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Keywords:

  • aquatic animals;
  • biotin;
  • fish;
  • nutrition;
  • vitamin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

Biotin, a water-soluble vitamin, is essential for normal growth, development and health of all animals. In terrestrial animal nutrition, biotin has recently spurred scientific interest because of the increasing body of knowledge on biotin involvement in gene expression, cell cycle and reproduction in mammals, and recent advances in molecular biology techniques allowing a more effective estimation of biotin effects in metabolism and physiology. In contrast, this information is scarce in aquatic animal nutrition, as studies have essentially focused on the estimation of minimum biotin requirement for maximum growth and tissue storage as well as for the formulation of least-cost diet. This scarcity of information is also due to the lack of well-established indicators of biotin status in aquatic organisms. The present review is a comparative analysis of current knowledge on biotin physiology and nutritional biochemistry in terrestrial and aquatic animal nutrition. Also, general information on biotin sources, bioavailability, deficiency and requirement in mammals and fish is provided in order to plan further studies. In the future, biotin nutrition studies in aquaculture should also include haematological parameters, histopathology of the gills, liver and kidney, gonad development, gamete quality and quantity, fecundity, larvae survival and gene expression. Dietary biotin requirement levels should be estimated at every life history stage of farmed fish. The potential contribution of intestinal microflora to biotin supply in different fish species should be investigated. All this information will allow a better understanding of the essentiality of biotin in fish growth, development, reproduction and health.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

Vitamins are organic compounds that are required in small amounts ranging from micrograms to a few milligrams kg−1 diet from an exogenous source (usually the diet) for normal growth, reproduction and health (Bender 2003; Combs 2008; Lall 2010). They cause a specific deficiency disease if absent from the diet or improperly absorbed or utilized. They are unable to be synthesized by the host in sufficient amounts to meet the physiological needs of the animal and therefore must be obtained from the diet. In aquatic animal nutrition, vitamins are among the most expensive ingredients used in complete diet formulation (Gaylord et al. 1998).

Vitamins play essential roles in the organism, acting principally as cofactors for enzymes; thus, inadequate supply leads to reduced enzyme activities and in turn to both non-specific findings such as poor growth, low survival and increased susceptibility to infections and diseases (NRC 1993, 2011; Halver 2002) as well as more specific deficiency signs and symptoms (Combs 2008). Through their coenzyme functions and other properties, vitamins maintain normal metabolic functions and optimal health (Sauberlich & Machlin 1992; Bender 2003).

While the nutrition, biochemistry, cell biology and physiology of vitamins have been extensively studied in mammals (Institute of Medicine 2000; Higdon 2003; Bender 2003; Combs 2008), a smaller number of studies have been conducted in aquatic animals. Generally, vitamin nutrition studies in aquaculture focus on vitamin requirements for growth and tissue storage (Ogino et al. 1970; Poston 1976; Castledine et al. 1978; Robinson & Lovell 1978; Lovell & Buston 1984; Woodward & Frigg 1989; Gunther & Meyer-Burgdorff 1990; NRC 1993, 2011; Mæland et al. 1998; Shiau & Chin 1999; Shaik Mohamed et al. 2000; Li et al. 2010; Yossa et al. 2013a), interactions between vitamins (Hilton 1989; Sealey & Gatlin 2002; Lee & Dabrowski 2003; Yildirim-Aksoy et al. 2008; Tatina et al. 2010), interactions among vitamins and with minerals (Hilton 1989; Lim et al. 2000).

Unlike other water-soluble vitamins, information on the quantitative dietary requirement of biotin and physiological and pharmacological responses to intake of this vitamin is limited (McMahon 2002). Biotin was discovered while searching for a factor that could treat the “egg-white injury” observed in animals fed a diet containing non-denatured egg white as the sole protein source (Boas 1927). Egg white contains a biotin antagonistic factor, avidin, a heat labile glycoprotein that specifically binds biotin (Boas 1927). Biotin has been classified as one of the B-complex vitamins. Nevertheless, biotin has recently spurred scientific interest because of increasing knowledge of its metabolism and nutritional physiology and the unique tight interaction of biotin with avidin.

