The blood toll of arsenic: addressing hematological disorders and future directions

INTRODUCTION

Arsenic, a naturally occurring and widely distributed metalloid which exists in four oxidation states, i.e., +5, +3, 0 and -3, is a potent environmental pollutant responsible for multiple organs damage and oncogenesis. A major source of human exposure to arsenic is arsenic-contaminated groundwater used for drinking and agricultural purposes, and levels in several countries, including India, are well above the permissible limit of 0.05 mg/l set by the WHO.¹ Arsenic toxicity, also known as arsenicosis, is a serious health concern around the world, and it has been estimated that more than 150 million people are affected by it worldwide. Arsenic toxicity has different reversible and irreversible, clinical and subclinical manifestations, of acute, sub-chronic and chronic nature. Acute poisoning results in nausea, vomiting, abdominal pain, diarrhoea, renal and respiratory disorders, along with hematological anomalies, whereas chronic exposure can cause a wide range of disorders, including specific skin lesions like pigmentation, along with keratosis, non-malignant lung disease, dyspepsia, black foot disease, urinary bladder and lung cancers.²

The major routes by which arsenate [H₂AsO₄- and HASO4₂-] and arsenite [H₃AsO₃- and H₂AsO₃-], the primary inorganic arsenic species responsible for toxic effects, enter the human body are oral, dermal exposure and inhalation, being other minor routes. Ingested arsenic is absorbed in the small intestine through an electrogenic process involving a proton gradient and finally travels via the portal vein to liver. In the liver, it undergoes biomethylation to give rise to organic arsenic derivatives monomethylarsenous (MMAIII) and dimethylarsenous (DMAIII) ions, which are then released into circulation. The presence of several sulfhydryl (-SH) group-containing proteins, along with low-molecular-weight compounds such as glutathione and cysteine, further aids in the retention of arsenic in circulation, making hematological cells an easy target for arsenic poisoning and its toxic manifestations.

Although studies related to arsenic-mediated anaemia, its signalling and the subsequent mitigation reports are available in the literature, there is a dearth of collective information available for researchers engaged in this field. Hence, the main purpose of the present article is to thoroughly review the arsenic-induced hematological alterations and erythrocyte morphological response and to critically discuss the possible remedial measures with dietary supplements to overcome hematotoxicity caused by arsenic poisoning.

METHODS

A comprehensive literature search was executed utilizing the PubMed and Web of Science databases. The scope of inclusion was strictly limited to full-text scientific journal articles, without imposing any temporal constraints. Although a substantial body of research exists concerning arsenic toxicity, its preventive strategies, and mechanisms of action, publications directly pertinent to the specific objectives of this review were found to be limited. Consequently, no date restrictions were applied during the literature survey. The search strategy employed the following keywords: "Arsenic," "Arsenic toxicity," "Blood," ‘Hematology," and "Remedy." Trends in publication volume across decades and the geographical distribution of publishing countries, specifically pertaining to arsenic-mediated hematological alterations and their ameliorative measures, are visually represented using a bar diagram and a lollipop plot, respectively (Figure 1). All graphical presentations were generated using RStudio. Figures were created using Biorender and Chembiodraw ultra 12.0.

TEMPORAL AND GEOGRAPHICAL PUBLICATION TRENDS

Between 2010 and 2020, publications concerning the hematological effects of arsenic reached their zenith (Figure. 2). Pinpointing the exact reasons for any perceived decline in research output on arsenic toxicity and blood-related alterations is challenging without comprehensive publication trend data, though this article offers a glimpse into the subject's research trajectory. It's plausible that as arsenic remediation efforts in drinking water become more widespread, the urgency for research into novel interventions and protracted health consequences might diminish, thereby contributing to a perceived dip in publications. Nevertheless, country-specific publication trends indicate a sustained and significant research focus on this topic, with India at the forefront. Furthermore, contemporary research consistently unearths previously unrecognized dimensions of arsenic contamination in the Bengal Basin. Therefore, a comprehensive review of this topic still highlights the need for further research.

