Abstract
Chromosome instability (CIN) consists of high rates of structural and numerical chromosome abnormalities and is a well-known hallmark of cancer. Aluminum is added to many industrial products of frequent use. Yet, it has no known physiological role and is a suspected human carcinogen. Here, we show that V79 cells, a well-established model for the evaluation of candidate chemical carcinogens in regulatory toxicology, when cultured in presence of aluminum—in the form of aluminum chloride (AlCl3) and at concentrations in the range of those measured in human tissues—incorporate the metal in a dose-dependent manner, predominantly accumulating it in the perinuclear region. Intracellular aluminum accumulation rapidly leads to a dose-dependent increase in DNA double strand breaks (DSB), in chromosome numerical abnormalities (aneuploidy) and to proliferation arrest in the G2/M phase of the cell cycle. During mitosis, V79 cells exposed to aluminum assemble abnormal multipolar mitotic spindles and appear to cluster supernumerary centrosomes, possibly explaining why they accumulate chromosome segregation errors and damage. We postulate that chronic aluminum absorption favors CIN in mammalian cells, thus promoting carcinogenesis.
Highlights
The present study aimed at exploring the impact of aluminum on chromosome stability by using a well-established cell model system and an adapted OECD method in carcinogenesis screening, while parallelly providing evidence of the intracellular presence of the metal under the tested conditions
We show that V79 cells cultured in the presence of aluminum in the form of AlCl3 do incorporate the metal, as do mammary epithelial cells of both mouse and human origin, including primary human mammary epithelial cells
Our Lumogallion stainings show that aluminum added to the culture medium in the form of AlCl3 can enter the cells when these are cultured under standard culture conditions (10% FCS) and to an extent significantly higher when cultured under serum-free conditions
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The carcinogenic potential of aluminum has been evidenced by Mandriota et al (2016, 2020), by showing that normal mouse mammary epithelial cell models cultured in the presence of AlCl3 undergo malignant transformation in vitro and form tumors and metastases in vivo in nude, NOD-SCID and immunocompetent syngenic mice [18,19] The mechanisms of such transformation are still poorly understood; a 2.3 to 3-fold increased number of unique structural chromosome rearrangements was observed in those cells, compared to controls [19]. Under these experimental conditions, the cells exposed to aluminum exhibit a dose-dependent increase in chromosomes harboring DNA double strand breaks (DSB) and in aneuploidy These effects seem to be mediated, at least in part, by the perturbation of sister chromatid segregation during mitosis, since, upon aluminum exposure, V79 cells assemble abnormal multipolar spindles and appear to cluster extra centrosomes. Our results demonstrate that aluminum concentrations in the range of those detected in human tissues promote CIN in a wellrecognized cell model for chemical carcinogesis evaluation, providing compelling evidence that aluminum is a human carcinogen
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