Int. J. Biosci.

2020

International Journal of Biosciences | IJB |

ISSN: 2220-6655 (Print), 2222-5234 (Online)
http://www.innspub.net
Vol. 16, No. 2, p. 113-123, 2020

RESEARCH PAPER OPEN ACCESS

Study of hematological and biochemical effects of sub-lethel

doses of the blue green alga Lyngbya aestuarii

E.Y.A. Al-Sultan1*, F. S. Kataa1, A.M. Eassa2

1
Department of Biology, College of Education for Pure Science, University of Basra, Iraq
2
Department of Marine Chemistry, Marine Science Center, University of Basra, Iraq

Key words: Lyngbya aestuarii - Toxicity - Hematological aspects - Biochemical aspects - Female mice.

http://dx.doi.org/10.12692/ijb/16.2.113-123 Article published on February 05, 2020

Abstract
Cyanobacteria are photosynthetic prokaryotic organisms that colonize a wide variety of habitats. They are the
source of more than 300 bioactive secondary compounds. Among those secondary metabolites, the cyanotoxins
which have received most of the research attention therefore, the present work aimed to study the detrimental
effects of methanolic extract of Lyngbya aestuariion on some physiological aspects in female mice.
Hematological parameters were analyzed with automated Hematological analyzer while other biochemical
parameters were achieved with commercial kits using spectrophotometer apparatus according to manufacture
instructions. The present results showed a significant increase in the red blood corpuscles' count in both low and
high dose groups comparable with control group and there are a significant increase in both HGB and HCT in
low dose group comparable with control. Also, there are significant increase in percentage of monocytes in high
dose group comparable with control group. Liver enzymes showed significant differences in mice groups for AST
only where the low dose treatment registered significant increase in concentrations comparable with control
treatment. Concentration of both urea and creatinine showed significant increase in low dose group only
comparable with control group which reflect kidney dysfunction. There are significant decreasing in
concentration of HDL among mice groups comparable with control group. Finally, total protein concentrations
showed significant increase in high dose treatment comparable with control treatment. In conclusion, the
detrimental effect of the toxic extract of L. aestuarii was on kidney function.
* Corresponding Author: Al-Sultan  [email protected]

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Introduction except few studies were conducted on both genders

Cyanobacteria are photosynthetic prokaryotic (AL-Sultan et al., 2015; AL-Sultan and Abass, 2017;
organisms that colonize a wide variety of habitats, AL-Sultan and Aubaed, 2017; Kata et al.,
from freshwater and marine environments to 2017).Therefore, the present workaimed to study the
hydrothermal vents, from desert rocks to antarctic detrimental effects of methanolic extract of Lyngbya
lakes (Testai et al., 2016). Cyanobacteria are aestuarii and their toxins on some physiological
characterized by an active secondary metabolism, that aspects in female mice.
is, a group of processes obviously not involved in
primary metabolism (e.g., photosynthesis, Material and methods
respiration). They are the source of more than 300 Extraction of L. aestuarii
bioactive compounds, many of which are yet of The toxic blue green alga "L. aestuarii" was collected
unknown function. Among those secondary from Shatt Al-Arab River as a unialgal bloom and its
metabolites, cyanotoxins have received most of the toxic compounds were detected with LC-tandem MS.
research attention so far (Cirés et al., 2017). They were neosaxitoxin, Cryptophycin C and
Dudawalamide B and they previously published by
Human deaths caused by acute exposure to Al-Sultan et al. (2019).
cyanotoxins are limited to few cases so far. In 1996,
several cases of liver failure and human death Twenty grams of lyophilized alga were weighed and
occurred in Brazilian dialysis clinic which named extracted twice with 75 % methanol (1 liter) then it is
Caruaru syndrome, being caused by the exposure of re-extracted twice with 1 % acetic acid (40 mililiter),
the patients to microcystins-contaminated water then both extractions were mixed together before
when used for dialysis (Pouria et al., 1998; desiccation with Freeze dryer (Rangel et al., 2013).
Carmichael et al., 2001). In 2002, a swimmer boy
died after swallowing water with a blue-green algae Experimental design
scum at Wisconsin/USA. He suffered from a Seizure The LD50 of algal crude extract was 560 mg/kg
and died as a result of heart failure (Weirich and according to AL-Sultan et al. (2019).Twenty four
Miller, 2014). Food-supplements containing blue- adult female mice weighing about 23-26 gram were
green algae supplements (BGAS) are another route of divided into three groups, each group comprised of
chronic exposure to cyanotoxins. Dietrich et al. eight mice and the groups were injected with two
(2007) pointed that a woman died after its doses derived from the LD50 value for fifteen days.
consumption of blue-green algae supplements The highest dose represented 1/7 LD50 and it was 80
(BGAS) for a long period. mg/kg b.w. while the lowest dose represented 1/14
LD50 and it was 40 mg/kg b.w. At the end of
Cyanobacteria species were investigated in Iraqi treatment period, mice were anesthetized by
surface and drinking water (AL-Sultan, 2007; AL- chloroform, and sacrificed for blood collection by
Shaheen, 2011; Abed, 2013;Abed, 2015;Al Hassany et heart puncture.
al., 2014;Al- Hussieny et al., 2015 ; Ali, 2016,
abdulsalam et al., 2016; Hassan et al., 2017) but there Hematological aspects
is a limited ecological studies on the prevalence of Blood samples used for hematological analysis were
cyanotoxins in Iraqi fresh waters (AL-Shaheen, 2002, collected into lavender EDTA-containing tubes.
Al-Sultan and Mahmood, 2016; AL-Sultan and Erythrocytes (RBCs), total leucocytes count (WBCs),
Aubaed, 2017 and AL-Sultan, et al., 2019).Also, there hemoglobin (HGB), hematocrit value (HCT), mean
are few studies concerned with physiological and corpuscular volume (MCV), mean corpuscular
histopathological effects of toxic cyanobacteria on haemoglobin (MCH), mean corpuscular haemoglobin
mice. Majority of them were conducted on male mice concentration (MCHC) and WBC differential were