Biotin is well known as a coenzyme for five carboxylases which catalyse essential steps in the metabolism of carbohydrates, proteins and lipids in all animals (Dakshinamurti 1994, 2005; Bender 2003; Higdon 2003; Rodriguez-Melendez & Zempleni 2003; Combs 2008). An increasing body of evidence observed in mammals indicates that biotin also functions as a regulator of gene expression, likely via a multiprotein gene repression complex that incorporates holocarboxylase synthetase that catalyses covalent modification of specific lysine residues in histones (Ramaswamy 1999; Dakshinamurti 2003, 2005; Rodriguez-Melendez & Zempleni 2003; Bao et al. 2010). In addition, studies providing evidence that marginal biotin deficiency develops spontaneously in a substantial proportion of normal human pregnancies (Mock 2009) has recently led to renewed interest in both valid indicators of biotin status and in the effects of biotin deficiency on reproductive efficiency and outcome in mammals (Shaw & Phillips 1942; Delost & Terroine 1956; Terroine 1960; Watanabe 1983; Paulose et al. 1989; Watanabe et al. 1995; Zempleni & Mock 2000a; Dakshinamurti 2005; Cammalleri et al. 2009). However, there are few validated indicators of biotin status in fish. This is due to both the lack of fundamental studies conducted on biotin physiology and nutritional biochemistry in farmed aquatic animal species, and to technical and experimental challenges associated with collection and accurate measurement of these indicators in the aquatic environment (Zempleni & Mock 2001), although considerable progress has been made recently in terrestrial animals (Horvath et al. 2010, 2011; Stratton et al. 2011a,b). For instance, it is difficult to collect sufficient urine and faeces samples for analysis of this vitamin from fish reared in aquatic environment, while the rearing environment is not a constraint in biotin nutrition studies in terrestrial animals such as mammals.

The main goal of this review was to examine recent progress on biotin physiology and nutrition research in both terrestrial and aquatic animals, identify the gaps in knowledge and identify various biochemical indicators used to measure biotin status in mammals which can be used to undertake fundamental studies in biotin nutrition in fish. It will also allow researchers to better understand the function of biotin in growth, reproduction and health of aquatic organisms.

General properties of vitamins and biotin

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

Vitamins are organic compounds with a low molecular weight. Nicotinic acid (vitamin B3) has the smallest molecular weight (123 g mol−1), whereas vitamin B12 has the highest (1355 g mol−1) (Combs 2008). Each vitamer in a vitamin family may have a distinct biopotency; for this reason, the vitamins are generally classified on the basis of their solubility (Combs 2008) either as fat-soluble (liposoluble vitamins) or water-soluble (hydrosoluble vitamins). Vitamins A, D, E and K are classified as fat soluble. Fat-soluble vitamins can be characterized by their predominantly aromatic and aliphatic characteristics (Bender 2003; Combs 2008). Fat-soluble vitamins characteristically contain five-carbon isoprenoid units, which are derived initially from acetyl-CoA during their synthesis by prokaryotes or plants (Combs 2008). Fat-soluble vitamins may play a structural role in some cells, as they are part of cell membranes, and some of them act as hormones (Lall 2010). Thiamine, niacin, vitamin B12, folate, vitamin C, riboflavin, vitamin B6, pantothenic acid and biotin are classified as water-soluble vitamins. These vitamins are characterized by the presence of one or more polar or ionisable groups (carboxyl, keto, hydroxyl, amino or phosphate) (Bender 2003; Combs 2008). However, water-soluble vitamins are heterogeneous in both their structure and in pathways of their synthesis (Combs 2008). Water-soluble vitamins generally act as essential cofactors of specific enzymes in animals.

Biotin is the common name used to designate the compound cis-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanoic acid, which was previously known as vitamin H or coenzyme R (Combs 2008), with the chemical formula C10H16O3N2S (Halver 2002). Its structural formula is shown in Fig. 1. Biotin is a monocarboxylic acid, which is soluble in water and alcohol, but not in lipophilic organic solvents (Halver 2002). In dry form, biotin is fairly stable to heat, air and light and is destroyed by alkali and by oxidizing agents like peroxides and permanganate (Halver 2002; Combs 2008). Of the eight possible stereoisomers, only the naturally occurring (+)-isomer (called d-biotin) has biological activity (Higdon 2003; Combs 2008) and is used in animal nutrition.

image

Figure 1. The structural formula of biotin.

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Biotin sources and bioavailability

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

The information on bioavailability of most vitamins in feed ingredients is very limited. Vitamins exist as precursor compounds or coenzymes bound or complexed with other components in feed ingredients and they must be hydrolysed in the digestive tract prior to absorption. Biotin is present in many feedstuffs and important sources are egg products, yeast, liver, kidney and peanuts (Halver 2002; Higdon 2003; Combs 2008). Corn, wheat, meat and fish by-products are relatively poor sources (NRC 1982). It is generally assumed that the natural ingredients used to formulate commercial fish feeds supply sufficient biotin to satisfy the requirements of farmed aquatic animals (NRC 1993, 2011; Halver 2002); however, no systematic work has been done to determine the optimum biotin concentration and its bioavailability. The biotin contents of ingredients commonly used to formulate fish diets vary from 0.04 mg biotin kg−1 in dried casein and rice bran to 1.63 mg biotin kg−1 in dried corn distillers solubles (NRC 2011). In general, these feedstuffs contain biotin in both its free form and as covalently bound to protein (Institute of Medicine 2000; Halver 2002; Combs 2008). It has been found that the total content of biotin in various feedstuffs is less and varies substantially compared to that of other water-soluble vitamins (NRC 1993, 2011; Higdon 2003; Combs 2008).

