Most of hepatocytes appeared with necrotic nuclei and cytoplasmic vacuolization. Some cells had irregular-shaped nuclei, while others were devoid of nuclei Fig.
Moreover, the blood sinusoids revealed dilatation and congestion as well as white blood cell infiltration and Kupffer cells activation Figs. B Section from rat treated with tartrazine showing necrosis of most hepatocytes H , congestion of blood vessel star and leucocytic infiltration arrow. C Section from rat treated with tartrazine showing vacuolated hepatocytes H , others devoid of nuclei star , leucocytic infiltration arrow and Kupffer cells K.
D—G Electron micrographs of liver sections from control and tartrazine-treated rats. D Section from control rat, showing part of the hepatocyte with nucleus N , rough endoplasmic reticulum rER , numerous mitochondria M and glycogen particles arrows. E Section from rat treated with tartrazine, showing irregular and pyknotic nuclei N , numerous lipid droplets L and electron dense mitochondria M. F Section from rat treated with tartrazine, showing abnormal shaped mitochondria M , dilated rough endoplasmic reticulum cisternae rER , scattered ribosomes arrows and clear area of cytoplasm star.
G Section from rat treated with tartrazine, showing less electron dense nucleus N , clear area of cytoplasm star , electron dense mitochondria M and fragmented endoplasmic reticulum cisternae rER. Electron microscope investigation revealed significant structural aberations in liver and kidney of tartrazine-treated rats. Nuclei of hepatocytes appeared irregular or pyknotic and others were with less electron dense chromatin as compared to control Figs. Alterations in the lipid contents of cells were observed by the presence of numerous lipid droplets that vary in size and shape Fig.
Abnormal shaped mitochondria were observed with condensed opaque matrices and lack internal organization. The cisternae of rough endoplasmic reticulum appeared dilated and fragmented Fig.
Rarefied areas in the cytoplasm could be resulting from dissociation of cellular organelles as well as scattered ribosomes that were also observed Fig. Moreover, obvious histological changes were observed in the structure of the kidney in the animal group treated with tartrazine when compared to controls Figs.
These changes includes degeneration in glomerular structure, loss of renal tubules integrity and the presence of areas of huge vacuoles Fig. Membrane injury in apical surfaces of tubular epithelial cells and degeneration in the basal membrane of cells were also noticed Fig.
B Kidney section from rat treated with tartrazine showing degenerated glomeruli G , loss of renal tubules integrity RT , huge cavity with fragmented areas star and inflammation arrow. C Kidney section from rat treated with tartrazine showing damage in renal tubules membrane arrows and degenerated glomeruli G. D—H Electron micrographs of kidney sections from control and tartrazine-treated rats. D Kidney section from control rat showing proximal tubular cells with apical microvilli mv , basement membrane Bm , basal infoldings arrow , nucleus N , numerous mitochondria M and lysosomes Ly.
E Kidney section from rat treated with tartrazine showing disrupted proximal tubular cells with irregular nucleus N , vacuolated cytoplasm arrows and disordered mitochondria M. F Kidney section from control rat showing distal tubular cell with nucleus N , mitochondria M and basement membrane Bm.
G Kidney section from rat treated with tartrazine showing disrupted distal tubular cells with nucleus N , mitochondria M and vacuoles arrows. X H Enlarged part of proximal tubular cell from rat treated with tartrazine showing part of pyknotic nucleus N , destructed mitochondria M , numerous lysosomes Ly , Gologi vesicles Gv and microvilli mv.
Electron microscope investigation showed remarkable ultrastructural alterations in the kidney of rats treated with tartrazine. These changes includes degenerated proximal and distal tubular cells with nuclei containing clumps of marginated heterochromatin Figs. Some of these nuclei appeared with irregular outline,while others were pyknotic. Vacuolated cytoplasm was a prominent feature in both proximal and distal tubular cells Figs. Also, pleomorphic and disorganized mitochondria as well as increased number of lysosomes and Golgi vesicles were observed in proximal tubular cells Fig.
In distal tubular cells, some mitochondria appeared normal while others were disrupted Fig. Comet assay resulted that tartrazine possesses a genotoxic effect in the white blood cells of treated rats Figs. A Fluorescence micrograph representing nuclei of leucocytes after the comet assay. Control nuclei of untreated animals appear intact with no detectable DNA damage. Nuclei of tartrazine-treated animals appear damaged. B Bar graph showing the tail DNA damage in percentage in nuclei of leucocytes of control and tartrazine-treated animals subjected to comet assay.
The increased levels of liver enzyme activities in blood is an indication of possible tissue damage. These results are in accordance with data reported by other investigators who attributed similar changes in liver function to hepatocellular impairment. Serum levels of creatinine and urea are major factors in determination of both, the glomerular filtration efficacy and proximal tubular secretion rate Azu et al.
Such damage in the the filtering compartments of kidney, blood levels of creatinine and urea increase. Our results show a significantly elevated serum levels of creatinine, urea and uric acid in tartrazine-treated group as compared to controls. These results are in agreement with Tawfek et al.