UPTAKE AND INTRACELLULAR TRANSPORT OF ARSENIC

The main route of exposure of inorganic arsenic is oral, and the intestinal epithelium is the first physiological barrier that it must cross in order to get absorbed. It has been observed that the Caco-2 cells (a colorectal cell line), prefer arsenate (AsV) among different arsenic species.³ The study further suggested the possible involvement of phosphate transporters (due to structural analogy between arsenate and phosphate, the phosphate inhibited arsenic uptake by cells) and H+-dependent transporter (as the acidic environment in the stomach and proximal intestine favoured arsenic absorption) in the uptake of arsenic. The sodium-coupled phosphate transporters were also reported to be involved in arsenic uptake. Among its different subtypes, type IIb (Na-Pi-IIb) has the highest affinity for arsenate compared to type IIa (Na-Pi-IIa) and type IIc (Na-Pi-IIc). Involvement of certain other transporters in arsenic uptake by different cells has also been reported which include glucose transporters (GLUT2 and 5), sodium-glucose co-transporter (SGLT), organic anion transporting polypeptides (OATP), aquaporin’s (AQP 7, 9 and 10), P-glycoprotein (P-gp), MDR1 (Multi drug resistance protein 1)/ABCB1, multidrug resistance-associated protein1, 2 and 3 (MRP-1, 2& 3).⁴ Though very little information is available regarding the arsenic influx in erythrocyte, except the role of erythroid anion exchanger 1 (AE1), also known as Band3 protein, which is involved in the preferential uptake of arsenate but not for arsenite. Several interesting studies explored some other unique transporters, namely arsenite-specific resistance protein (Acr3p), yeast cadmium resistance factor (Ycf1p, a member of the ABC transporter family) involved in efflux of arsenic from cytosol either by pumping out or by vacuolization. Recent review literature stated that arsenic compounds are extruded from the cells by specialized arsenic efflux pumps such as ArsB, Acr3, ArsK or ArsP, or are transformed with the help of enzymes like ArsC, ArsM, or GAPDH prior to efflux.⁵ The mode of transport and intracellular uptake of arsenic has been illustrated in Figure 2.

INTRACELLULAR METABOLISM OF ARSENIC

The toxicity caused by inorganic arsenic largely depends on its oxidation states (AsIII or AsV) and also on methylation levels (monomethyl, dimethyl and trimethyl) which occur in mammalian liver. Two mechanisms are proposed for the biotransformation of inorganic arsenic in the liver, namely 1) oxidative methylation and 2) glutathione conjugation (Figure 3). According to the first mechanism, inorganic arsenic mostly enters into the body in the form of arsenate and about 50-70% is absorbed. Absorbed arsenate is reduced to arsenite by the catalytic activity of arsenate reductase or PNP (purine nucleoside phosphorylase). The conversion of inorganic arsenic involves alternating steps of oxidative methylation and reduction. In this process, arsenite is methylated by the donor S-adenosylmethionine (SAM) to form mono-methyllarsonic acid (MMAV), which is then reduced to monomethylarsonous acid (MMAIII) before undergoing further methylation to dimethylarsinic acid (DMAV). The second theory proposes that the reduction and complex formation occur in two steps, firstly, arsenate is reduced to arsenite in the presence of 2 moles of glutathione followed by its conjugation with 3 moles of glutathione to form the glutathione-arsenite complex by its linkage with cysteinyl-sulfhydryl of glutathione. The biotransformation of inorganic arsenic occurs in the presence of two proteins, which are MMA reductase (MMAR) and arsenic methyl transferase-reductase (As3MTR).⁶ This bio-methylation process can be considered as a possible detoxification mechanism as the end-products are less toxic (in the order MMAIII>arsenite>arsenate>MMAV=DMAV), less reactive and more easily excreted via urine than the inorganic forms. In contrary to other methylated derivatives, MMAIII is even more toxic than arsenite, which raises the question whether bio-methylation is truly a method of detoxification. The study has also raised the same question about the bio-methylation-dependent detoxification mechanism as a universal detoxification mechanism for arsenic. The report also states that some primates lacking methyl-transferase activity do not excrete methylated arsenicals as the end product.⁶