The factors that impact biotin bioavailability are not yet well defined, because the process of intestinal degradation of protein-bound biotin and the contribution of intestinal microbes to absorbed biotin have not yet been fully elucidated (Institute of Medicine 2000). Given that the bioavailability of a nutrient is dependent on the rates, extent, and location of its release by digestion as well as on the efficiency of absorption and on the extent of intraluminal metabolism, differences in bioavailability of biotin contained in different feeds and feedstuffs are not surprising and are thought to arise mostly from differences in release from feeds and feedstuffs (Bender 2003; Combs 2008; Lall 2010). All biotin linkages to dietary protein are covalent amide bonds between the carboxyl group of the biotin side chain and ε-amino group of peptidyl lysine residues of the proteins (Bender 2003; Rodriguez-Melendez & Zempleni 2003; Combs 2008; Lall 2010). One of the products of digestion is biotinyl lysine (biotin covalently bound to lysine residues), which is referred to as biocytin. The liberation and utilization of such a bound biotin depends on both the digestion of the protein and the hydrolysis of these amide bonds (Bender 2003; Combs 2008; Lall 2010). In mammals, an average of <50% of the biotin in feedstuffs is bioavailable; all the biotin present in corn is bioavailable, but only 20–30% of that contained in most other grains, and none in wheat is bioavailable (Combs 2008). Given that biotin bioavailability data do not currently exist in aquatic organisms, no comparison can be done at the present time regarding the bioavailability of biotin from feed ingredients between warm-blooded terrestrial animals and poikilothermic aquatic animals. However, some practical measures can be taken in order to ensure an optimum utilization of dietary biotin, especially from semi-purified or purified formulations such as that used in fish nutrition studies. These measures include the protection of the diet from strong oxidizing agents, from situations that induce the oxidation of the feed ingredients, and from egg by-products that contain avidin (Lall 2000; Halver 2002).

Another important source of biotin supply to animals is the endogenous production by intestinal microflora (McMahon 2002), as some vitamins are synthesized by the intestinal microflora of the proximal colon and can be absorbed by the colon. In both rats and humans, the total faecal biotin content is higher than the quantity of dietary biotin; the excess biotin originates from enteric microbes (Combs 2008). The total biotin excretion in human urine and faeces exceeds the biotin supplied by the diet by three to six times fold, and most of this extra biotin has been attributed to bacterial synthesis (Bender 2003). A similar situation appears to be present in fish (Sugita et al. 1992; Lall 2010). An endogenous supply of vitamin has been reported for vitamin B12 (Limsuwan & Lovell 1981; Sugita et al. 1991) and biotin (Robinson & Lovell 1978) in channel catfish, and for vitamin B12, niacin, pantothenic acid, thiamine and riboflavin in carp (Kashiwada & Teshima 1966). Sugita et al. (1992) have also reported a high biotin production by the intestinal microflora and its absorption by ayu fish Plecoglossus altivelis; this species harbours biotin-producing bacteria as a major part of the microbial community, and biotin-consuming bacteria constitute only a minor part of that species’ enteric microbial community. Recently, Yossa et al. (2011b) found that intestinal microbial synthesis was a significant source of biotin in zebrafish Danio rerio, based on the observation that fish fed an antibiotic-supplemented diet (1% succinylsulfathiazole, mass/mass) exhibited reduced growth, reduced whole-body biotin content, reduced survival and impaired feed utilization. The antibiotic succinylsulfathiazole has successfully been supplemented previously in feed to suppress the intestinal microflora, and consequently to reduce the microbial biotin supply in rats (Stokstad 1954), as well as in some fish species (Tomiyama & Ohba 1967; Limsuwan & Lovell 1981; Burtle & Lovell 1989; Duncan et al. 1993; Deng et al. 2002; Shiau & Su 2005). Sugita et al. (1992) argued that if body biotin requirement was the same among all the gnotobiotic freshwater fish species, the dietary biotin requirement would be established by the balance between biotin-producing and biotin-consuming species of the intestinal microflora; in the situation of a predominance of intestinal biotin-producing bacteria, the dietary biotin requirement would be low while in the predominance of intestinal biotin-consuming bacteria this requirement will be high. This assumption of a strong contribution of intestinal microflora to biotin nutrition is supported by the observation that in experimental terrestrial animals fed diets free of biotin and cellulose, supplementation of cellulose, sorbitol or dextrin, as a substrate for bacterial fermentation, eliminated vitamin deficiency and restored the health of the animals (Couch et al. 1948; Bender 2003).

