**4. Biological effect of aflatoxins on the body organs and body systems**

Aflatoxins have been reported to affect the various body organs like the liver, kidneys, lungs, brain, testes and many endocrine and exocrine organs, the heart, skeletal muscles and the different body systems.

#### **4.1. Role of aflatoxins in hepatic injury and other body organs and tissues**

Aflatoxins have been reported to cause liver cirrhosis as well as liver cancers [4, 6, 7, 26, 80]. Hepatic injury can be acute or chronic form caused by a variety of toxic agents like aflatox‐ ins, chemicals and drugs, trauma and infectious agents [2, 4, 6, 7, 26, 61, 76, 80, 81]. The re‐ duced level of total protein is indicative of the toxic effect of AFB1 to the liver due to the failure in synthesis of the proteins and kidney in which aflatoxins are known to impair pro‐ tein biosynthesis by forming adducts with DNA, RNA and proteins, inhibits RNA synthesis, DNA-dependent RNA polymerase activity and causes degranulation of endoplasmic reticu‐ lum [58-60]. Acute hepatic injury due to aflatoxin causes a rise in serum enzymes including aspartate aminotransferase, lactate dehydrogenase, glutamate dehyrogenase, gamma-gluta‐ myltransferase and alkaline phosphatase and bilirubin that reflect liver damage as well as other biochemical changes such as proteinura, ketonuria, glycosuria and hematuria [4, 5, 40]. The other frequently used liver enzymes are the alkaline phosphatase (ALP) and Gam‐ ma-glutamyltransferase and gamma-glutamyltranspeptidase (GGT and GGTP) that indicate obstruction to the biliary system, either within the liver or in the larger bile channels outside the liver [9, 45, 61]. The presence of jaundice and neurological disorders due to brain dam‐ age leading to hepatic encephalopathy are associated with liver failure. Chronic liver failure leads to accumulation of metabolites in circulation such as ammonia and fatty acids that eventually lead to brain damage and hence hepatic encephalopathy [40, 82]. The liver failure makes it unable to detoxify ammonia, the product of protein and amino acid metabolism leading to hyperammonemia that may cross the blood brain barrier leading to increased synthesis of glutamate neurotransmitters henceleading to cytotoxicity of the brain cells and hence the hepatic encephalopathy [82-84]. AFB1 has been reported to cause pallor discolora‐ tion of liver and enlargement of liver and kidneys, congestion of liver parenchyma, cytoplas‐ mic vaculation or fatty change of hepatocytes, necrosis of hepatocytes and newly formed bile ducts, mononuclear and heterophilic cell infiltration are reported in aflatoxin fed broiler chicks [85]. It is also reported that there is a decrease in protein content in skeletal muscle, heart, liver and kidney in aflatoxin-fed animals due to the AFB1's potent mutagenic, carcino‐ genic, teratogenic, immunosuppressive and its ability to inhibits several metabolic systems such as protein synthesis thus leading to liver, kidney and heart damage [58-60]. In chicken, the activity of serum or plasma enzymes like the sorbitol dehydrogenase, glutamic dehydro‐ genase, lactate dehydrogenase, alkaline phosphatase, acid phosphatase, aspartate amino‐ transferase and alanine aminotransferase were reported to be increased in aflatoxicated chickens [22].

damage to critical cellular macromolecules such as DNA, lipids and proteins. Cellular fatty acids are readily oxidized by ROS to produce lipid peroxyl radicals which can subsequently propagate into MDA that may interact with cellular DNA to cause DNA-MDA adduct that may affect energy production in the brain [29, 49, 50, 54]. The role of ROS has been postulat‐ ed in the development of aging and chronic degenerative diseases, inflammatory diseases and brain cancers [52]. Aflatoxins may also deplete the myelin sheath of the nerves, an im‐ portant substance that covers the nerves and hence become exposed to insults. Mycotoxins especially aflatoxins have been reported to be toxic to various aspects of brain chemistry and their function [4, 50, 82]. AFB1 also alters the levels of various biogenic amines (neurotrans‐ mitters) and their precursors in rat and mouse brains. Acute AFB1 treatment in experimental animals has been reported to cause a decrease in regional brain acetylcholinesterase en‐ zymes that may affect the cognitive functions as well as memory and learning of the indi‐ vidual while chronic exposure increases adenohypophyseal acetylcholinesterase [24]. Aflatoxin causes a decrease in dopamine, serotonin and alterations in the levels of the pre‐ cursor's tyrosine and tryptophan [86-88]. Deficiencies in these neurotransmitter lead to neu‐ rological symptoms such as neurocognitive decline and alteration of sleep cycle and symptoms of brain damage like dullness, restlessness, muscle tremor, convulsions, loss of memory, epilepsy, idiocy, loss of muscle coordination, and abnormal sensations [89, 90]. AFB1 has also been reported to increase the central and peripheral nervous system Na+