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 Int. J. Biosci. 2020

analyzed with automated Hematological analyzer. one-way analysis of variance (ANOVA). In all
statistical tests, a value of P ≤ 0.05 was considered
Biochemical aspects significant. All analysis was performed using
Blood samples were transferred to serum separating statistical package for social sciences (SPSS) for
tubes, these tubes with golden cap contain particles Windows, Version 21.
that cause blood to clot quickly, as well as a gel to
separate blood cells from serum. Blood samples were Results
left to clot and then centrifuged at 3000 r.p.m for 10 Hematological aspects
minutes at room temperature to separate the serum Effect of methanolic extract of L. aestuarii on Red
and finally the serum is stored at -20°C until assay. Blood Corpuscles' parameters
The biochemical tests includes ALT, AST, ALP, urea, The present results showed a significant increase (p ≤
creatinine, glucose, total protein, total cholesterol, 0.05) in the red blood corpuscles ‘count in both low
triglycerides, HDL and LDL which achieved with and high dose groups comparable with control group.
commercial kits using spectrophotometer apparatus
according to manufacture instructions. While there are a significant increase (p ≤ 0.05) in
both HGB and HCT in low dose group comparable
Statistical analysis with control group but there is no significant changes
Results are expressed as mean ± standard deviation. (p ˃ 0.05) observed in MCV, MCH and MCHC (Table
The difference between the means was determined by 1).

Table 1. Hematological effects of methanolic extract of L. aetuarii on red blood corpuscles' parameters for
female mice (n=8) after 15 days of i.p. injection.
Parameters RBC (106/mm3) HGB (g/dL) HCT (%) MCV (fL) MCH (pg) MCHC (g/dL)

Treatments
Control b b b
7.29±0.47 10.46±0.67 31.98±2.83 43.80±1.22 14.28±0.25 32.74±1.14
Low dose (40 mg/kg) a a a
8.58±0.41 12.30±0.73 39.86±1.96 46.52±0.97 14.30±0.51 30.82±0.90
High dose (80 mg/kg) a ab ab
7.99±0.58 10.98±1.72 35.64±4.24 44.52±3.02 13.72±2.12 30.84±4.05
R.L.S.D. 0.44 1.61 4.11 N.S. N.S. N.S.
a,b indicate the presence of significant difference (p ≤ 0.05) among treatment groups.