Biotin absorption, transport and storage

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

Dietary biotin absorption

During digestion, intestinal proteases hydrolyse protein complexes to release protein-bound biotin in the form of biocytin (ε-N-biotinyl lysine adduct) or in the form of short oligopeptides that contain biocytin (Mock 1996; Bender 2003). Biocytin and the biocytin-containing oligopeptides are further hydrolysed by biotinidase (a biotin amide aminohydrolase) that is present in pancreatic juice and intestinal mucosal secretions, releasing biotin (Mock 1996; Bender 2003; Combs 2008).

The mechanism of enteric biotin absorption was recently investigated (Said 2009, 2011). At physiological pH, the carboxylate group of biotin is negatively charged. Thus, biotin is at least moderately water-soluble and requires a transporter to cross cell membranes. Biotin transport must occur across two structurally and functionally different membrane domains of human intestinal epithelial cells: the brush border (apical) membrane that faces the intestinal lumen and the basolateral membrane that faces the interstitium in contact with blood that perfuses the intestine. Although biocytin is not absorbed to any significant extent (Bender 2003), free biotin in physiological concentrations is readily transported across the apical membrane by a saturable, Na+-dependent, carrier-mediated mechanism by a specific transporter – sodium-dependent multi-vitamin transporter (SMVT). The SMVT also mediates the uptake of lipoic acid and pantothenic acid by the cell, and biotin uptake can be competitively inhibited by either pantothenic or lipoic acids (Said 2009, 2011). In the intestine, the uptake of biotin by the cells can also be inhibited by the phosphorylation of the SMVT, which involves the activation of protein kinase C, and also by the presence of biocytin and dethiobiotin (Said 2009, 2011). SMVT is inhibited by certain anticonvulsant drugs and by chronic exposure to ethanol in humans (Subramanya et al. 2011). Biotin transport across the basolateral membrane is also a carrier-mediated mechanism. However, this carrier is Na+-independent, electrogenic and cannot accumulate biotin against a concentration gradient. At high luminal concentrations, free biotin is also absorbed through a non-saturable, simple diffusion mechanism that likely involves the paracellular pathway and so called tight junctions.

Significant absorption of biotin occurs in the proximal colon (Said et al. 1998), which emphasizes the potential contribution of the intestinal microflora to biotin nutrition in animals in general (Bender 2003), and in humans (Institute of Medicine 2000), as well as in some freshwater fish species (Sugita et al. 1992) in particular.

Biotin transport and storage

In mammals, biotin concentrations in plasma are small relative to other water-soluble vitamins. Most biotin in plasma is free and dissolved in the aqueous phase of plasma. However, approximately 7% is reversibly bound to plasma protein, and approximately 12% is covalently bound to plasma protein (Mock & Malik 1992). The binding to human serum albumin likely accounts for reversible binding. Biotinidase has been proposed as a biotin-binding protein or biotin-carrier protein for transport into cells. Some studies suggest that a major part of the biotin that circulates in the bloodstream is specifically bound to biotinidase (Bender 2003) (Wolf et al. 1985; Institute of Medicine 2000; Bender 2003; Combs 2008). Biotinidase exhibits two specific affinity binding sites for biotin and therefore may contribute to biotin transport and entry into cells (Wolf et al. 1985; Institute of Medicine 2000; Bender 2003; Combs 2008).

A biotin-binding plasma glycoprotein has been observed in pregnant rats. Although the importance of protein binding in the transport of biotin from the intestine to the peripheral tissues is not yet clear, the immunoneutralization of this protein led to decreased transport of biotin to a foetus and early death of the embryo (Mock 2005). SMVT is widely expressed in human tissues. Studies by Said and co-workers (Said et al. 1998; Said 2009, 2011; Subramanya et al. 2011) provide strong evidence that biotin uptake by liver (and likely many other somatic tissues) occurs via SMVT. Metabolic trapping (e.g. biotin bound covalently to intracellular proteins) is also important. Zempleni and co-workers (Daberkow et al. 2003) have provided evidence in favour of monocarboxylate transporter 1 (MCT1) as the lymphocyte biotin transporter. MCT1 may also be responsible for biotin transport in keratinocytes (Ramaswamy 1999; Bender 2003; Combs 2008).

The repartition of biotin in the cell is proportional to the presence of its dependent carboxylases; therefore, the majority of the biotin content of a cell is distributed in the cytoplasm and the mitochondria, which are, respectively, the location of acetyl-CoA carboxylase 1 (ACC1) and the location of the rest of the biotin-dependent carboxylases. Less than 1% of biotin is located in the nucleus, probably primarily attached to histones or the associated multiprotein complexes (Combs 2008). Significant biotin storage has been found to occur in the liver. The liver biotin content varies significantly among different species and among individuals of the same species with varying biotin status in terrestrial (Combs 2008) and aquatic (Gunther & Meyer-Burgdorff 1990; Mæland et al. 1998; Shiau & Chin 1998) animals.