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251

ATPase, β-glucuronidase and β-galactosidase while inhibiting the Mg2+-ATPse in experi‐ mental animals and this also is important in the normal functioning of the glutamate neurotransmitter and their NMDA receptors [24, 53, 91-93]. The liver failure makes it unable to detoxify ammonia, the product of protein and amino acid metabolism leading to hyper‐ ammonemia that may cross the blood brain barrier leading to increased synthesis of gluta‐ mate neurotransmitters hence leading to cytotoxicity of the brain cells and hence the hepatic encephalopathy [82-84]. Toxic encephalopathy was originally described in children with Reye's syndrome associated with consumption of Aflatoxin B1 and/or salicylates [78] and subsequently in cases of aflatoxicosis in canines and Chinese children were reported [94]. Aflatoxins also have been linked to Reye's syndrome that is characterized by symptoms of encephalopathy and fatty degeneration of the viscera. It is a pediatric disease characterized by cerebral edema and neuronal degeneration. Toxic encephalopathy due to aflatoxins in‐ volves multiple symptoms like loss of balance, recent memory decline, headaches, light‐ headedness, spaciness/disorientation, insomnia, loss of coordination [4, 18, 50, 82]. Aflatoxins have been reported to be associated with a Reye-like Syndrome in Thailand, New Zealand, Czechoslovakia, the United States, Malaysia, Venezuela and Europe [4, 9, 24, 50, 78]. Aflatoxins especially AFB1 have been reported to cause tumors in both the central and peripheral nervous system and several nonepithelial neurogenic tumors like the schwanno‐

mas, gliomas, meningiomas and granular cell tumors have been reported [24].

The gastrointestinal tract (GIT) is the main route of entry of aflatoxins as a result of con‐ sumption of aflatoxin-contaminated foods especially AFB1. It is also the main route of excre‐ tion aflatoxin metabolites from the bile. The aflatoxins, metabolites and AF-8,9-epoxides