Effect of methanolic extract of L. aestuarii on White 0.05) in percentage of monocytes in high dose group
Blood Cells parameters comparable with control group (Table 2).
The present results show a significant increases (p ≤

Table 2. Hematological effects of methanolic extract of L.aestuarii on white blood cells parameters for female
mice (n=8) after 15 days of i.p. injection.
Parameters WBC Lymphocytes (%) Monocytes (%) Granulocytes (%)
(103/mm3)
Treatments
Control b
9.62±2.58 6.36±1.90 0.18±0.08 3.08±0.64
Low dose (40 mg/kg) b
8.48±2.48 5.66±1.88 0.20±0.00 2.62±0.71
High dose (80 mg/kg) a
11.94±10.00 8.16±8.14 0.54±0.27 3.24±2.04
R.L.S.D. N.S. N.S. 0.21 N.S.

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 Int. J. Biosci. 2020

Biochemical aspects significant increase (p ≤ 0.05) in low dose group only

Effect of methanolic extract of L.aestuarii on liver comparable with control group (Table 4).
parameters
The present results showed significant differences in Effect of methanolic Extract of L.aestuarii on lipid
mice groups for AST only where the low dose profile
treatment registered significant increase in There are no significant changes in concentration of
concentrations comparable with control treatment total cholesterol (TC), triglycerides (TG) and low-
(Table 3). density lipoprotein-cholesterol (LDL) among female
mice groups but there are significant decreasing (p ≤
Effect of methanolic extract of L.aestuarii on kidney 0.05) in concentration of high-density lipoprotein-
parameters cholesterol (HDL) among mice groups comparable
Concentration of both urea and creatinine showed with control group (Table 5).

Table 3. Effect of methanolic extract of L.aestuarii on hepatic enzymes for female mice (n=8) after 15 days of i.p.
injection.
Parameters ALP (U/l) ALT (U/l) AST (U/l)

Treatments
Control c
8.05±4.35 21.94±1.16 5.51±1.96
Low dose (40 mg/kg) a
9.86±2.35 37.47±14.18 126.61±19.27
High dose (80 mg/kg) b
6.89±2.56 32.54±9.08 77.78±19.87
R.L.S.D. N.S. N.S. 14.50

Effect of methanolic extract of L.aestuarii on glucose increase in RBC count are related to increase in
and total proteins erythropoiesis (Lai et al., 2006). The reduction in
Glucose concentrations did not show any significant RBC count and/or their hemoglobin content yield a
difference (p ˃ 0.05) between control group and other hypoxia which is occurred as a result of exposure to
treated groups. While protein concentrations showed neosaxitoxin in the methanolic extract of L. aestuarii
significant increase (p ≤ 0.05 in high dose treatment (Silva de Assis et al., 2013). According to hospital case
comparable with control treatment (Table 6). reports, Patients intoxification with saxitoxins in
Chile after their eating poisonous mussels suffered
Discussion from hypoxia with low arterial oxygen pressure
Hematological aspects concomitant with bradycardia as a consequence of
Effect of Methanolic Extract of L. aestuarii on Red respiratory failure (Carcía et al., 2005). In the present
Blood Corpuscles (RBC) study, hypoxia gives rise to increased erythropoiesis
The hematological indices for female mice exhibited a as evidence by increasing in RBC count, HGB and
significant increase in the RBC count in both low and HCT (Vargas et al., 2011). Under normal conditions,
high dose groups comparable with control group expression of erythropoietin in kidneys is responsible
while both HGB and HCT exhibited a significant for erythrocytes production. Erythropoietin is
increase in low dose group comparable with control secreted to the plasma and in the bone marrow it
group but there are no significant changes observed binds to erythropoietin receptors on the surface of
in both MCH and MCHC. In the present study, the erythroid progenitor cells. Both erythropoietin