Although information on precise mechanisms for biotin absorption, transport and storage in aquatic animals is currently scarce, it is believed that these mechanisms are similar to those observed in terrestrial animals as presented above, because the same enzymes and vitamin transporters exist in both animal groups. Nevertheless, further comparative studies conducted in this regard would be informative.

Biotin metabolism and metabolic function

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

Biotin metabolism

The attachment of unbound biotin to each of its five apoenzymes is at a consensus biotinylation amino acid sequence (-Ala-Met-biotinyl-Lys-Met-). This reaction is catalysed by holocarboxylase synthetase (Fig. 2) (Rodriguez-Melendez & Zempleni 2003; Dakshinamurti 2005; Combs 2008). The biotin-containing holoenzymes are eventually recycled or degraded to biocytin; under the action of biotinidase, the biotinyl lysine bond is cleaved to produce unbound biotin, which is thereafter re-attached to one of its apoenzymes or catabolized to an inactive form (Rodriguez-Melendez & Zempleni 2003; Dakshinamurti 2005; Combs 2008).

image

Figure 2. Metabolism and recycling of biotin [adapted from Bender (2003) and Combs (2008)].

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During the catabolism of biotin, the majority of biotin is degraded to produce bisnorbiotin via β-oxidation (Fig. 2) (Bender 2003; Rodriguez-Melendez & Zempleni 2003; Combs 2008); a portion of biotin sulfoxide is further β-oxidized to tetranorbiotin. A small portion of both biotin and bisnorbiotin is degraded by sulphur-oxidation to produce biotin D- and L-sulphoxide in the microsomes; a portion of biotin sulfoxide is further oxidized to sulphone, while keeping intact the ureido ring system (Bender 2003; Combs 2008). In humans, it has been found that about half of the biotin is catabolized to bisnorbiotin and biotin sulfoxide (Mock 2007); that the molar ratios of biotin, bisnorbiotin and biotin sulfoxide are about 3:2:1 both in the urine and the plasma (Mock 1996); and that at normal dietary biotin intake, almost 30% of biotin is excreted intact, and 50% to 60% is excreted in the form of bisnorbiotin and bisnorbiotin methyl ketone, while sulphoxides and biotin sulphone represent the remaining portions (Zempleni & Mock 1999).

Metabolic functions of biotin

Biotin serves as a covalently bound coenzyme for five carboxylases: acetyl-CoA carboxylase 1 and 2 (E.C. 6.4.1.2), pyruvate carboxylase (E.C. 6.4.1.1), propionyl-CoA carboxylase (E.C. 6.4.1.3); and 3-methylcrotonyl-CoA carboxylase (E.C. 6.4.1.4) (Dakshinamurti 1994, 2005; Bender 2003; Higdon 2003; Rodriguez-Melendez & Zempleni 2003; Combs 2008; Lall 2010). Through this attachment to its specific carboxylases, biotin is essential in the transfer of CO2 in several steps of intermediary metabolism (Rodriguez-Melendez & Zempleni 2003; Combs 2008; Lall 2010). Pyruvate carboxylase, which is found in the mitochondria, catalyses the production of oxaloacetate from pyruvate in the citric acid cycle, through an anapleurotic reaction. Because oxaloacetate can be converted in the gluconeogenic tissues to phosphoenolpyruvate and then onto glucose, pyruvate carboxylase is an essential enzyme for gluconeogenesis from amino acids (Higdon 2003; Dakshinamurti 2005; Combs 2008; Lall 2010). Biotin deficiency may therefore lead to fasting hypoglycaemia and ketosis (Higdon 2003; Dakshinamurti 2005; Combs 2008) and causes fatty liver kidney syndrome of the chicken; this disease involves fatal hypoglycaemia caused by failure of gluconeogenesis.

Both isoenzymes of acetyl CoA carboxylase (ACC-1 and ACC-2) catalyse the incorporation of bicarbonate into acetyl CoA to form malonyl CoA, but ACC-1 and ACC-2 have two very different roles in cellular metabolism; one controls fatty acid synthesis, and the other controls fatty acid oxidation (Higdon 2003; Dakshinamurti 2005; Combs 2008). ACC-1 is located in the cytosol and produces malonyl CoA; because availability of malonyl CoA is rate limiting, activity of ACC-1 controls fatty acid synthesis (elongation) and is tightly regulated in a sophisticated fashion. Cytosolic ACC-1 exists as a very large polymer with a molecular mass in the millions of daltons and is inactivated by dissociation into its protomer units. Citrate activates ACC-1 by increasing polymerization. The CoA itself activates ACC-1 by lowering the Km for acetyl CoA. The ACC-1 is inhibited by the products of fatty acid synthesis, the long-chain acyl CoAs, which also act to depolymerize the enzyme. In addition, ACC-1 activity is regulated by covalent modification (phosphorylation) in response to the hormones insulin and glucagon. A high insulin-to-glucagon ratio typical of the immediate postprandial state with increased blood glucose level favours the dephosphorylation of ACC-1 to an active form, whereas a low insulin-to-glucagon ratio (typical of fasting) favours the phosphorylation to the inactive form. The amount of ACC-1 protein also responds to changes in dietary and hormonal conditions. ACC-2 is located on the outer mitochondrial membrane and regulates the availability of fatty acids for oxidation through the inhibition of carnitine palmitoyltransferase I by malonyl CoA. Carnitine palmitoyltransferase I catalyses the rate limiting transfer of the fatty acid from CoA to carnitine; the fatty acyl carnitine is transported into the mitochondrial matrix converted back to the CoA derivative and oxidized.

