Cadmium induces microcytosis, hypochromicity, and anisocytosis without anaemia in hypertensive rats

doi:10.21203/rs.3.rs-3204119/v1

Background and Aim: Dietary cadmium (Cd2+) intake is implicated in the pathogenesis of hypertension and anaemia, but there is a paucity of information on the haematological changes in hypertensive conditions. This study, therefore, aims to evaluate the effects of Cd2+ on blood pressure (BP) and haematological indices in the Sprague-Dawley rat model.

Method: Three cohorts (n=10 each) of control and Cd2+-fed male Sprague-Dawley rats were selected. Cd2+-exposed rats received 2.5 or 5 mg/kg b.w. cadmium chloride via gavage thrice- weekly for eight weeks, while control animals received tap water. BP and flow were measured non-invasively from rat tails twice-weekly using a CODA machine, while weights were measured thrice-weekly. Haematological indices were assessed using the Cell-Dyn Emerald Haematology Analyzer (Abbott Diagnostics, IL, USA). Data were reported as mean ± SEM, and statistically analyzed using One-Way Analysis of Variance. Bonferroni post hoc test was used for multiple comparisons.

Results: Cd2+-exposure induced hypertension by significantly (p<0.05) elevating systolic, diastolic, and mean arterial BPs, pulse pressure, and heart rate (HR), and increased (p<0.05) blood flow. Mean cell volume (MCV) and haemoglobin (MCH) were significantly (p<0.05) reduced, and red cell distribution width (RDW) significantly (p<0.01) increased by exposure to 5 mg/kg b.w. Cd2+. Haemoglobin concentration (MCHC), haematocrit, haemoglobin, red blood cell, platelet, mean platelet volume, and white blood cell counts were unaffected by Cd2+-exposure.

Conclusion: Cd2+ induced hypertension, hypochromicity, and anisocytosis without anaemia, which may be precursor to microcytic anaemia and coronary artery disease. This study is important in Cd2+-exposed environments and warrants further investigations. Keywords: Cadmium; Hypertension; Microcytosis; Hypochromic anaemia; Anisocytosis

haematological parameters

hypertension

hypochromia

red cell distribution width

While most reports have focused on either hypertension or haematological parameters, this study connects the two aspects and highlights the presence of microcytosis, hypochromicity, and anisocytosis without anaemia in the hypertensive condition.

Dietary intake of Cd²⁺ is implicated in the pathogenesis of hypertension (Donpunha et al. 2011; McCalla et al. 2021; Nwokocha et al. 2013), however, specific mechanisms are still debatable and reports of the haematological changes in the hypertensive condition are warranted. The global burden of hypertension represents at least 25% of the world’s population, with a projected 29.2 % by 2025 (Kearney et al. 2005). Cd²⁺ is a toxic, non-biodegradable naturally occurring heavy metal that has a widespread industrial distribution and it bio-accumulates in the upper levels of the food chain (Amzal et al. 2009; Donpunha et al. 2011). Exposure to Cd²⁺ reportedly reduces the bioavailability of the potent vasodilator, nitric oxide, and causes oxidative damage, all of which result in vascular dysfunction and ultimately hypertension (Donpunha et al. 2011; Washington et al. 2006; Yoopan et al. 2008). This has caused the World Health Organization (WHO) to be concerned (WHO 1999).

There is also a paucity of literature and conflicting reports surrounding the impact of Cd²⁺ on haematological indices, so this study will be exploratory in this area. The study hypothesizes that Cd²⁺ induces hypertension with haematological alterations. The objectives were to induce hypertension in male Sprague-Dawley rats using two doses Cd²⁺ (2.5 and 5 mg/kg b.w.). and evaluate its effects on haematological indices. This study will also indicate whether or not anaemia is present with hypertension induced by Cd²⁺.

2.1. Ethical approval

Experiments were conducted in accordance with the guidelines and regulations stipulated by the University Hospital of the West Indies/University of the West Indies Faculty of Medical Sciences (UHWI/UWI FMS) Ethics Committee, University of the West Indies, Mona (approval number AN 16, 12/13).