HEMATOLOGICAL ARSENICOSIS

Arsenic toxicity on erythrocytes

Arsenic toxicity, either acute, chronic or sub-chronic, is known to interfere with hematopoietic and immune systems. The first tissue that encounters arsenic in the body after its systemic absorption is blood, and probably for this reason, hematological manifestations are the most common features of arsenic poisoning, which is characterised by pancytopenia, i.e., reduction of the number of erythrocytes, leucocytes and platelets, associated with reduced haemoglobin content. The exposure of arsenic may lead to its accumulation in erythrocytes and cause anaemia. After entering the bloodstream, arsenic uptake by erythrocytes, probably through AE1 protein, takes place, followed by formation of a complex with the globin part of the haemoglobin.⁷ Thus, as the most populous cellular species, erythrocytes appear to be the primary target of arsenic toxicity. The hematotoxic effects of arsenic exposure are commonly characterized by erythrocyte morphological response, haemolysis, impaired hematopoiesis, haeme biosynthesis, and leucopenia. Leucopenia and anaemia were found to be more frequent in the female patients who were underweight, thereby indicating that the poor nutritional status of the patients increases the complications of chronic arsenic toxicity. Prevalence of anaemia in pregnant women(a prevalence proportion ratio of 2.87 with respect to any anaemia) has also been reported.⁸ Taken together, these finding suggests that women are probably more prone to arsenic-induced hematotoxicity.

Arsenic toxicity on leukocytes

Earlier, it has been reported that exposure to arsenic from drinking water leads to DNA methylation in whole blood (leukocytes) collected from adults.⁹ Kile et al had shown that maternal exposure to arsenic leads to significant LINE-I methylation in cord blood. In utero exposure to arsenic is associated with altered development, activation, and proliferation of T cell population ( both CD4+ T cell and CD8+ T cell) as well as cord blood leukocyte subpopulation.⁹ It has been also been reported that arsenicosis distorts the balance of Th17/Treg cell in circulating peripheral blood mononuclear cell (PBMC) and it has been evident that there was an increase in Th17 cells in PBMC population, favouring and proinflammatory milieu in arsenicosis patients.¹⁰ In addition, RORγt -mRNA and FOXP3- mRNA levels respectively increased and decreased in arsenicosis patients.¹⁰

At pharmacological concentrations arsenic trioxide (As₂O₃) leads to apoptosis of blood monocytes during the differentiation in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and macrophage colony-stimulating factor. Another study showed that proliferation of T cells was decreased when PBMCs collected from individuals exposed to arsenic were stimulated with phytohemaglutinin (PHA).¹¹ Same study showed that PBMCs treated with sodium arsenite caused reduction in IL-2 secretion and proliferation of T-cell induced by PHA.¹¹ It has also been reported that non-cytotoxic concentration of sodium arsenite (0.25-2 μM) markedly decreased T cell proliferation by growing the share of non-dividing cells blocked in G1 phase.

Recently, it has been reported that total red blood cell (RBC) and white blood cell (WBC) count were decreased in arsenic nano-particles (AsNPs) treated Labeo rohita. Another study showed that there were significant decreases in total WBC, lymphocyte, and monocyte count in arsenic-treated Swiss albino mice, on the other hand neutrophil and eosinophil count were increased in arsenic arsenic-treated group when compared with the control group. Effect of arsenic toxicities on leucocytes cumulatively presented in Figure 4.

MECHANISM OF HEMATOTOXICITY

Mechanism of arsenic induced erythrocyte damage

Arsenic intoxication in erythrocytes is manifested as a change in the morphology or deformability of cells. Morphological aberrations of erythrocytes due to chronic inorganic arsenic exposure are associated with loss of membrane integrity, which often leads to microvascular occlusion and related peripheral vascular effects. Erythrocytes, when targeted by inorganic arsenic, undergo morphologic changes, converting discocytes into echinocytes, a form with invaginated spicules. The spicules then bud off, forming extracellular vesicles that form a spherical form called spheroechinocytes. Arsenate appeared to be more toxic to erythrocytes than arsenite, as it results in the formation of irreversible spheroechinocytes while the latter form restricts the damage to the formation of stage 2 echinocyte. The main attributes of arsenic-induced haemolysis include ATP depletion, cell shrinkage along with morphological alterations, increased membrane rigidity, increased deformability, loss of lipid asymmetry, which exposes phosphatidylserine on the outer leaflet of erythrocyte membrane, stimulating eryptosis.¹² This morphological deformity may lead to increased osmotic fragility, disturbances in peripheral circulation, and, ultimately, anaemia, as supported by epidemiological studies on arsenic intoxication, also mentioned earlier that arsenate and arsenite have different effects on erythrocytes and cause toxicity by separate mechanisms. The more toxic arsenate form causes toxicity by a process called ‘arsenolysis’ by replacing phosphate as a phosphate analogue followed by inhibition of ATP synthesis, whereas arsenite binds with sulfhydryl groups and inhibits the pyruvate dehydrogenase multienzyme complex and mitochondria-based citric acid cycle.