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concentration and erythropoietin receptor activation content were significantly higher in all fish groups fed
are important for triggering erythrocyte production with L. hieronymusii compared with the control
by erythroblastic islands (Srbová, 2011). The process group for all doses and periods. Also, WBC count was
of stimulation an erythropoiesis known as stress significantly higher in some of fish groups after
erythropoiesis. Stress erythropoiesis has been studied feeding them with L. hieronymusii at different doses
mainly in mice models of acute anaemia (Riley et al., and for different periods. So, in the present study, the
2001; Vignjević et al., 2014).In addition to stimulation of erythropoiesis in female mice may be
erythropoietin role, several additional growth factors due to an increase in percentage of monocytes in
have been implicated in stress erythropoiesis. Our blood stream (Miller, 1989; Moldawer et al., 1989).
findings are in agreement with Ramamurthy et al
(2013) when they fed the fish Platycephalus gibbosus Macrophages play an important role in supporting
with the cyanobacterium Lyngbya hieronymusii and stress erythropoiesis by increasing erythropoietic
found that both RBC count and their hemoglobins activity (Heideveld et al., 2018).

Table 4. Effect of methanolic extract of L. aestuarii on kidney parameters for female mice (n=8) after 15 days of
i.p. injection.
Parameters Urea (mg/dL) Creatinine (mg/dL)

Treatments
Control b b
27.14±1.90 0.44±0.22
Low dose (40 mg/kg) a a
32.59±3.25 0.98±0.51
High dose (80 mg/kg) b ab
27.57±1.25 0.83±0.34
R.L.S.D. 6.62 0.39

Effect of methanolic extract of Lyngbya aestuarii on sequential exposure of recreational people to low
White Blood Cells (WBC) levels of the cyanotoxins such as MC-LR and LPS
Monocytes percentages were increased significantly leads to a hypo-responsiveness condition known as
in high dose group comparable with control group. cyanotoxin tolerance. This is an important and active
Our present findings are in agreement with findings immune response to chronic exposure to cyanotoxins
of Esmaeel (2017) in that the increasing of monocytes that prevents excessive inflammatory responses
percentage were in female mice only after injection (Pandey and Prasad, 2016). It initiated by the first
them with crude extract of Oscillatorialimosa. exposure, mediates by a short-term memory
Monocytes are precursors of macrophages which macrophages and low level of liberated TNF-α. Then
represent the body's second line of defense against gradually resulting in a complete canceling of TNF-α
infection (Lu and Kacew, 2002; Kemal, 2014). release (Stewart, 2004). It had been found that
Therefore an increasing in percentage of monocytes, fishermen who ate shellfish containing low
in the present study, is due to immunological concentrations of saxitoxins were less susceptible for
response of female mice to the methanolic extract of harmful effects of these toxins. Also, tolerance of
L. aestuarii which contains lipopolysaccharides (LPS) saxitoxins had been induced in experimental rodents
of the cell walls and neosaxitoxin. This response is where their injection with sub-lethal doses made
similar to human response after exposure to them not affected by lethal doses (Alexander et al.
cyanobacteria during recreation on beaches. The 2009).

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Table 5. Effect of methanolic extract of L. aestuarii on lipid profiles for female mice (n=8) after 15 days of i.p.
injection.
Parameters TC TG HDL (mg/dL) LDL (mg/dL)
(g/dL) (mg/dL)
Treatments
Control a
126.67±45.45 104.80±27.17 11.05±4.50 94.65±50.12
Low dose (40 mg/kg) b
147.98±32.42 96.69±21.51 0.02±0.00 128.64±30.79
High dose (80 mg/kg) b
129.14±38.55 94.11±16.72 0.92±0.43 109.39±37.57
R.L.S.D. N.S. N.S. 7.42 N.S.

