMGTM in proximal tubule cells (arrow). No mercury is seen in glomeruli (G) or in distal tubules (arrowhead). AMG/hematoxylin (66). (B) AMG with CD10 immunostaining shows red proximal tubule cells containing black mercury grains (arrows). No mercury is seen in CD10-negative distal tubules (arrowhead), or in a glomerulus (G) whose cells stain lightly with CD10. AMG/CD10/hematoxylin (66). (C) LA-ICP-MSI shows mercury, lead, cadmium and iron in kidney cortex or medulla, but not nickel or silver (66). Scale = counts per second (proportional to abundance). CO: cortex, ME: medulla (within dashed outlines). (D) A pancreas with ^AMGTM in peripheral (arrow) and internal islet cells. Scattered periductal cells (open arrowheads), one enlarged in the upper right inset, contain ^AMGTM. Lower left inset: an acinar cell contains ^AMGTM (closed arrowhead). AMG/hematoxylin (65). (E) Individual and groups of pancreatic carcinoma cells contain ^AMGTM (arrows). AMG/hematoxylin. (F) Normal breast tissue, with fine grains of ^AMGTM (open arrows) attached to the luminal surface of lobule epithelial cells, and particulate ^AMGTM in scattered epithelial cells (closed arrows). The lumen of one lobule (right) contains black ^AMGTM-stained secretion (artefactually shrunken); in the left lobule the secretion has fallen out during processing. AMG/hematoxylin (76). (G) LA-ICP-MSI of (^AMGTM-containing) normal breast lobules showing mercury (red/green) in the luminal secretion and epithelium, and iron and nickel (green) in the epithelium (76). (H) Breast cancer with numerous neoplastic ductules containing black luminal ^AMGTM. Enlarged view shows ^AMGTM in neoplastic duct cells, with ^AMGTM grains (arrow) attached to the nuclear membrane. ^AMGTM is present in the ductule lumen (asterisk). AMG/hematoxylin (76).