Delnomdedieu et al have found that the most important binding site for arsenite is free sulfhydryls in erythrocytes, and in this regard, apart from intracellular glutathione, haemoglobin, having 8 -SH groups, is another site of arsenic conjugation.¹³ Sulfhydryl groups play an important role in maintaining the shape and motility of the erythrocyte membrane, and a reduction in their content is thus deleterious to the cell. The gaseous form, i.e. arsine gas (AsH₃), has also deleterious effects on erythrocytes. It has been observed that it also reacts with the sulfhydryl groups and Na+ K+ATPase pump present in the membrane resulting in cell swelling and lysis. The binding induces oxidative stress by reducing reduced glutathione levels, but unlike arsenites, they do not interfere with ATP levels. Arsine toxicity results in haemoglobin oxidation and denaturation, and this disrupts the normal functioning of erythrocytes.¹⁴ The other concomitant effects include loss of cell volume control, potassium efflux, sodium influx, and an increase in hematocrit. These changes are followed by disturbances in membrane ultra-structure. Such events cause haemolysis, which appears to depend on membrane disruption. Although arsine is a reducing agent, it has been postulated that it damages cells through oxidative mechanisms, possibly by forming hydrogen peroxide (H₂O₂) and inhibiting catalase. Arsine causes hemachrome and methaemoglobin formations, while H₂O₂ treatment results in the formation of ferrihaemoglobin. Catalase and glutathione peroxidase, two major peroxide scavenging enzymes, have little effect on the initial haemoglobin -O₂ changes caused by AsH3. The following equation demonstrates possible reactions involving AsH₃ and HbO₂,

H₂-As-H+HbO₂=H₂As+HbO₂-H=met-Hb+H₂As-OOH

Alternatively, the reaction may produce H₂O₂ and arsenic adduct, such as arsine-haemoglobin (H₂As-Hb) or arsine-haeme (H₂As-haeme), which has not yet been identified.¹⁵

Mechanism of arsenic-induced leucocyte damage

Arsenic-mediated carcinogenicity may be due to increasing the longevity of premalignant cells by elongation of telomere length.¹⁶ Epidemiological studies showed that exposure to arsenic is significantly associated with elongation of telomeric length in peripheral blood leukocytes and up upregulates the expression of telomerase.¹⁶ Arsenic toxicity leads to ROS generation and subsequent suppression of the cell's antioxidant activity. On the other hand, telomeres are vulnerable to the accretion of oxidative guanine lesions. Furthermore, the existence of oxidative DNA damage inhibits telomerase activity and prevents binding of TRF1, TRF2 and RAP1protein and also inhibits DNA repair by NHEJ (non-homologous end joining).¹⁷

Arsenic exposure is negatively associated with global 5-hmc (5-hydroxy methyl cytosine) and positively associated with percentage of 5-mc (5-methyl cytosine) percentage of 5-hmc in females and males, respectively. Another study showed that As₂O₃ leads to a decrease in DNA binding of p65 nuclear factor-κβ, along with this As₂O₃ was accountable for a decrease in protein level expression of X-linked inhibitor of apoptosis protein and FLICE-inhibitory protein. It has also been reported that genes that are responsible for the expression of MIP2, CCL19, CCL18, CCL1 chemokines, chemokine receptors such as CXCR5, CCR1, CCR2 and IL-10RB, IL-13RA2, IL-18R1 were downregulated in PBMCs, collected from arsenic-exposed individuals.¹⁸ It has also been reported that the PBMC from arsenic-exposed individuals showed a marked up-regulation of BCL-xl, caspase-2, Bok, CD30, TNFRSF5 and TNFRSF10B when compared to the control group.¹⁸

