Abstract
Simple SummaryAlcoholic beverages and acetaldehyde formed during their metabolism are carcinogenic to humans. Alcohol drinking may affect bone marrow stem cell niche, suppressing physiological hematopoiesis and ultimately reducing the organism’s capacity to fight against cancer, infections, and to promote tissue regeneration. To elucidate in vivo the cellular mechanisms associated with alcohol intake toxicity, we used a mouse model in which proliferating cells produce the firefly’s light-emitting protein. In this animal, alcohol exposure transiently “turns off the light”, indicating a negative effect on cell proliferation in the bone marrow and spleen. Pharmacological treatment with substances interfering with ethanol metabolism, reducing acetaldehyde production, partially restores the physiological cell proliferation rate. Over 560 million people worldwide have increased susceptibility to acetaldehyde toxicity and 4% of cancer deaths are attributable to alcohol. Our model might provide a suitable tool to further investigate in vivo the effects of alcohol metabolism and aldehydes production on carcinogenesis.Endogenous acetaldehyde production from the metabolism of ingested alcohol exposes hematopoietic progenitor cells to increased genotoxic risk. To develop possible therapeutic strategies to prevent or reverse alcohol abuse effects, it would be critical to determine the temporal progression of acute ethanol toxicity on progenitor cell numbers and proliferative status. We followed the variation of the cell proliferation rate in bone marrow and spleen in response to acute ethanol intoxication in the MITO-Luc mouse, in which NF-Y-dependent cell proliferation can be assessed in vivo by non-invasive bioluminescent imaging. One week after ethanol administration, bioluminescent signals in bone marrow and spleen decreased below the level corresponding to physiological proliferation, and they progressively resumed to pre-treatment values in approximately 4 weeks. Boosting acetaldehyde catabolism by administration of an aldehyde dehydrogenase activity activator or administration of polyphenols with antioxidant activity partially restored bone marrow cells’ physiological proliferation. These results indicate that in this mouse model, bioluminescent alteration reflects the reduction of the physiological proliferation rate of bone marrow progenitor cells due to the toxic effect of aldehydes generated by alcohol oxidation. In summary, this study presents a novel view of the impact of acute alcohol intake on bone marrow cell proliferation in vivo.
Highlights
Alcoholic beverages contain different amounts of ethanol and low levels of methanol
We determined the systemic effect of acute alcohol administration on cell proliferation in MITO-Luc mice subjected to a single administration of ethanol solution (6 g/kg body weight), described as the dose mimicking binge drinking in humans [9,32]
Five days after acute ethanol administration, bioluminescence imaging (BLI) signals in the spleen were below the level observed before ethanol administration and in control animals receiving saline solution, corresponding to physiological proliferation (Figure 1)
Summary
Alcoholic beverages contain different amounts of ethanol (ethyl alcohol, CH3−CH2−OH or C2H6O) and low levels of methanol (methyl alcohol, CH3-OH, or CH4O). Acetaldehyde and formaldehyde are endogenously produced, respectively, during the metabolism of ethanol and methanol ingested via alcoholic drinks. Consumption of alcoholic beverages may reduce the generation of inflammatory mediators leading to immunologic alterations, with increased susceptibility to infection and tumor formation and reduced healing after traumatic injury [2,3,4,5,6,7,8]. Maternal ethanol consumption causes immune deficiencies in newborns [11]. Some of these harmful consequences of alcohol exposure on the hematopoietic system [12] may determine an increased risk of some types of cancer [13,14]
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