Chronic Hexavalent Chromium (Cr(6+) Exposure Induces Cancer Stem Cell (CSC)-Like Properties and Tumorigenesis by Increasing c-Myc Expression

The metal chromium (Cr) is present during the manufacturing of many consumer products — plus being present in particulate matter from vehicle and other emissions. The valency states of Cr found in occupational and the general environment include Cr(0), Cr(III), and Cr(VI); intriguingly, only Cr(VI) (hexavalent chromium) is recognized as a human carcinogen. This topic fits nicely with the GEITP’s theme of gene-environment interactions: i.e. Cr is the environmental signal, and, via one or more genetic networks, cancer can be a potential outcome.

Cancer stem cells (CSCs) are defined as usually a small subpopulation of cells within tumors — having capabilities of self-renewal, differentiation, and tumorigenicity — when transplanted into an animal host. Several cell-surface markers (e.g. CD44, CD24, and CD133) are often used to identify and enrich for CSCs. The CSC theory proposes that neoplasms might actually originate from CSCs. It has been shown that chronic metal carcinogen exposure is capable of transforming normal pluripotent embryonic stem cells (ESCs) into CSC-like cells. [For example, chronic arsenic exposure is reported to transform (human normal prostate stem/progenitor) WPE-stem cells, and (normal rat kidney stem/progenitor) RIMM-18 cells into CSC-like cells.] Chronic Cr(VI) exposure to immortalized human bronchial epithelial cells is reported to produce CSC-like cells. Other steps (there might be 3 or 10, there might be 30)— between the metal entering the cell and the outcome of neoplasia — remain open to further study.

The MYC gene is a proto-oncogene, which when activated and/or abnormally expressed, appears to be involved in the process of carinogenesis. It has been shown that MYC is associated with malignant cell transformation and tumorigenesis — by inducing uncontrolled cell proliferation, genomic instability, dysregulated tumor cell metabolism, and tumor angiogenesis.

Authors [see attached article] show that — by knocking down MYC expression in Cr(VI)-transformed human bronchial epithelial cells [BEAS-2B-Cr(VI)] — their CSC-like properties and ability to cause tumors (when the cells are transplanted into mice) are substantially diminished. It was also found that over-expression of MYC, in nontransformed BEAS-2B cells is capable of inducing CSC-like properties and cell transformation. Authors found that chronic Cr(VI) exposure increases MYC expression — by down-regulating the level of microRNA-494 (miR-494); moreover, over-expressing miR-494 significantly decreased Cr(VI)-induced CSC-like properties, cell transformation, and tumorigenesis — principally by down-regulating MYC expression. This study therefore uncovers an important role, associating MYC with Cr(VI) carcinogenesis.

Toxicol Sci Dec 2019; 172: 252-264

COMMENT: ***, chromated copper arsenate (CCA) is an excellent topic worthy of GEITP discussion — for the precise reason you mentioned (i.e. this has been used for decades to seal and protect wood decks). There are a number of CCA formulations in the market; however, only CCA-C has a specific percent of the three metals, and formulation is based on the percent oxides of these metals. CCA-C is a mixture of three inorganics: CuO, As2O5, CrO3 — having valences of copper(II) oxide, arsenic(V) oxide, and chromium(VI) oxide, respectively. Because the CCAs have been the most widely used wood preservatives in the U.S., in 2003 the U.S. Environmental Protection Agency (USEPA) restricted CCA to only industrial use, because it “poses an unreasonable human health risk.”

From the 2017 edition of Veterinary Medicine (“Systemic and Multi-Organ Diseases”) — I found the following: “CCA can still be used in animal production facilities, on utility poles, and in other cases. It is reported that animals would need to eat at least 28 grams of CCA-treated wood, per day, for a month, before chronic poisoning sets in. ‘Horses that crib or chew’ could eat more than that — and could theoretically become poisoned. The risk to animals, however, is not so much ingesting treated wood, but rather consuming ashes left from burning treated lumber. Burning concentrates arsenic in the ashes; cattle, in particular, (which ENJOY eating ashes) have been poisoned in this manner.”

[Presumably, humans inhaling large amounts of burning CCA-treated wood — might also have an increased risk of toxicity or cancer from the arsenic(III) and chromium(VI)…] 😊


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