EXPERIMENTAL EVIDENCES OF HEMATOLOGICAL ALTERATIONS IN ARSENICOSIS

The effects of arsenic exposure on blood trace element levels in rats reveal significant imbalances in essential elements such as iron and zinc. The study also noted sex-based differences in these alterations, suggesting that males and females may respond differently to arsenic exposure. Different animal models of experimental arsenicosis have been pursued to explore the extent of damage to blood cell components, which are critically analysed and summarised in Table 1 and Figure 3. Experimental model with radioactive labelled arsenite (As74) provides evidence of poor binding of arsenic to plasma proteins which results in retention of arsenic in blood cells rather than plasma. Cysteine residue at the 13th position of the α-chain of haemoglobin has also been identified as a binding site of trivalent DMAIII, suggesting that erythrocytes may serve as a major site for arsenic accumulation in blood.¹⁹ Altered hematological responses were observed when mice were exposed to arsine, and the decrements were linear with increasing arsine concentration. In another study, oral arsine exposure to adult rats for 14 days showed a significant decrease in erythrocytes, hematocrit, lymphocyte and platelet counts, whereas mean corpuscular volume (MCV) and mean corpuscular cell haemoglobin concentration (MCHC) increased significantly.²⁰ Also, observation from another study claimed a significant reduction (p<0.05) in packed cell volume (PCV), haemoglobin concentration (Hb), and RBC after arsenic exposure in male Wistar rats, but total WBC count was elevated, and serum total protein, albumin, and globulin levels were insignificantly reduced.²¹ The abnormalities manifested with the administration of arsenic to both mice and rats indicated the severity of arsenic-induced toxicity in the hematological system. Studies on the mouse model of arsenic toxicity show a reduction in counts of leucocytes and erythrocytes, along with a decrease in haemoglobin level, accompanied by damage to lymphocytes, which was distinctly observed.²² Studies using rat model reported severe leucocytopenia with reduced ALAD and GSH levels, elevated zinc protoporphyrin (ZPP) levels, an indicator of iron deficiency, and ultimately haeme-biosynthesis impairment. Relatively altered activities of lipid peroxidation marker like TBARS along with other redox markers, i.e., SOD, GSH, etc. suggest that arsenic may alter the cellular metabolism by ROS generation in blood cells.²⁵ The increased lipid peroxidation and reduced GSH level in erythrocytes may be attributed to arsenic accumulation in erythrocytes.²⁶ Anaemia, leucocytopenia, thrombocytopenia, and lymphocytopenia associated with an increase in ZPP have been reported in several reports, which further attest to the previous studies using a similar rodent model. A recent study further asserted the negative effect of arsenic on the bone marrow of mice, indicating disruption of cellular turnover and increased apoptosis in hematopoietic stem and progenitor cells, potentially impairing blood cell formation and immune function.²⁷

Non-rodent animal models also confirm similar effects of arsenic exposure on hematological parameters. Fish model of arsenicosis using Catla catla showed a decrease of cell count, haemoglobin concentration, and hematocrit, though MCV, MCH and MCHC levels were increased.²⁸ Contradictory results like increased Hb, hematocrit (Hct) and leucocyte counts were also reported in Catla species.²⁹ In the experimental goat model, arsenic toxicity revealed morphological alterations along with significant differences in the counts of erythrocytes, leukocytes and haemoglobin concentration when compared with the control. Furthermore, while lymphocyte count has been found to be decreased, eosinophil and monocyte counts were increased, suggesting impaired bone marrow function.³⁰ Histopathological examination showed degeneration of lymphocytes and increased erythrophagocytic activity in the spleen, indicating the immunotoxic effects of arsenic. Increased expression of Caspase 3, and Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) followed by fragmentation of DNA implies the genotxic impact of arsenic on bone marrow.³¹ In the experimental Labeo rohita model, a significant drop in Hb concentration (from 10.2 to 8.7) and a comparable drop in hematocrit levels (32.5 to 28.1) were noted. The red blood cell count was significantly decreased (from 4.8 million/µl to 3.6 million/µl), which is a symptom of hematological damage brought on by arsenic.³² Experiments on Zebu cattle in the arsenic-affected area, considered as the subclinical form of arsenic toxicity, showed a significant decrease in total erythrocyte count, packed cell volume, and total plasma protein concentration compared to the same values revealed from the cattle of the unaffected zone. The results also showed decreased superoxide dismutase and catalase activity in erythrocytes, followed by a reduction in plasma nitrite level and consequent elevation in lipid peroxidation and protein carbonylation, which led to altered hemato-biochemical parameters, and all these enzymatic and nonenzymatic alterations might be responsible for the hematological changes.³³