Recently, Nabila et al. It occurs when the overall level of ROS exceeds the potential of the antioxidants. In the present study, elevated levels of malondialdehyde MDA, end product of lipid peroxidation and nitric oxide NO clearly indicates oxidative stress occurrence in the tartrazine-treated rats.
The increased lipid peroxidation may be attributed to the generation of ROS that result from tartrazine administration. Because tartrazine belongs to the group of azo dye food colorants,it is metabolized inside the body into aromatic amines by intestinal microflora.
NO is considered as another important source of free radicals that might contribute to alterations in energy metabolism. Peresleni et al. Histological and ultrastructural results clearly showed that administration of tartrazine had led to distortion of hepatic architecture as well as degeneration in kidney structure of rats. Light microscopic figures showed tartrazine-induced necrosis of most hepatocytes, congestion of blood sinusoids, infiltration of white blood cell, activated Kupffer cells, damaged glomerular and renal tubule membranes.
These findings are in agreement with Himri et al. Rus et al. Several ultrastructural alterations were recorded in the livers and kidneys of rats treated with tartrazine. The hepatocytes and renal tubule epithelium appeared with irregular or pyknotic nuclei.
Large numerous lipid droplets, disorganization of mitochondria, rough endoplasmic reticuli rER and degenerated cytoplasmic areas were observed in the cytoplasm of hepatocytes. Meanwhile, proximal and distal tubular cells possess vacuolated cytoplasm and defective mitochondria.
The presence of pyknotic nuclei and necrosis of hepatocytes and tubular cells in the current work clearly indicates toxicosis as previously described by Deveci et al. Cheville reported that toxins may affect ribosomes and their ability to produce peptide chains and decreases the amount of proteins involved in the transport of triglycerides, that are produced at their normal rates, causing accumulation of lipid globules.
It also affected the integrity of mitochondrial membranes, which is critical for maintaining vital mitochondrial functions and determination of apoptosis in cells. Our electron microscopic results showed a clear destruction of hepatocytic cytoplasm. Concerning the genotoxicity of synthetic colors, the obtained results revealed that tartrazine caused DNA damage in leucocytes as detected by comet assay.
This genotoxic effect is probably due to the direct contact of tartrazine with nuclear DNA Himri et al. Data pertaining to the genotoxic effect of tartrazine with positive results are available.
This finding agrees with Mpountoukas et al. Hassan also revealed that administration of a daily dose of tartrazine 7. On one hand, a study carried out by Poul et al. On the other hand, induction of tartrazine-induced DNA damage in comet assays was observed in cells from the colon of mice Sasaki et al. Therefore, further comet assay investigations performed according to the latest recommended protocol Hartmann et al.
According to the above-discussed results, it can be concluded that tartrazine is able to generate ROS thus accelerating oxidative stress, altering the structure and biochemical profiles in hepatic and renal tissues. Therefore, controlling the consumption of tartrazine is important for the health and limiting the use of tartrazine, especially in foods used by children, is highly advisable. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests The authors declare there are no competing interests. Author Contributions Latifa Khayyat analyzed the data, wrote the paper, reviewed drafts of the paper.
Animal Ethics The following information was supplied relating to ethical approvals i. Data Availability The following information was supplied regarding data availability:. National Center for Biotechnology Information , U. Journal List PeerJ v. Published online Feb Author information Article notes Copyright and License information Disclaimer. Corresponding author. However, other studies demonstrated that tartrazine has potential clastogenic activity. It was shown to induce chromosomal aberrations in Chinese hamster Ishidate et al.
Sasaki et al. EFSA reviewed these latter studies and concluded that the transient DNA damage observed could be partly attributed to local cytotoxicity of the dye. The biological significance of the positive genotoxicity results is uncertain in view of the negative carcinogenicity studies. Maekawa et al. Behavioural development of offspring was not affected in any of these studies. Reproductive parameters were also examined in the chronic toxicity and carcinogenicity studies referred to above and reviewed by EFSA No treatment-related effects were observed.
The major controversy in the field of artificial food colours is the suggestion first made in the s that artificial food colours and additives, including tartrazine, may have detrimental effects on children inducing 'hyperactivity' Burrows , cited by Arnold et al. A specific hypothesis relating to this relationship was developed in by Feingold who proposed that hyperactivity and learning problems in children were due to certain foods and food additives as well as foods containing natural salicyclates.
The work was criticised by the medical profession. However, his hypothesis was accepted by many parents following media reports comprehensively reviewed by Arnold et al. Thus, no clear relationship between ingestion of food colours including tartrazine and the development of attention deficit hyperactivity symptoms in children Arnold et al. The use of non-standardised diagnosis, questionable sample selection, imperfect blinding and non-standardised outcome measures utilised by previous investigators may have been key factors contributing to the ambiguity surrounding tartrazine consumption and these reactions.
Interest in the relationship between food colours and hyperactivity in children was revived again in when McCann et al.