**4.3. Effect of aflatoxins on the gastrointestinal tract (GIT)**

/K+ -

#### **4.2. Effect of aflatoxins on the central nervous system**

In the brain or central nervous system, the neurons have a high metabolic rate but little ca‐ pacity for anaerobic metabolism and subsequently, inadequate oxygen flow to the brain kills the neuronal brain cells within minutes. Some compounds damage neurons or neurotoxic and thus inhibit their function. Mycotoxins especially aflatoxins and its metabolites and oth‐ er products such as the reactive oxygen species (ROS) like the AFB-8,9-epoxides may inter‐ fere with the normal functioning of the nerve cells by forming DNA adducts, protein adducts, oxidative stress factors, mitochondrial directed apoptosis of the nerve cells as well as inhibiting their synthesis of protein, RNA and DNA [40, 44, 47, 50, 52, 54]. Aflatoxins also cause abnormalities in mitochondrial DNA, structure and function, including defective oxi‐ dative phosphorylation in the brain cells [29, 49, 50, 54]. The oxidative stress may result in damage to critical cellular macromolecules such as DNA, lipids and proteins. Cellular fatty acids are readily oxidized by ROS to produce lipid peroxyl radicals which can subsequently propagate into MDA that may interact with cellular DNA to cause DNA-MDA adduct that may affect energy production in the brain [29, 49, 50, 54]. The role of ROS has been postulat‐ ed in the development of aging and chronic degenerative diseases, inflammatory diseases and brain cancers [52]. Aflatoxins may also deplete the myelin sheath of the nerves, an im‐ portant substance that covers the nerves and hence become exposed to insults. Mycotoxins especially aflatoxins have been reported to be toxic to various aspects of brain chemistry and their function [4, 50, 82]. AFB1 also alters the levels of various biogenic amines (neurotrans‐ mitters) and their precursors in rat and mouse brains. Acute AFB1 treatment in experimental animals has been reported to cause a decrease in regional brain acetylcholinesterase en‐ zymes that may affect the cognitive functions as well as memory and learning of the indi‐ vidual while chronic exposure increases adenohypophyseal acetylcholinesterase [24]. Aflatoxin causes a decrease in dopamine, serotonin and alterations in the levels of the pre‐ cursor's tyrosine and tryptophan [86-88]. Deficiencies in these neurotransmitter lead to neu‐ rological symptoms such as neurocognitive decline and alteration of sleep cycle and symptoms of brain damage like dullness, restlessness, muscle tremor, convulsions, loss of memory, epilepsy, idiocy, loss of muscle coordination, and abnormal sensations [89, 90]. AFB1 has also been reported to increase the central and peripheral nervous system Na+ /K+ - ATPase, β-glucuronidase and β-galactosidase while inhibiting the Mg2+-ATPse in experi‐ mental animals and this also is important in the normal functioning of the glutamate neurotransmitter and their NMDA receptors [24, 53, 91-93]. The liver failure makes it unable to detoxify ammonia, the product of protein and amino acid metabolism leading to hyper‐ ammonemia that may cross the blood brain barrier leading to increased synthesis of gluta‐ mate neurotransmitters hence leading to cytotoxicity of the brain cells and hence the hepatic encephalopathy [82-84]. Toxic encephalopathy was originally described in children with Reye's syndrome associated with consumption of Aflatoxin B1 and/or salicylates [78] and subsequently in cases of aflatoxicosis in canines and Chinese children were reported [94]. Aflatoxins also have been linked to Reye's syndrome that is characterized by symptoms of encephalopathy and fatty degeneration of the viscera. It is a pediatric disease characterized by cerebral edema and neuronal degeneration. Toxic encephalopathy due to aflatoxins in‐ volves multiple symptoms like loss of balance, recent memory decline, headaches, light‐ headedness, spaciness/disorientation, insomnia, loss of coordination [4, 18, 50, 82]. Aflatoxins have been reported to be associated with a Reye-like Syndrome in Thailand, New Zealand, Czechoslovakia, the United States, Malaysia, Venezuela and Europe [4, 9, 24, 50, 78]. Aflatoxins especially AFB1 have been reported to cause tumors in both the central and peripheral nervous system and several nonepithelial neurogenic tumors like the schwanno‐ mas, gliomas, meningiomas and granular cell tumors have been reported [24].

#### **4.3. Effect of aflatoxins on the gastrointestinal tract (GIT)**

ins, chemicals and drugs, trauma and infectious agents [2, 4, 6, 7, 26, 61, 76, 80, 81]. The re‐ duced level of total protein is indicative of the toxic effect of AFB1 to the liver due to the failure in synthesis of the proteins and kidney in which aflatoxins are known to impair pro‐ tein biosynthesis by forming adducts with DNA, RNA and proteins, inhibits RNA synthesis, DNA-dependent RNA polymerase activity and causes degranulation of endoplasmic reticu‐ lum [58-60]. Acute hepatic injury due to aflatoxin causes a rise in serum enzymes including aspartate aminotransferase, lactate dehydrogenase, glutamate dehyrogenase, gamma-gluta‐ myltransferase and alkaline phosphatase and bilirubin that reflect liver damage as well as other biochemical changes such as proteinura, ketonuria, glycosuria and hematuria [4, 5, 40]. The other frequently used liver enzymes are the alkaline phosphatase (ALP) and Gam‐ ma-glutamyltransferase and gamma-glutamyltranspeptidase (GGT and GGTP) that indicate obstruction to the biliary system, either within the liver or in the larger bile channels outside the liver [9, 45, 61]. The presence of jaundice and neurological disorders due to brain dam‐ age leading to hepatic encephalopathy are associated with liver failure. Chronic liver failure leads to accumulation of metabolites in circulation such as ammonia and fatty acids that eventually lead to brain damage and hence hepatic encephalopathy [40, 82]. The liver failure makes it unable to detoxify ammonia, the product of protein and amino acid metabolism leading to hyperammonemia that may cross the blood brain barrier leading to increased synthesis of glutamate neurotransmitters henceleading to cytotoxicity of the brain cells and hence the hepatic encephalopathy [82-84]. AFB1 has been reported to cause pallor discolora‐ tion of liver and enlargement of liver and kidneys, congestion of liver parenchyma, cytoplas‐ mic vaculation or fatty change of hepatocytes, necrosis of hepatocytes and newly formed bile ducts, mononuclear and heterophilic cell infiltration are reported in aflatoxin fed broiler chicks [85]. It is also reported that there is a decrease in protein content in skeletal muscle, heart, liver and kidney in aflatoxin-fed animals due to the AFB1's potent mutagenic, carcino‐ genic, teratogenic, immunosuppressive and its ability to inhibits several metabolic systems such as protein synthesis thus leading to liver, kidney and heart damage [58-60]. In chicken, the activity of serum or plasma enzymes like the sorbitol dehydrogenase, glutamic dehydro‐ genase, lactate dehydrogenase, alkaline phosphatase, acid phosphatase, aspartate amino‐ transferase and alanine aminotransferase were reported to be increased in aflatoxicated