Propionyl-CoA carboxylase, which is found in the mitochondria, catalyses metabolism of the propionyl CoA that arises from the metabolism of the branched-chain amino acids, methionine and threonine, and from the ruminal and gastrointestinal microflora to methylmalonyl-CoA (Higdon 2003; Dakshinamurti 2005; Combs 2008; Lall 2010). Inborn deficiency of propionyl-CoA carboxylase causes propionic acidemia, a potentially fatal metabolic condition associated with severe ketosis and acidosis (Higdon 2003; Dakshinamurti 2005; Combs 2008). The metabolic disturbances reported in association with biotin deficiency are similar but characteristically less severe.

Methylcrotonyl-CoA carboxylase, which is found in the mitochondria, catalyses the degradation of the essential ketogenic amino acid, leucine (Higdon 2003; Dakshinamurti 2005; Combs 2008). The lack of the activity of this carboxylase, due to biotin deficiency, leads to an alternative metabolism to 3-hydroxyisovaleryl carnitine and 3-hydroxyisovaleric acid. These compounds are excreted in human urine (Mock & Mock 1992; Mock et al. 1997; Stratton et al. 2011b).

In terrestrial animals, each biotin-dependent carboxylase catalyses reactions through a unique “two-site ping-pong mechanism” during which a part of the whole reaction occurs at each sub-site of the enzyme (Bender 2003; Combs 2008). The primary step, the biotin carboxylase, takes place at the carboxylase sub-site, and it is characterized by an enzymatic reaction in which the bicarbonate/ATP system supplies the carboxyl for biotin carboxylation to carboxybiotin (Bender 2003; Combs 2008). The subsequent reaction, the carboxyl transferase, takes place at the carboxyl transferase subsite, and it is characterized by the transfer of the carboxyl group from the carboxybiotin produced in the first step to the acceptor substrate (Bender 2003; Combs 2008).

Unlike terrestrial animals, the mechanisms through which biotin is metabolized and exerts its metabolic function have not been specifically studied in fish. Nonetheless, the current knowledge on biotin nutrition suggests that biotin is metabolized and acts in similar manner in all the animals (Bender 2003; Mock 2007; Combs 2008), including aquatic animals, possibly in varying degrees depending on species-specific metabolic rate.

In addition to its roles in intermediary metabolism, biotin has been recognized to be involved in three non-coenzyme functions, especially in the regulation of gene expression (Bender 2003; Rodriguez-Melendez & Zempleni 2003; Dakshinamurti 2005; Combs 2008), in the regulation of the cell cycle (Bender 2003; Dakshinamurti 2005; Combs 2008), and in reproduction (Terroine 1960; Paulose et al. 1989; Cravens et al. 1944; Couch et al. 1948; Báez-Saldaña et al. 2009; Landenberger et al. 2004; Dakshinamurti 2005; Cammalleri et al. 2009).

Biotin in molecular biology

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

A potential role for biotin in regulation of mammalian gene expression was first offered in 1968, along with the observation that the expression of ornithine transcarbamylase and glucokinase were reduced by about one half in biotin-deficient rats (Dakshinamurti & Cheah-Tan 1968). Although a role for biotin in gene expression is well established, the molecular mechanisms of biotin metabolism remain to be elucidated (Zempleni & Mock 2000a; Rodriguez-Melendez & Zempleni 2003; Dakshinamurti 2005). It has been found that biotin affects the expression of about 2000 genes in humans (Combs 2008) and the expression of biotin-dependent carboxylases in fish (Yossa et al. 2011a; Sarker et al. 2012).

Several investigators have reviewed the cell signals and transcription factors involved in the mechanisms through which biotin regulates gene expression (Rodriguez-Melendez & Zempleni 2003; Dakshinamurti 2005; Zempleni 2007). Rodriguez-Melendez and Zempleni (2003) have also classified the genes regulated by biotin into two categories, genes that are affected by biotin at the transcriptional level and those that are affected at the post-transcriptional level. The reader is referred to these review articles for detailed information on the action of biotin on gene expression in mammals.