2.2. Experimental animals

The protocol employed by McCalla et al. (2021) was followed. Briefly, male Sprague-Dawley rats weighing 170-200 g were obtained from the Animal House, The University of the West Indies, Mona, and fed daily with a standard rat chow diet and water ad libitum. All animals were kept at a constant 12 h light/dark cycle with constant humidity and temperature. The animals were acclimated to the laboratory conditions for one to two weeks prior to the start of the experimental procedures. Animals were randomized into groups of 10 and treated for eight weeks with Cd²⁺ (2.5 or 5 mg/kg b.w.). Normal control animals received water only. Cadmium chloride was administered via gavage three times weekly. We, and others, have already shown that a higher concentration of 100 mg/kg b.w. elevates mean arterial pressure (MAP) and systolic blood pressure (SBP) (Almenara et al. 2013; Nwokocha et al. 2013). The chosen concentrations in this study fall within the range of 0.5-10 mg/kg b.w. Cd²⁺ which have also been shown to significantly elevate BP and MAP, thereby causing hypertension, and smoking (especially tobacco) is one of the most important sources of Cd²⁺ in humans (Ashraf 2012; Yoopan et al. 2008). Weights were measured three times weekly using an Ohaus triple beam animal balance (Ohaus, NJ, U.S.A.) while BP, blood flow, and heart rate (HR) were measured twice weekly using a CODA non-invasive BP apparatus (Kent Scientific Corporation, CT, U.S.A.). SBP, diastolic BP (DBP), and MAP, as well as HR readings were generated automatically by the CODA machine. The difference between SBP and DBP was used to denote the pulse pressure (PP). Prior to BP measurements, rats were restrained in a rat restrainer and preconditioned for approximately 5 minutes. Fifteen to thirty inflation and deflation cycles were performed per rat per measurement session. The occlusion cuff was inflated to 250 mm Hg and deflated over 20 s. The volume-pressure recording (VPR) sensor cuff detected changes in the blood volume of the tail while blood returned to the tail during deflation of the occlusion cuff. These steps were done via operator blinding. Rats were sacrificed by cervical dislocation and blood was collected from the heart for haematological assessment via the Cell-Dyn Emerald Haematology Analyzer (Abbott Diagnostics, IL, USA), and stored at -80 °C prior to use.

2.3 Collection of blood samples

At the end of the eight-week assessment period, whole blood (~5 mLs) was collected via cardiac puncture by inserting a 22 G butterfly needle tip into the heart (around 5 mm). The blood was collected into the vacuum collection tube by inserting the rubber end of the butterfly needle into a vacutainer with EDTA (anticoagulant) or heparin. For the haematological indices, the vacutainer was gently inverted several times to mix the anticoagulant with the blood sample. The vacutainers were then placed on a shaker prior to use or on ice vertically before being transferred to storage in a refrigerator at 4 °C to preserve integrity. Stored blood was used within 2 hours.

2.4 Assessment of haematological indices

Haematological indices were assessed using the Cell-Dyn Emerald Haematology Analyzer (Abbott Diagnostics, IL, USA) after eight weeks of Cd²⁺ treatment. Whole blood was collected by the Cell-Dyn analyzer via suction to generate results for red and white blood cell indices: haemoglobin (Hb), haematocrit or packed cell volume (Hct or PCV), mean corpuscular/cell volume (MCV), mean corpuscular/cell haemoglobin (MCH), mean corpuscular/cell haemoglobin concentration (MCHC); total white blood cell (WBC) count, monocyte, lymphocyte, and granulocyte count and percent; platelet count and mean platelet volume (MPV). The suction device was wiped with sterile cotton gauze between blood samples to avoid contamination by the previous sample.

2.5. Data analysis

The results were reported as means ± SEM (standard error of the mean) using the Origin Pro 7.0 software, with ‘n’ indicating the number of animals used per experimental treatment. BP changes were expressed as percentages of baseline (pre-injection) values. Statistical analysis was done using IBM SPSS Statistics version 22 to determine the significance of the mean difference between groups via One-Way Analysis of Variance (ANOVA). Levene’s test of homogeneity was followed by the Bonferroni post hoc test for multiple comparisons and a p-value less than 0.05 was considered statistically significant. Graphs were plotted using the Origin Pro 7.0 software.

3.1. Cadmium elevates SBP, DBP, MAP, PP, HR, and blood flow without affecting weight

The BPs were significantly elevated in Cd²⁺-exposed animals without affecting mean body weight (Table 1 and Fig. 1).

Table 1. The effect of cadmium on mean blood pressures.

BP (mm Hg)	Control	Cd²⁺ (2.5 mg/kg b.w.)	Cd²⁺ (5 mg/kg b.w.)
SBP	120 ± 1	160 ± 2 *	155 ± 1 *
DBP	81 ± 1	119 ± 2 *	110 ± 1 *
MAP	94 ± 1	133 ± 2 *	125 ± 1 *
PP	39 ± 1	43 ± 1 **	45 ± 1 **

Both doses of cadmium significantly elevated SBP, DBP, MAP, and PP. BP, blood pressure; Cd, cadmium; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure. * p < 0.001 versus control; ** p < 0.05 versus control.

