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. 2023 Feb 22;15(3):448.
doi: 10.3390/w15030448. Epub 2023 Jan 22.

Arsenite Methyltransferase Is an Important Mediator of Hematotoxicity Induced by Arsenic in Drinking Water

Sebastian Medina  1   2 , Haikun Zhang  1 , Laura V Santos-Medina  2 , Zachary A Yee  2 , Kaitlin J Martin  2 , Guanghua Wan  1 , Alicia M Bolt  1 , Xixi Zhou  1 , Miroslav Stýblo  3 , Ke Jian Liu  1   4
Affiliations

Arsenite Methyltransferase Is an Important Mediator of Hematotoxicity Induced by Arsenic in Drinking Water

Sebastian Medina et al. Water (Basel). .

Abstract

Chronic arsenic exposures via the consumption of contaminated drinking water are clearly associated with many deleterious health outcomes, including anemia. Following exposure, trivalent inorganic arsenic (AsIII) is methylated through a series of arsenic (+III oxidation state) methyltransferase (As3MT)-dependent reactions, resulting in the production of several intermediates with greater toxicity than the parent inorganic arsenicals. The extent to which inorganic vs. methylated arsenicals contribute to AsIII-induced hematotoxicity remains unknown. In this study, the contribution of As3MT-dependent biotransformation to the development of anemia was evaluated in male As3mt-knockout (KO) and wild-type, C57BL/6J, mice following 60-day drinking water exposures to 1 mg/L (ppm) AsIII. The evaluation of hematological indicators of anemia revealed significant reductions in red blood cell counts, hemoglobin levels, and hematocrit in AsIII-exposed wild-type mice as compared to unexposed controls. No such changes in the blood of As3mt-KO mice were detected. Compared with unexposed controls, the percentages of mature RBCs in the bone marrow and spleen (measured by flow cytometry) were significantly reduced in the bone marrow of AsIII-exposed wild-type, but not As3mt-KO mice. This was accompanied by increased levels of mature RBCS in the spleen and elevated levels of circulating erythropoietin in the serum of AsIII-exposed wild-type, but not As3mt-KO mice. Taken together, the findings from the present study suggest that As3MT-dependent biotransformation has an essential role in mediating the hematotoxicity of AsIII following drinking water exposures.

Keywords: anemia; arsenic; arsenic (+III oxidation state) methyltransferase (As3MT); arsenite (AsIII); biotransformation; red blood cells.

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Conflict of interest statement

Conflicts of Interest: The authors have no conflict of interest to declare.

Figures

Figure 1.
Figure 1.
Drinking water exposure to AsIII suppresses the formation of BFU-E colonies in wild-type, but not As3mt-KO mice following exposure to control (untreated, tap water) or 1 ppm AsIII in their drinking water for 60 days. Number of BFU-E colonies (expressed relative to the number of viable cells recovered per femur and tibia set of each mouse) formed in EPO containing serum-free methylcellulose-based medium (i.e., Methocult M3436; STEMCELL Technologies) for 14 days. Data are expressed as mean ± SD of duplicate cultures per mouse. Statistically significant differences compared to untreated control in one-way ANOVA followed by Tukey’s post hoc test; n = 5 mice/group, *p < 0.05
Figure 2.
Figure 2.
Percentages of early and late-stage erythroblasts were altered in the bone marrow of wild-type and As3mt-KO mice following 60-day drinking water exposure to 1 ppm AsIII. (A) Representative flow cytometry dot plot showing the gating strategy used to define early erythroid progenitors (Early EryP; CD71+, TER119−/low events) or late-stage erythroblasts (CD71+,−, TER119+ events) in the bone marrow. Percentages of (B) early and (C) late-stage erythroblasts were measured by flow cytometry in bone marrow collected from wild-type and As3mt-KO mice following 60-day exposure to control (untreated, tap water) or or 1 ppm AsIII. Data are expressed as mean ± SD. Statistically significant difference compared to control in one-way ANOVA followed by Tukey’s post hoc test; n = 5 mice/group, *p < 0.05, **p < 0.01, non-statistically significant.
Figure 3.
Figure 3.
AsIII exposure increases the percentage of mature TER119+ erythroblasts in the spleen of wild-type mice. (A) Representative flow cytometry histograms showing an unstained sample and the gating strategy used to enumerate the percentage of TER119+ erythroblasts and the spleen. (B) Percentages of TER119+ erythroblasts and the spleen wild-type and As3mt-KO mice following 60-day drinking water exposures control (untreated, tap water) or 1 ppm AsIII. Data are expressed as mean ± SD. Statistically significant difference compared to control in one-way ANOVA followed by Tukey’s post hoc test; n = 5 mice/group, **p < 0.01, ns = non-statistically significant.
Figure 4.
Figure 4.
Elevated serum EPO levels in wild-type mice following drinking water exposure to AsIII. EPO concentrations were measured using the Mouse EPO Quantikine ELISA Kit (R&D Systems) in collected from wild-type and As3mt-KO mice following exposure to control (untreated, tap water) or 1 ppm AsIII for 60 days.EPO positive (+) control was a standard prepared at a known concentration of 500 pg/mL. In the box plot, crosses indicate the mean and black horizontal lines indicate the median. Data are expressed as mean ± SD. Statistically significant difference compared to control in one-way ANOVA followed by Tukey’s post hoc test; n = 5 mice/group, *p < 0.05.
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