Biochemical aspects their levels have increased in blood. The present

Liver parameters results show highly significant increasing in urea
The present results do not show any significant concentration which indicate renal failure. Urea is
alteration in both ALT and ALP concentrations derived from metabolism of protein and is excreted in
among treatment but they showed significant increase the urine. High level of urea in serum usually
in AST for low dose treatment comparable with indicates of acute renal dysfunction due to glomerular
control treatment. Our findings are in agreement with damage (Mounira, 2015). Creatinine is a metabolite of
those of Zepeda et al. (2014) in that intraperitoneal creatine degradation and is excreted completely in the
injection of rats with 6 µg/kg neosaxitoxin produced urine via glomerular filtration. The amount of
increased in concentrations of the hepatic AST creatine per unit of skeletal muscle mass is consistent
enzyme only. The estimation ALT is a more specific and the breakdown rate of creatinine is also
test for detecting liver necrosis since it is primarily consistent (Knaack et al., 2016; Coleman et al., 2018).
found in the liver. While AST is considered a less The present results show a significant increasing in
specific biomarker enzyme for hepatocellular injury creatinine concentrations in treated mice comparable
because it is also found in heart, skeletal muscles, with the control ones. Our findings are in agreement
brain, kidney and in erythrocytes. Injury to any of with those of Pan et al. (2008) who study the toxicity
these tissues can cause an elevated concentration of of crude extract of Anabaena flos-aquae in mice and
AST in serum (Nsiah et al., 2011; Woreta and they found an elevation in both urea and creatinine
Alqahtani, 2014). Several cyanotoxins are levels in mice serum. Also, an elevation in creatinine
biotransformed in the liver of vertebrates through concentrations in serum may be indicated to both
phase I and phase II reactions. García et al. (2010) kidney dysfunction and muscular dystrophy (Lu and
confirmed the metabolism of some saxitoxins in Kacew, 2002; Martin and Sheaff, 2007; Basten, 2010;
human using human liver microsomes. Also, Ramos Kopp et al., 2010).
et al. (2014) have observed alterations in the
antioxidant machinery in rat liver after oral exposure Lipid profile
to sub-lethal doses of saxitoxin which indicated that The present results did not show any significant
the liver is susceptible to oxidative stress. alteration in total cholesterol, triglycerides and LDL
but they showed decreasing in HDL in treated mice
Kidney function comparable with control ones.High- density
Urea and creatinine are general markers of renal lipoproteins (HDL) involved in VLDL metabolism and
function both in man and rodents. In injured kidney, also in cholesterol transport (Murray et al., 2008).
these substances are not excreted normally, therefore HDL serve as acceptor of excess cholesterol from

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 Int. J. Biosci. 2020

various tissues and as transporter of unused cardiovascular diseases (Haghpanah et al., 2010;
cholesterol from the tissue back to the liver where it is Seixas et al., 2010). So, the decline in HDL
broken down to bile acids and then excreted or re- concentration for female mice would subject them to
utilized (Al-hassan, 2012). They promote the removal cardiovascular disorders which have been provoke by
of cholesterol from tissues and its secretion into the exposure to saxitoxin as proved by experimental
bile by the liver. It is known to be the good cholesterol animals after their intravenously injection (i.v.) with 1
in the body as it decreases the occurrence of µg saxitoxin/kg body weight (Alexander et al., 2009).

Table 6. Effect of L. aestuarii on glucose, total proteins and total bilirubins for female mice (n=8) after 15 days
of i.p. injection.
Parameters Glucose (mg/dL) Total proteins (g/dL)

Treatments
Control b
112.88±55.41 4.98±1.06
Low dose (40 mg/kg) ab
103.80±24.31 5.55±0.64
High dose (80 mg/kg) a
105.97±9.27 6.51±1.20
R.L.S.D. N.S. 1.05

Glucose and total proteins of Ramamurthy et al. (2013) when they registered an
The present results did not show any significant elevation in serum total protein in the fish P. gibbosus
differences in glucose concentrationsamong female after feeding them with the cyanobacterium L.
mice treatments but the results show significant hieronymusii and these higher concentrations of total
increase in concentration of total protein in high dose protein were associated with stimulation of both
for female mice comparable with control mice only erythropoiesis and non-specific immunity response in
which reflects the enhancement role of algal extract fish blood.
on stimulation of protein synthesis by liver
wheremajority of plasma proteins like albumins and Conclusion
globulins are produced in the liver (Al-Hassan, 2012). The present study showed the detrimental effect of
the toxic extract of L. aestuarii on kidney function
Our present findings are in agreement with those of while less effect was on liver functions.
Palikova et al. (2004) in that total protein
concentrations were increased after exposure of the Akcnowlegment
carp fish (Cyprinus carpio L.) to stress caused by We would like to acknowledge Department of
toxic cyanobacterial extract containing microcystins Biology/College of Education for Pure Sciences for
and the biomarkers of this stress represented by support usin our research.
increasing in RBC count, HGB and HCT in the
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