chickens [22].

250 Aflatoxins - Recent Advances and Future Prospects

**4.2. Effect of aflatoxins on the central nervous system**

In the brain or central nervous system, the neurons have a high metabolic rate but little ca‐ pacity for anaerobic metabolism and subsequently, inadequate oxygen flow to the brain kills the neuronal brain cells within minutes. Some compounds damage neurons or neurotoxic and thus inhibit their function. Mycotoxins especially aflatoxins and its metabolites and oth‐ er products such as the reactive oxygen species (ROS) like the AFB-8,9-epoxides may inter‐ fere with the normal functioning of the nerve cells by forming DNA adducts, protein adducts, oxidative stress factors, mitochondrial directed apoptosis of the nerve cells as well as inhibiting their synthesis of protein, RNA and DNA [40, 44, 47, 50, 52, 54]. Aflatoxins also cause abnormalities in mitochondrial DNA, structure and function, including defective oxi‐ dative phosphorylation in the brain cells [29, 49, 50, 54]. The oxidative stress may result in

The gastrointestinal tract (GIT) is the main route of entry of aflatoxins as a result of con‐ sumption of aflatoxin-contaminated foods especially AFB1. It is also the main route of excre‐ tion aflatoxin metabolites from the bile. The aflatoxins, metabolites and AF-8,9-epoxides have been reported to cause intestinal tumors especially the human colon cancers like colon carcinomas and similar results have been reported in experimental animals [24]. Aflatoxins have also been reported to cause serious acute effects on the GIT [95]. Aflatoxins have been implicated as potential factors in the increased incidence of human gastrointestinal and hep‐ atic neoplasms in Africa, Philippines and China [22]. Aflatoxins have been reported to cause digestive system effects such as diarrhea, vomiting, intestinal hemorrhage, and liver ne‐ crosis and fibrosis [89]. Aflatoxins have been reported also to damage the integrity of the pancreas. In domestic animals, aflatoxins cause changes in the GIT physiology especially de‐ creased rumen motility and function in cows [24]. In birds, aflatoxins interfere with intesti‐ nal morphology, sialic acid production and apparent digestible energy [96].

**4.6. Effect of aflatoxins on the blood and blood cells**

The aflatoxins and its metabolites as well as the generated reactive oxygen species(ROS) has been reported to have a deleterious effects on the bone and blood cells as well as induction of cancers on the hemopoietic system in bone marrow and lymphoid organs where blood, blood cells and blood components are produced [52]. The blood system can be damaged by agents that affect blood cell production (bone marrow), the components of blood (platelets, red blood cells, and white blood cells), or the oxygen-carrying capacity of red blood cells or impair blood clotting and their poor growth rates. Oxidative damage by the AFB1 on human lymphocytes has been reported [100] and significant declines in both the proportion of pe‐ ripheral blood lymphocytes and in the percentages of ANAE-positive peripheral blood lym‐ phocytes (T-lymphocytes) in a dose dependent manner has been observed [101]. Aflatoxins have been linked to anemia in pregnancy [7, 102] and alterations in erythrocytes during in‐ duced chronic aflatoxicosis in rabbit also have been reported [103, 104]. Aflatoxin causes hematopietic suppression and anemia, decrease in total erythrocytes, packed-cell volume and hemoglobin [16] as well as toxicity to red blood cells [103]. Aflatoxin is known to pro‐ duce hemolytic anemia by decreasing the circulating mature erythrocytes [104]and conse‐ quently the spleen appear congested because of an unusually high concentration of inorganic iron and debris from the circulation [103, 104]. In birds, AFB1 is reported to causes hematological changes [105]. Aflatoxicosis has been reported to cause lymphocytopenia and monocytopenia and increased percentage of neutrophil counts [106]. In cattle, aflatoxins are reported to cause blood coagulation defects that may involve impairment of prothrombin, factors VII and X and possibly factor IX and similar effects are reported in dogs [5]. General‐ ly aflatoxins have been reported to depress growth and alter many aspects of humoral and

Review of the Biological and Health Effects of Aflatoxins on Body Organs and Body Systems

http://dx.doi.org/10.5772/51201

253

cellular immunity and thus affecting the hematological parameters [101, 107].