The study implied that mixtures of certain artificial food colours and sodium benzoate could increase the mean level of hyperactivity profile behaviours in two age groups of children years old and 8—9 years old from the general population. However, lack of consistency in the results with respect to the age and sex of the children and the type of observer parent, teacher, or independent assessor ; the unknown clinical relevance of the effects measured; the use of mixtures in the study and lack of information on dose-response resulted in the European Food Safety Authority EFSA rejecting suggestions of a direct link between artificial food colours and hyperactivity Watson Thus, the FDA concluded that a causal relationship between exposure to tartrazine and other colour additives and hyperactivity in children in the general population could not established.
Neither EFAS nor the FDA found any compelling evidence to alter current regulations on acceptable daily intakes of tartrazine in foods, drugs and cosmetics. From a toxicological point of view, tartrazine does not appear to represent a risk for the consumer.
It is recommended that the TGA allow the use of tartrazine for oral use and to label those products as to tartrazine content in line with New Zealand. It is strongly recommended you download this document to your own computer and open from there. Cochrane Database of Systematic Reviews. Not possible to provide firm conclusions as to the effects of tartrazine on asthma control. Bartle WR Tartrazine-containing drugs. Canadian Medical Association Journal.
Borzelleca, J. Food Chem. Burrows A. Palette of our palates: a brief history of food coloring and its regulation. Collins, T. Psychopharmacol Bull. Ann Allergy. Dipalma JR. Am Fam Physician. Durnev, A. EFSA Journal. EFSA Journal Elhkim M, Heraud F et al. An updated toxicological assessment, intolerance reactions and maxiumum theoretical daily intake in France.
Regulatory Tox Pharmacol. Available online. Feingold BF. Am J Nurs. J Food Sci. Giri, A. Sister chromatid exchange and chromosome aberrations induced by curcumin and tartrazine on mammalian cells in vivo. The addition of dense chromatin, enlargement of the nucleolus and loss of nuclear polarity in the moderate stage made up severe atypia. To analyze the eosinophilic and mitotic cellular component, the grated eyepiece technique was used.
Only two animals did not survive till the end of the study. Moreover, no other pathologic events were observed during the 46 weeks of the study. Animal number 6, from group A, died in the 39 th week and no cause was determined by necropsy. Animal number 30, from group B, died in the 40 th week due to indifferentiated round cell malignancy involving the intestinal wall and pancreas, with liver metastases.
Figure 3. Our results have shown that daily yellow dye tartrazine, at the acceptable daily intake dose, significantly increased the number of eosinophils in the antrum and also produced an even more significant increase of lymphocytes in the same region. We have not been able to find studies specifically targeting changes in the gastric mucosa of rats on tartrazine, although Aboel-Zahab et al. Sasaki et al. The increase in the number of gastric lymphocytes we were able to show has not been previously described, although an experimental study with a different method describes cytotoxicity and immunosuppressive effects of tartrazine on human peripheral blood lymphocytes, with mitotic proliferation and inhibition of their lytic activity Koutsogeorgopoulou et al.
Ishidate et al. We found neither carcinogenetic lesions in the gastric cells nor a significant presence of other malignancies in the animals, in accordance with the data from Borzelleca and Hallagan who failed to show any significant difference in the incidence of neoplastic lesions in animals receiving tartrazine orally in 4 different concentrations for 2 years.
Notwithstanding, these authors highlighted the production of the aromatic amine sulfanylic acid by the intestinal microflora of animals on tartrazine. The increased number of cells from the immune system found in this study underscores the known allergenic effect of tartrazine and may constitute another carcinogenetic hazard, adding to the uncertainty surrounding its use, due to the association with the production of sulfanylic acid.
The teratogenetic effect of tartrazine was tested by Collins et al. Histopathological analysis of the stomachs of animals in groups A and B showed the presence of argetanffin granular cells, responsible for gastrointestinal mesenchimal tumors in humans.
Statistical analysis did not show any relation between the number of such cells and the gastric changes found.
We could not find any literature reference to these cells in tartrazine-treated rats Rubin et al. We acknowledge that diluting the dye in water and offering it ad libitum was not the best way to guarantee a precise intake, although several authors have offered tartrazine ad libitum in water or food Maekawa et al. The long period of the study coupled with insurmountable technical difficulties precluded the daily gavage of the animals.
We believe our approach was worthy in terms of intake, which was close to the maximum intended. The diversity of results found in studies on tartrazine, coupled with its ability to sensitize and produce aromatic amine, clearly point to the need for further studies to determine its carcinogenetic potential, cytotoxicity, and immunosuppressive effects.
So that the continued use of tartrazine in foods and drugs can be justified, studies using different doses and schedules, and investigating its combined effect with other food and environmental carcinogens are called for. Physiological effects of some synthetic food colouring additives on rats.
The reduction of dyes by the intestinal microflora. Food Chem. Nutrition , vol. Aspirin, Salicylate and Tartrazine Induced Bronchonstriction. Safe doses and Case Definition in Epidemiological Studies. Clin Epidemiol , vol. Tartrazine in atopic eczema. Arch Des Child , vol. Natural and man-made mutagens and carcinogens in the human diet.
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