In fish, it has recently been reported for the first time that the unavailability of dietary biotin has an effect on the expression of biotin-dependent genes (Yossa et al. 2011b; Sarker et al. 2012). In zebrafish fed experimental diets containing avidin (≥ 60 times excess avidin than the dietary biotin requirement level), the steady-state levels of acetyl CoA carboxylase-A (acca) transcripts in the liver decreased compared to that of the fish fed the biotin-sufficient diet (Yossa et al. 2011b). In contrast, the levels of hepatic propionyl CoA carboxylase (pcc), pyruvate carboxylase (pc) and acca transcripts were higher in tilapia fed diets containing higher avidin levels (Sarker et al. 2012). Therefore, although evidence is accumulating that expression of genes encoding biotin-dependent carboxylases plays an important role in biotin metabolism in mammals (Dakshinamurti 2003, 2005; Rodriguez-Melendez & Zempleni 2003; Ferreira & Weiss 2007), this phenomenon is not yet well understood in fish (Sarker et al. 2012). Additional studies are needed to better explain the molecular mechanisms involved in the expression of biotin-dependent genes. A first step in this regard could be to conduct studies on the effects of graded dietary biotin level and different biotin status on the expression of genes encoding the five biotin-dependent carboxylases in selected aquaculture species such as Atlantic salmon (Salmo salar), rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio), African catfish (Clarias gariepinus), channel catfish (Ictalurus punctatus), Asian catfish (Pagasius hypophthalmus), European sea bass (Dicentrarchus labrax), sea bream (Dentex dentex) and prawn (Penaeus monodon).

Biotin in cell cycle and reproduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

When mammalian cells were cultured in a biotin-deficient medium, the cell cycle arrested at the G1 phase, suggesting that biotin is essential for cell proliferation (Bender 2003; Dakshinamurti 2005; Combs 2008). Two additional observations support a role for biotin in the regulation of cell cycle. First, it has been noted that an increase in mitogenic activity involves an increased biotin uptake; consequently, an elevated expression of β-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase, holocarboxylase synthetase was noted, demonstrating that the more biotin uptake, the more carboxylation processes (Bender 2003). Second, the biotinylation of histones was higher in cells showing an elevated mitogenic activity than in quiescent cells, suggesting that biotin plays an important role in the regulation of the cell cycle (Zempleni & Mock 2000b; Zempleni et al. 2001; Bender 2003; Combs 2008).

Biotin may also be involved in animal reproduction (Shaw & Phillips 1942; Delost & Terroine 1956; Terroine 1960; Watanabe 1983; Paulose et al. 1989; Watanabe et al. 1995; Zempleni & Mock 2000a; Dakshinamurti 2005; Cammalleri et al. 2009). However, no study has elucidated the exact mechanism(s) through which biotin plays a role in animal reproduction. There are several potential mechanisms to consider in this area. In mammals, biotin deficiency affects spermatogenesis, including both delayed spermatogenesis and reduced sperm density (Terroine 1960; Dakshinamurti 2005; Cammalleri et al. 2009). Shaw and Phillips (1942), and Delost and Terroine (1956) reported decreased size and weight of testes in biotin-deficient rats. The effect of biotin status on spermatogenesis may be mediated through reduced production of testosterone; significantly lower levels of testosterone were observed in biotin-deficient than in biotin-sufficient rats (Paulose et al. 1989). Biotin may play a key role in the production of unidentified local testicular factors, which are needed, along with testosterone and follicle-stimulating hormone, for an effective communication among the somatic testicular cells, the leydig, sertoli and peri-tubular cells (Paulose et al. 1989; Dakshinamurti 2005). A third potential mechanism is suggested by observations in chickens and turkeys; biotin deficiency causes impaired embryonic development and survival, as well as low hatchability of the eggs (Cravens et al. 1944; Couch et al. 1948). Moreover, Báez-Saldaña et al. (2009) reported that biotin deficiency negatively affected the reproductive system in female mice; these findings are consistent with the reported decrease in fertility of biotin-deficient female fruit flies (Landenberger et al. 2004).