The kidney is susceptible to many toxic agents due to the high amount of blood it receives and about 20-25% of blood that flows in at rest coupled with the large amounts of circulat‐ ing toxicants that reach the kidneys [89]. The kidneys also have high oxygen and nutrient requirements because of their workload and therefore filters one-third of the blood reaching them and reabsorb 98-99% of the salt and water. Different parts of the nephrone are exposed to aflatoxins especially the AFB1 and its metabolites leading to nephrotoxicity before it is ex‐ creted in the urine [24, 58]. The aflatoxin induced reduction in protein content has been re‐ ported to be due to increased necrosis of the kidney [58-60, 90]. AFB1 has been reported to cause kidney tumors in experimental animals and a mixture of AFB and AFG was observed to cause renal and hepatic tumors in 80% of hamsters [24]. There were also renal lesions with features of megalocytosis in the proximal renal tubules. In Africa, birds exposed to AFB1 were reported to develop fatty and hemorrhagic kidney syndrome, thickening of the glomerular basement membrane, abnormal development of glomerular epithelial cells and degenerative changes in renal tubular cells, congestion and parenchyma hemorrhage [24, 85]. In other animals, there was a reduction in the glomerular filtration rate, glucose reab‐ sorption and tubular transport of electrolytes and organic anions, reduced activities of renal

**4.7. Effect of aflatoxins on the urinary system**

#### **4.4. Effect of aflatoxins on the respiratory system**

Aflatoxins have reported to have serious acute effects on the respiratory systems [95].The res‐ piratory tract is the only organ system with vital functional elements in constant and direct contact with the environment [97]. Many people working in food industries as their occupa‐ tional setting get exposed to aflatoxins especially AFB1 when they inhale aflatoxin-contaminat‐ ed dusts like during grain shelling and processing and have been reported to have a higher incidences of upper respiratory tract and lung cancers [24, 95]. In experimental animals, AFB1 was reported to induce 100% pulmonary adenomas. In the respiratory tract, aflatoxins may al‐ so be converted to active metabolites like in the nasal mucosa [23]. It is also reported that the in‐ tranasal administration of AFB1 lead to formation of tissue-bound metabolites in subtentacular cells, bowman's glands and in neuronal cells in the olfactory mucosa but there is no evidence that AFB1 may induce tumours in olfactory bulbs [98]. Epoxide hydrolase and glutathione-Stransferase (GST) are both involved in hepatic detoxification of activated AFB1 but the GST-cat‐ alyzed conjugation of glutathione to AFB1-8,9-epoxides is thought to play more important role in preventing epoxide binding to target macromolecules [23, 89, 99]. However, the low capaci‐ ty for GST-catalyzed detoxification of bio-activated AFB1 in lung may be an important factor in the susceptibility of the lung to AFB1 toxicity ([41]. Nose-only inhalation exposure of rats to AFB1 aerosols suppressed alveolar macrophage (AM). Intratracheal administration of AFB1 al‐ so suppressed the release of tumor necrosis factor-alpha from AMs and impaired systemic in‐ nate and acquired immune defenses as well as suppression of peritoneal macrophage phagocytosis and the primary splenic antibody response thus leading to suppression of respi‐ ratory tract defenses system [99].

#### **4.5. Effect of aflatoxins on the cardiovascular system, blood and blood cells**

Aflatoxins have reported to have serious acute effects on the cardiovascular systems includ‐ ing vascular fragility and hemorrhaging in tissues [58, 89, 95] as well as heart damage and teratogenic effects [59, 60]. It is reported that there is a decrease in protein content of the muscles of these tissues and organs as well as inhibition of their metabolic processes attrib‐ utable by the aflatoxin consumption of contaminated foods [59, 60].