IN VITRO EFFECT OF ARSENIC ON ERYTHROCYTES

In vitro studies with human blood also support the above observations and show that treatment of human erythrocytes with arsine gas (1 mM) alters cell volume, increasing hematocrit values and ultimately leading to haemolysis within 30 min of exposure, associated with the formation of toxic haemoglobin adducts. In another study, Pernis et al have shown that a dose-dependent haemolytic activity of arsenic with a haemolytic set point of glutathione depletion to about 40% of the control. Discocyte-echinocyte transformation of human erythrocytes ultimately results into spherocytosis after arsenic treatment. Recent study on both in vivo and in vitro model ended up with an interesting observation regarding arsenic mediated anaemia. Arsenic interacts with the N- and C-terminal zinc finger motifs of GATA-1 which is mandatory for erythropoiesis. Interaction of arsenic with GATA-1 caused loss of zinc and inhibition of DNA and protein binding activities, leading to dyserythropoiesis and an imbalance of hematopoietic differentiation.

BLOOD ARSENIC AND DISEASE ASSOCIATION

For continuous and steady exposure, such as through contaminated drinking water, blood arsenic levels rapidly achieve a steady-state concentration, serving as a reliable indicator of the extent of exposure. Most of the arsenic species have a short half-life in blood, and it is also considered a difficult matrix for chemical analysis. Instead of this shortcoming, recent scientific evidence claimed blood arsenic as an important biomarker for disease risk conditions like diabetes, cancers, hypertension, skin lesions and oxidative stress.^34-36 A comprehensive study involving blood samples from 512 gallbladder cancer patients in Bihar unveiled a remarkably high prevalence of elevated arsenic concentrations within the population, with a peak concentration reaching 746 μg/l. Notably, 350 out of the 512 samples exhibited arsenic levels exceeding 2 μg/l, indicating that a substantial 68% of the cohort demonstrated significant arsenic exposure.³⁷ A study from the same authors also claimed a strong correlation coefficient between blood arsenic levels and the occurrence of cancers in male and female patients from Bihar, India (r=0.003; p<0.05).³⁴ Among patients with elevated blood arsenic levels, the most frequently observed malignancies include leukaemias, lymphomas, gallbladder cancer, ovarian cancer, and head and neck cancers.³⁴ Higher incidence of oxidative stress was even associated with the presence of low blood arsenic amount, like 8.74 μg/l.³⁸ The levels of blood arsenic and its association with disease conditions are given in Table 2.^39,40

Remedial measures

The primary measures against arsenic toxicity are to reduce the levels of arsenic species in drinking water and to implement the government's policies in this regard. A parallel thrust area in combating such toxicity is the identification and/or development of pharmaceutical/ therapeutic agents with the potential to prevent and/or cure arsenic-induced pathophysiological changes. The measures can broadly be classified into two groups: use of chelating agents, which can chelate free arsenic or arsenic derivatives, thus making them unavailable for causing any pathological consequences; use of nutrients/nutraceuticals as dietary supplements, which have the potential to prevent and/or cure arsenic-induced damages. DMSA (dimercaptosuccinic acid) and DMPS (sodium-2, 3 3-dimercaptopropane-1-sulphate), MiADMSA (Monoisoamyl DMSA), NAC (N-acetyl cysteine), ascorbic acid, α-tocopherol, lipoic acid and the extract of different parts of various plants, etc., are the ameliorative agents used for this purpose. The hemato-protective activities of these agents are presented in Table 3. These agents bring about the changes by normalizing hematological counts, haemoglobin content, restoring the redox balance and by quenching the free arsenic species in blood and tissues.