SBP was elevated within three weeks, while DBP and MAP were elevated within two weeks of Cd²⁺ administration. The PP was elevated after four and six weeks of receiving the lower and higher doses of Cd²⁺ respectively. While heart rate (HR) decreased throughout the assessment period, the higher dose of Cd²⁺ (5 mg/kg b.w.) significantly (p < 0.05) elevated HR (485 ± 5 beats per minute, bpm) compared to controls (469 ± 10 bpm) and those receiving the lower dose of Cd²⁺ (452 ± 5 bpm) from as early as three and five weeks, respectively. Peak HRs were: 521 ± 7 bpm (controls), 533 ± 8 bpm (2.5 mg/kg b.w. Cd²⁺), and 513 ± 7 bpm (5 mg/kg b.w. Cd²⁺). Blood flow was significantly (p<0.05) increased from week 5 to 8 compared to controls, ranging from 23.41 ± 1.24 and 24.06 ± 0.95 vs 18.02 ± 0.74 to 26.25 ± 1.20 and 28.28 ± 1.24 vs 19.6 ± 0.91 mL/min for Cd²⁺ (2.5 and 5 mg/kg b.w.) vs control respectively.

Mean weights from week 1 to 8 were: 190.09 ± 6.06 to 315.56 ± 9.00 g in controls versus 190.37 ± 2.41 to 326.54 ± 9.70 g and 190.44 ± 2.33 to 316.44 ± 10.46 g for Cd²⁺-treated rats (2.5 and 5 mg/kg b.w., respectively).

3.2. Cadmium reduces mean cell volume (MCV) and haemoglobin (MCH) and elevates red cell distribution width (RDW) in rats

The higher dose of Cd²⁺ (5 mg/kg b.w.) significantly (p < 0.05) reduced the mean cell (corpuscular) volume (57.17 ± 0.63 vs 60.45 ± 0.84 fL) and mean cell (corpuscular) haemoglobin (MCH) (20.66 ± 0.29 vs 21.93 ± 0.32 pg) compared to controls (Table 2). On the other hand, the higher dose of Cd²⁺ significantly (p < 0.01) elevated the RDW percentage (17.42 ± 0.80 vs 14.60 ± 0.21 and 15.23 ± 0.29 %) compared to the controls and those receiving the lower dose of Cd²⁺ (2.5 mg/kg b.w.), respectively. Platelet (Plt) and white blood cell (WBC) indices were unaffected (Table 2).

Table 2. Effect of cadmium on red and white blood cell and platelet indices (n=10).

Index	Normal Control	Cd²⁺ (2.5 mg/kg b.w.)	Cd²⁺ (5 mg/kg b.w.)
RBC (x106 uL)	6.34 ± 0.38	7.20 ± 0.12	7.14 ± 0.22
Hb (g/dL)	13.89 ± 0.85	15.29 ± 0.21	14.73 ± 0.41
Hct (%)	38.40 ± 2.49	42.14 ± 0.45	40.73 ± 0.93
MCV (fL)	60.45 ± 0.84	58.63 ± 0.78	57.17 ± 0.63 *
MCH (pg)	21.93 ± 0.32	21.28 ± 0.37	20.66 ± 0.29 *
MCHC (g/dL)	36.30 ± 0.25	36.29 ± 0.29	36.10 ± 0.27
RDW (%)	14.60 ± 0.21	15.23 ± 0.29	17.42 ± 0.80 **#

PLT (x103 uL)	564.50 ± 79.76	781.30 ± 56.73	662.70 ± 70.71
MPV (fL)	6.71 ± 0.20	6.24 ± 0.11	6.25 ± 0.12

WBC (x10³ uL)	3.64 ± 0.51	3.75 ± 0.41	5.86 ± 0.92
LYM # (x10³ uL)	2.50 ± 0.34	2.82 ± 0.34	4.07 ± 0.61
MONO # (x10³ uL)	0.34 ± 0.07	0.32 ± 0.02	0.55 ± 0.12
GRA # (x10³ uL)	0.80 ± 0.17	0.62 ± 0.05	1.23 ± 0.29
LYM %	69.19 ± 2.27	74.291 ± 1.62	70.38 ± 2.47
MONO %	9.23 ± 1.02	8.83 ± 0.58	8.98 ± 0.64
GRA %	21.58 ± 2.56	16.88 ± 1.24	20.64 ± 1.96

Cd²⁺ (5 mg/kg b.w.) significantly reduced MCV and MCH, while reducing RDW. Cd, cadmium; RBC, red blood cell; Hb, haemoglobin; Hct, haematocrit; MCV, mean cell volume; MCH, mean cell haemoglobin; MCHC, mean cell haemoglobin concentration; RDW, red cell distribution width; PLT, platelet; MPV, mean platelet volume; WBC, white blood cell; LYM, lymphocyte; MONO, monocyte; GRA, granulocyte. * p < 0.05 vs Control; ** p < 0.01 vs Control; # p < 0.05 vs Cd²⁺ (2.5 mg/kg b.w.)