#### **4.6. Effect of aflatoxins on the blood and blood cells**

have been reported to cause intestinal tumors especially the human colon cancers like colon carcinomas and similar results have been reported in experimental animals [24]. Aflatoxins have also been reported to cause serious acute effects on the GIT [95]. Aflatoxins have been implicated as potential factors in the increased incidence of human gastrointestinal and hep‐ atic neoplasms in Africa, Philippines and China [22]. Aflatoxins have been reported to cause digestive system effects such as diarrhea, vomiting, intestinal hemorrhage, and liver ne‐ crosis and fibrosis [89]. Aflatoxins have been reported also to damage the integrity of the pancreas. In domestic animals, aflatoxins cause changes in the GIT physiology especially de‐ creased rumen motility and function in cows [24]. In birds, aflatoxins interfere with intesti‐

Aflatoxins have reported to have serious acute effects on the respiratory systems [95].The res‐ piratory tract is the only organ system with vital functional elements in constant and direct contact with the environment [97]. Many people working in food industries as their occupa‐ tional setting get exposed to aflatoxins especially AFB1 when they inhale aflatoxin-contaminat‐ ed dusts like during grain shelling and processing and have been reported to have a higher incidences of upper respiratory tract and lung cancers [24, 95]. In experimental animals, AFB1 was reported to induce 100% pulmonary adenomas. In the respiratory tract, aflatoxins may al‐ so be converted to active metabolites like in the nasal mucosa [23]. It is also reported that the in‐ tranasal administration of AFB1 lead to formation of tissue-bound metabolites in subtentacular cells, bowman's glands and in neuronal cells in the olfactory mucosa but there is no evidence that AFB1 may induce tumours in olfactory bulbs [98]. Epoxide hydrolase and glutathione-Stransferase (GST) are both involved in hepatic detoxification of activated AFB1 but the GST-cat‐ alyzed conjugation of glutathione to AFB1-8,9-epoxides is thought to play more important role in preventing epoxide binding to target macromolecules [23, 89, 99]. However, the low capaci‐ ty for GST-catalyzed detoxification of bio-activated AFB1 in lung may be an important factor in the susceptibility of the lung to AFB1 toxicity ([41]. Nose-only inhalation exposure of rats to AFB1 aerosols suppressed alveolar macrophage (AM). Intratracheal administration of AFB1 al‐ so suppressed the release of tumor necrosis factor-alpha from AMs and impaired systemic in‐ nate and acquired immune defenses as well as suppression of peritoneal macrophage phagocytosis and the primary splenic antibody response thus leading to suppression of respi‐

nal morphology, sialic acid production and apparent digestible energy [96].

**4.5. Effect of aflatoxins on the cardiovascular system, blood and blood cells**

utable by the aflatoxin consumption of contaminated foods [59, 60].

Aflatoxins have reported to have serious acute effects on the cardiovascular systems includ‐ ing vascular fragility and hemorrhaging in tissues [58, 89, 95] as well as heart damage and teratogenic effects [59, 60]. It is reported that there is a decrease in protein content of the muscles of these tissues and organs as well as inhibition of their metabolic processes attrib‐

**4.4. Effect of aflatoxins on the respiratory system**

252 Aflatoxins - Recent Advances and Future Prospects

ratory tract defenses system [99].

The aflatoxins and its metabolites as well as the generated reactive oxygen species(ROS) has been reported to have a deleterious effects on the bone and blood cells as well as induction of cancers on the hemopoietic system in bone marrow and lymphoid organs where blood, blood cells and blood components are produced [52]. The blood system can be damaged by agents that affect blood cell production (bone marrow), the components of blood (platelets, red blood cells, and white blood cells), or the oxygen-carrying capacity of red blood cells or impair blood clotting and their poor growth rates. Oxidative damage by the AFB1 on human lymphocytes has been reported [100] and significant declines in both the proportion of pe‐ ripheral blood lymphocytes and in the percentages of ANAE-positive peripheral blood lym‐ phocytes (T-lymphocytes) in a dose dependent manner has been observed [101]. Aflatoxins have been linked to anemia in pregnancy [7, 102] and alterations in erythrocytes during in‐ duced chronic aflatoxicosis in rabbit also have been reported [103, 104]. Aflatoxin causes hematopietic suppression and anemia, decrease in total erythrocytes, packed-cell volume and hemoglobin [16] as well as toxicity to red blood cells [103]. Aflatoxin is known to pro‐ duce hemolytic anemia by decreasing the circulating mature erythrocytes [104]and conse‐ quently the spleen appear congested because of an unusually high concentration of inorganic iron and debris from the circulation [103, 104]. In birds, AFB1 is reported to causes hematological changes [105]. Aflatoxicosis has been reported to cause lymphocytopenia and monocytopenia and increased percentage of neutrophil counts [106]. In cattle, aflatoxins are reported to cause blood coagulation defects that may involve impairment of prothrombin, factors VII and X and possibly factor IX and similar effects are reported in dogs [5]. General‐ ly aflatoxins have been reported to depress growth and alter many aspects of humoral and cellular immunity and thus affecting the hematological parameters [101, 107].