Earlier, it has been evident that blood cell count, liver enzymes’ activity were restored in arsenic-treated Charles Foster rats exposed to ethanolic extracts of cumin seed and coriander leaves.⁴¹ Another study showed that lycopene was responsible for reversing hematological alterations in sodium arsenite-treated male Wistar rats.⁴² Turmeric and P. foetida powder significantly increased (p<0.05) haemoglobin content and total erythrocyte count in arsenic-treated sheep.⁴³ On the other T. Cordifolia reversed the oxidative damage at biochemical, histopathological and hematological levels in Charles Foster rats.⁴⁴ Recently, it has been reported that garlic extract was reasonable to restore SGPT, ALP, CRE, ALT, as well as WBC, lymphocyte, and monocyte to normal levels in arsenic-treated Swiss albino mice.²¹ Another study showed that Aspalathus linearis extract restored hematological parameters such as RBC count and PCV to normal levels in arsenic-treated rats.⁴⁵ Stratification of vitamin D (vit D) exerts a significant impact on Th17 and IL-17A production in arsenic-exposed human.⁴⁶ Vitamin D level <20 ng/ml caused a decrease in the level of Th17. Researchers have theorized that the unusual interactions observed between arsenic (As) or its metabolic byproducts and vitamin D could be attributed to arsenic's substantial upregulation of T-cell receptor (TCR) pathways. This upregulation occurs through an increase in the protein tyrosine kinases Lck and Fyn. Consequently, vitamin D's influence on T-cell tolerance might elucidate this phenomenon.

CONCLUSION

Arsenic, a ubiquitous metalloid, poses a significant threat to global health, with its insidious impact on the hematopoietic system being a major concern. While this review is limited by its reliance on secondary data analysis and meta-analysis of hematological changes and remedial measure outcomes, it has highlighted the current status of knowledge on arsenic-induced hematological disorders, ranging from mild conditions like anaemia to severe and life-threatening malignancies such as leukaemia. The mechanisms underlying arsenic's toxicity are complex, involving oxidative stress, DNA damage, altered gene expression, and disruption of crucial cellular pathways. The prevalence of arsenic-related hematological issues varies geographically, with regions heavily reliant on contaminated groundwater, such as parts of Asia, facing the greatest burden. This is particularly concerning in developing countries, where the lack of affordable and effective arsenic filtration systems exacerbates the problem, limiting access to safe drinking water and water for irrigation. While the link between high-dose arsenic exposure and hematological malignancies is well-established, the effects of low to moderate exposure levels remain a subject of ongoing research. Emerging evidence suggests that even lower levels can contribute to subtle but significant hematological abnormalities, potentially increasing the risk of long-term complications. Given the challenges in eliminating arsenic from the environment, particularly in resource-limited settings, there is a growing need for interventions that can mitigate its toxic effects in exposed populations. This review has discussed the work carried out to date regarding the hematological aberrations caused by arsenic poisoning, and the probable mechanisms through which these changes occur. Recent research strongly suggests that dietary supplementation with specific nutrients or nutraceutical regimes may offer a promising avenue for reducing arsenic toxicity in both humans and animals. These interventions could represent a more immediate and cost-effective remedy in the face of widespread contamination. In conclusion, arsenic exposure remains a significant global public health challenge, with a wide spectrum of adverse effects on the hematopoietic system. A multi-pronged approach is essential to effectively address this issue. Primary prevention, through the provision of safe drinking water and the reduction of occupational exposure. Technological advancements in water filtration and remediation offer promising avenues for mitigating arsenic contamination. For affected individuals, early diagnosis and intervention are crucial. While chelation therapy has limitations, it can be beneficial in acute cases. Supportive care, including blood transfusions and growth factors, plays a vital role in managing hematological complications. Further research is needed to delineate the exact mechanisms by which dietary supplements and other potential therapeutic agents counteract arsenic poisoning, and also which of the nutraceuticals have more potential to alleviate the toxicity. This will be crucial for developing more potent and targeted interventions in the future. By combining preventive strategies, improved diagnostic tools, and innovative therapeutic approaches, we can strive to reduce the burden of arsenic-induced hematological disorders, particularly in vulnerable populations.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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