The objective of the study was to induce hypertension in male Sprague-Dawley rats and evaluate the haematological indices. We successfully induced hypertension and our results showed that Cd²⁺ induced hypertension by elevating SBP, DBP, MAP, PP and HR. We previously reported that this hypertension did not affect contractility or relaxation of the thoracic aorta and was accompanied by a compensatory response (McCalla et al. 2021). Assmann et al. (2005) reported an association between increased SBP, DBP, and PP by 10 mm Hg and greater hazard ratio (approximately 10 %) of coronary heart disease. The significant elevation in PP with exposure to Cd²⁺ (2.5 and 5 mg/kg b.w.) may be a sign of aortic stiffening, which can lead to elevated BP and hypertension, as reported by Reymond et al. (2012). BP increase in response to exposure to 5 mg/kg b.w. Cd²⁺ was associated with elevated HR in this study.

In addition to elevated BPs and HR, this study also observed significant increase in caudal blood flow with Cd²⁺- exposure (2.5 and 5 mg/kg b.w.), as measured at the tail of the rats. This is in tandem with observation by Chen et al. (2019) regarding carotid blood flow with the use of 4 mg/kg b.w. Cd²⁺ intravenously. On the other hand, the same study reported decreased carotid blood flow with 8 mg/kg b.w. Cd²⁺, showing dose-dependent effects. Similarly, Thomas et al. (2021) reported decreased blood flow at the tail with isoproterenol exposure to induce myocardial infarction. Chen et al. (2019) also observed that the direction of carotid blood flow was in sync with tissue oxygen level and local blood flow.

Haematological indices can be used to evaluate the status of health, indicating inflammation, certain blood diseases such as anaemia, or pointing to cardiovascular disorders Feng et al. (2017). We, therefore, investigated whether low doses of Cd²⁺ would affect the haematological indices. With a reduced MCV, 5 mg/kg b.w. Cd²⁺ induced microcytosis (small RBCs) in the tested animals, however, normal RBC, Hb, and Hct counts rule out the presence of anaemia. This microcytosis, therefore, may be a precursor to the genesis of anaemia which may occur with prolonged exposure to Cd²⁺or exposure to higher concentrations. Horiguchi et al. (2011) observed that exposure of female Wistar rats to 2 mg/kg b.w. Cd²⁺ for 3 months caused anaemia. Furthermore, a previous study from our laboratory, reported by Nwokocha et al. (2013) indicated that a much higher dose of Cd²⁺ (100 mg/kg b.w.) induced anaemia by significantly reducing RBC, Hb, and Hct counts, while MCV, MCH, and MCHC were unaffected. Exposure of embryonic chicks to lower doses of Cd²⁺ (6 and 8 µg) resulted in lower MCV and higher RBC, Hb, Hct and MCHC counts in comparison to the controls, hence no anaemia, while MCH was unaffected (Bojarski et al., 2022).

In the present study, MCH was significantly (p < 0.05) reduced, pointing to reduction in the average mass of Hb present in each cell. MCH is a measure of the total mass of Hb relative to the number of RBCs in a given volume of blood. The amount of Hb in each RBC is dependent on the synthesis of Hb as well as the size of the RBC. MCH is calculated as (Hb x 10)/RBC and is diminished in hypochromic anaemias. The RBC mass is determined by iron, the core of the Hb molecule, which binds the protein globin chains of the Hb molecule. Given that the MCH represents the mass of one RBC, the microcytic cells are pointing to the genesis of iron deficiency anaemia, and the tendency is for RBCs to become lighter in this condition. While MCH was unaffected in the studies of Nwokocha et al. (2013) and Bojarski et al. (2022), another study by Andjelkovic et al. (2019) showed significant (p < 0.01 and 0.05) elevation in MCH with acute doses of Cd²⁺ (15 and 30 mg/kg b.w.). This points to conflicting results, which may be a factor of duration and concentration of exposure.