#### **4.7. Effect of aflatoxins on the urinary system**

The kidney is susceptible to many toxic agents due to the high amount of blood it receives and about 20-25% of blood that flows in at rest coupled with the large amounts of circulat‐ ing toxicants that reach the kidneys [89]. The kidneys also have high oxygen and nutrient requirements because of their workload and therefore filters one-third of the blood reaching them and reabsorb 98-99% of the salt and water. Different parts of the nephrone are exposed to aflatoxins especially the AFB1 and its metabolites leading to nephrotoxicity before it is ex‐ creted in the urine [24, 58]. The aflatoxin induced reduction in protein content has been re‐ ported to be due to increased necrosis of the kidney [58-60, 90]. AFB1 has been reported to cause kidney tumors in experimental animals and a mixture of AFB and AFG was observed to cause renal and hepatic tumors in 80% of hamsters [24]. There were also renal lesions with features of megalocytosis in the proximal renal tubules. In Africa, birds exposed to AFB1 were reported to develop fatty and hemorrhagic kidney syndrome, thickening of the glomerular basement membrane, abnormal development of glomerular epithelial cells and degenerative changes in renal tubular cells, congestion and parenchyma hemorrhage [24, 85]. In other animals, there was a reduction in the glomerular filtration rate, glucose reab‐ sorption and tubular transport of electrolytes and organic anions, reduced activities of renal glutamate-oxaloacetate and pyruvate transaminases and alkaline phosphatase in rats attrib‐ uted to by the aflatoxins and their metabolites as well as the generated ROS. There was in‐ duced aggregation and loss of chromatin, mitochondrial degeneration and loss of microvilli induced by AFB1 in cultured kidney cell lines [24, 85].

ductive system by causing abortion, the birth of weak, deformed calves, reduced fertility due to reduced vitamin A levels [109]. The teratogenic effects of AFB1 were described as en‐ larged eye sockets and enlarged liver of embryos [60]. In poultry, AFB1 cause a reduction in semen volume, testes weight, spermatocrit and plasma testosterone as well as a reduction in

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Chronic consumption of aflatoxin-contaminated foods has been reported to cause immuno‐ suppression in both humans and animals worldwide [7, 89]. In human, aflatoxins affect both the cellular and humoral immune responses where they alter immunological parameters in participants with high AFB1 levels resulting in impairments in cellular immunity hence de‐ creasing the host resistance to infections [115-117]. Aflatoxin exposure has been shown to cause immune suppression, particularly in cell-mediated responses [115-117]. Chronic expo‐ sures of the individual to aflatoxins depress the phagocytic efficiency of the phagocytes and the delayed hypersensitivity reactions in birds [24]. Aflatoxins also deplete the cell popula‐ tions of the thymus; reduce the bone marrow and the red and white blood cells count, mac‐ rophage numbers and the phagocytic activity of the cells [24]. It also depresses the T-celldependent functions of splenic lymphocytes in mice. The natural killer cell function of the peripheral blood lymphocytes are also affected by aflatoxins especially AFB1 [24]. A reduc‐ tion in the leukocyte immunophenotypes in peripheral blood, CD4+ T cell proliferative re‐

reported. Children in developing countries appear to be naturally exposed to aflatoxin through their diet at levels that compromise the immune system. In general, the proportion of childhood growth stunting is directly correlated with the proportion of the population living below the national poverty line and is inversely correlated with gross domestic prod‐ uct per capita [7, 45]. As is the case with liver cancer, childhood stunting is prominent in re‐ gions such as Southeast Asia and Sub-Saharan Africa, where aflatoxin exposure through consuming contaminated food is common [7, 45]. It has been reported that the immunosup‐ pression and nutritional effects of chronic aflatoxin exposure may be linked to the high prevalence of HIV in Southern Africa [7, 74, 118, 119]. The CD4 proteins that have been weakened by aflatoxin exposure have been reported to correlate positively with HIV infec‐ tion [116]. Also high aflatoxin levels have been reported to increase risk of developing tuber‐ culosis in HIV positive individuals. Persons who are exposed to aflatoxin and are HIV positive have decreased plasma vitamin A and vitamin E in the blood, although there was no interaction detected between aflatoxin and HIV infection [120]. HIV infection is likely to increase aflatoxin exposure by two possible routes: (1) HIV infection decreases the levels of antioxidant nutrients that promote the detoxification of aflatoxin, or (2) the high degree of co-infection of HIV-infected people with hepatitis B also increases the biological exposure to aflatoxin [7, 118, 119]. Aflatoxin induce immunosuppression and increases susceptibility of toxicated birds and animals to bacterial, viral and parasitic infections [58]. It also affects the lymphoid follicles of caecum thus depleting the lymphocytes that may contribute to the ob‐

T cell cytokine profiles and monocyte phagocytic activity were

egg output [24].

sponse, CD4+

T and CD8+

**5. Effect of aflatoxins on the immune system**

#### **4.8. Effect of aflatoxins on the endocrine system**

Aflatoxin especially AFB has been reported to interfere with the functioning of the various en‐ docrine gland by disrupting the enzymes and their substrates that are responsible for the syn‐ thesis of the various hormones. Aflatoxins and their metabolites as well as the generated ROS have been reported to cause various cancers in different endocrine glands like pituitary gland, granulosa cell tumors of the ovary and adenomas and adenocarcinomas of the adrenal gland, kidneys, thyroid gland, ovaries, testes, thyroid gland, parathyroid glands and endocrine pan‐ creas [4, 90, 108]. The plasma testosterone and luteinizing hormone (LH) concentrations have been reported to reduce in aflatoxin-fed birds [90]. In laboratory animals, aflatoxin causes de‐ layed maturation of both males and females [4, 22, 90, 109]. Aflatoxicosis in white leghorn males chicken decreased feed consumption, body weight, testes weight and semen volume (Sharlin et al., 1980) and decreased plasma testosterone values [22].

#### **4.9. Effect of aflatoxins on the reproductive system**

In humans exposed to chronic aflatoxin-contaminated foods, it has been reported that high‐ er concentrations of aflatoxins occur in the semen of infertile men [3]. It is also associated with low birth weight, a risk factor for jaundice in infants as well as presence of AFM in ma‐ ternal breast milk where it can cause deleterious effect in the newborns [102]. In Nigeria, about 37% of the infertile men had aflatoxin in their blood and semen hence contributing to the incidence of infertility in Nigerians [110]. Experimental results indicate that certain agents like aflatoxins can interfere with the reproductive capabilities of sexes, causing sterili‐ ty, infertility, and abnormal sperm, low sperm count, and/or affect hormone activity in ani‐ mals. Aflatoxins have been reported to disrupt the reproductive system in both male and female animals after ingestion of aflatoxin-contaminated foods. Aflatoxins also cause patho‐ logical alterations in the form of coagulative necrosis especially in the growing and mature follicles and decrease in number and size of graffian and growing follicles with increased number of atretic follicles and small areas of degenerative changes in experimental animals [111]. AFB1 has been reported to have a deleterious effect on the reproductive capacity of laboratory and domestic female animals where they cause reductions in ovarian and uterine sizes, increases fetal resorption, implantation loss and intra-uterine death in the aflatoxin ex‐ posed female rats [111]. They also cause a reduction in the primary spermatocytes and sper‐ matids [112] and affect the morphology of the sperm cells produced [113]. Stillbirths were reported in the 15th to the 18th days of pregnancy in rats [108]. The levels of plasma testos‐ terone, plasma 5a-DHT and absolute and relative testes weights were reported in experi‐ mental animals of aflatoxin-treated males remained low in all age groups and a delay in the onset of sexual maturation during aflatoxicosis [114]. In cows, aflatoxins affected the repro‐ ductive system by causing abortion, the birth of weak, deformed calves, reduced fertility due to reduced vitamin A levels [109]. The teratogenic effects of AFB1 were described as en‐ larged eye sockets and enlarged liver of embryos [60]. In poultry, AFB1 cause a reduction in semen volume, testes weight, spermatocrit and plasma testosterone as well as a reduction in egg output [24].