The results of this study also point to defective Hb synthesis resulting in microcytosis with anisocytosis (increased RDW). This was previously observed by Walker et al. (1990). This defect in Hb synthesis may be due to iron deficiency, the most common cause of microcytic, hypochromic anaemia. In such a case, anisocytosis may be the first lab abnormality, even before anaemia and microcytosis are seen (Walker et al. 1990). The RDW is a numerical measure of anisocytosis in RBCs which varies with age and many diseases and their severity (Dugdale and Badrick 2018). The normal RDW ranges from 11.5 to 14.5 % (Sadaka et al. 2013; Şenol et al. 2013). A high RDW is suggestive of nutrient deficiency, infection, or other diseases such as cardiovascular disease, liver disease, and metabolic syndrome where there is a strong risk association (Hu et al. 2013; Laufer et al. 2015; Li et al. 2017; Montagnana et al. 2011). Feng et al. (2017) reported that increased RDW may be closely related to the development of ischaemic stroke, carotid artery atherosclerosis, and cerebral embolism, and higher RDW could independently predict adverse outcomes in patients having these conditions. Given that the WBC indices were unaffected, infection can be ruled out. It is likely that the hypertension and reduced MCH observed were contributory factors.

Xanthopoulos et al. (2017) observed that a high RDW was a prognostic marker in patients with diabetes and heart failure, and RDW was also found to be significantly higher in acute stroke patients (Kara et al. 2015). Horiguchi et al. (2011) reported that the anaemia induced by exposure of female Wistar rats to 2 mg/kg b.w. Cd²⁺ for 3 months, occurred via haemolysis, iron deficiency, insufficient erythropoietin (EPO) production (renal anaemia), and changes in iron metabolism. The effects of Cd²⁺ also worsened with prolonged exposure from 1-3 months (Horiguchi et al. 2011). Peters et al. (2021) reported that RDW was increasingly elevated across progressively higher quartiles of blood Cd²⁺ concentration.

Renal anaemia should be a point of interest in future studies, given that our previous report points to a dual mechanism of Cd²⁺-induced hypertension in the renal arteries: significant (p<0.05) elevation in the phosphorylation of renal MYPT1-Thr697 with exposure to 2.5 mg/kg b.w. Cd²⁺ and significant (p<0.05) augmentation of total renal p44 MAPK level with exposure to 5 mg/kg b.w. Cd²⁺ (McCalla et al. 2021). A high RDW with low MCV may be caused by iron deficiencyor sickle cell anaemia, and a high RDW may also predict the presence of coronary artery disease in persons with high BP (Dixon 2018). The finding of low MCH, symbolizing hypochromicity, warrants investigation into the iron concentration. Given also, that iron deficiency is the most common cause of microcytic, hypochromic anaemia, and our study points to a precursor to this type of anaemia, we believe that assessments of iron concentration and Hb synthesis are warranted. Assessment of the pallor of the RBCs will also confirm the results of the MCH.

Cd²⁺ induced hypertension, microcytosis, hypochromicity, and anisocytosis without anaemia and the red cell indices are suggestive of a precursor to anaemia. The study, therefore, shows haematological changes accompanying hypertension. Given the potential impact of Cd²⁺, this study is important in Cd²⁺-exposed environments and warrants further investigation in human populations.

Source of Funding

This work was funded by grants obtained from the Mona Campus Committee for Research and Publications and Graduate Awards of the School for Graduate Studies and Research, The University of the West Indies.

Competing Interests

The authors declare no competing interest.

Ethical Approval

Experiments were conducted in accordance with the guidelines and regulations stipulated by the University Hospital of the West Indies/University of the West Indies Faculty of Medical Sciences (UHWI/UWI FMS) Ethics Committee, University of the West Indies, Mona (approval number AN 16, 12/13).

Author Contribution

Conception and design were performed by Chukwuemeka Nwokocha. Material preparation, data collection and analysis were performed by Garsha McCalla. The first draft of the manuscript was written by Garsha McCalla and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding for the study was acquired by Garsha McCalla and Chukwuemeka Nwokocha. Resources for the study were provided by Chukwuemeka Nwokocha. The entire study was supervised by Chukwuemeka Nwokocha and Paul Brown.

Data Availability

All data used are reported in the manuscript or as supplementary information.

Acknowledgements

The authors would like to express gratitude to members of Basic Medical Sciences, The UWI, Mona for technical assistance.

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No competing interests reported.

Cadmium induces microcytosis, hypochromicity, and anisocytosis without anaemia in hypertensive rats

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