Nevertheless, little is known about the effect of biotin on fish reproduction. Recently, Yossa et al. (2013b) found lower gonado-somatic index, sperm density, sperm motility and lower sperm viability in biotin-deficient zebrafish. In addition, in the presence of a biotin-sufficient male zebrafish, the biotin-sufficient female spawned 12 times more eggs than the biotin-deficient female, while in the presence of the biotin-deficient males, both biotin-deficient and biotin-sufficient females spawned a substantial lower number of eggs, although biotin-sufficient females still produced 5 times more eggs than the biotin-deficient females (Yossa et al. 2013b). This result suggests that the spawning efficiency of the female zebrafish is influenced by the fitness or biotin status of the male which courts the female for spawning (Yossa et al. 2013b). Moreover, a higher percentage of visually fertilized eggs was obtained with the biotin-sufficient male zebrafish than the biotin-deficient ones, while a higher hatching rate of eggs and larvae survival at 7-day-post-fertilization was obtained with fertilized eggs produced by biotin-sufficient females than biotin-deficient ones (Yossa et al. 2013b). To the best of our knowledge, this study for the first time provides evidences of the importance of dietary biotin in fish reproduction, as the biotin status of the male has been demonstrated to be of high importance for successful breeding in zebrafish, because it significantly impacted the reproductive performance of the female. A study of the possible impact of biotin deficiency on spermatogenesis, vitellogenesis, the development of sex organs and the production of sex hormones would provide basic information to understand the precise effect of biotin on animal reproduction.

Biotin requirement

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

The quantitative nutrient requirement can be defined as the minimum amount of a specific nutrient that is required in the diet for normal growth, development and health of an animal (NRC 1993, 2011; Kaushik 2000). Therefore, a precise determination of a nutrient requirement is important for cost-effective feed formulation. Several approaches have been developed to assess the nutrient requirements of other animals, and have been well adapted to fish. Recently, the NRC (2011) reviewed in detail the basic concept and methodology for accurate estimation of nutrient requirements of fish and shrimp. The quantitative biotin requirement is difficult to establish because it is synthesized by microorganisms in the intestinal tract of several terrestrial animals and fish, and there is a large variability in the biotin content and bioavailability in feed ingredients.

In aquatic animals, the dietary vitamin requirements are generally quantified on the basis of production parameters such as growth performance, tissue storage levels, specific vitamin-dependent enzyme activities and stress or immune responses (NRC 1993, 2011). These parameters are used either separately or in combination with other parameters. Data are analysed either by a non-linear/polynomial regression model (Zeitoun et al. 1976; NRC 2011), linear/broken-line regression model (Robbins et al. 1979, 2006; NRC 2011), factorial model or bioenergetics modelling. In polynomial regression, the value that corresponds to maximal response, estimated by quadratic regression, describes the best dose of dietary nutrient (nutrient requirement level); beyond this dose, the response is depressed (Zeitoun et al. 1976; Shaik Mohamed et al. 2000; NRC 2011). The broken-line analysis is best applied when the data do not follow a quadratic regression, but rather a cubic regression. In this case, the intersection between the two linear lines generated by the broken-line analysis is the nutrient level that produces the maximum response in the animal (Robbins et al. 1979, 2006). The factorial model is based on “the determination of the bioavailability of the nutrient within the feed, availability of the nutrient from the water, the requirement for new tissue synthesis, and endogenous loss” (NRC 2011).

Using a dose–response method, the dietary biotin requirements have been evaluated for maximum growth of several fish species (Table 1). Methodological problems such as leaching, the range of supplemented biotin in the diets and the mathematical model used to analyse the data have been suggested in order to explain the high biotin requirement in fish (Shiau & Chin 1999; Shaik Mohamed 2001), while potential contribution of the biotin-producing intestinal microflora of the fish has been suspected for the low biotin requirements (Sugita et al. 1992; Shaik Mohamed 2001). Furthermore, the type of diet (purified, semi-purified or practical) and the response criteria used in biotin requirement studies in aquaculture (Table 1) likely have effects on the discrepancy in biotin requirement of different fish species, given that it is well known that the type diet affects the development of gut microbiota and that the intestinal microflora may produce and supply biotin in some fish species (Sugita et al. 1992). No dietary biotin requirement (and bioavailability) study in fish has considered the host's contribution of intestinal microflora, which would be important for an accurate quantification of the portion of the dietary vitamin that is effectively used by the farmed animal (Bender 2003).

Table 1. The d-biotin requirements for growing fish determined with chemically defined diets in a controlled environment
SpeciesRequirementaDiet typeResponseReferences
  1. WG, weight gain; MLS, maximum liver storage; LPC, liver/hepatopancreas pyruvate carboxylase activity; SS, swimming stamina; ACC, liver/hepatopancreas acetyl-CoA carboxylase activity; PER, protein efficiency ratio; FER, feed efficiency ratio; B, body biotin content; WMPC, white muscle pyruvate carboxylase activity; S, Survival.

  2. a

    Requirement expressed as mg of d-biotin per kg of as-is diet.

Brook trout (Salvelinus fontinalis)0.4PracticalMLSPhillips and Brockway (1947)
Brown trout (Salmo trutta)0.7PracticalMLSPhillips and Brockway (1947)
Rainbow trout (Oncorhynchus mykiss)0.4PracticalMLSPhillips and Brockway (1947)
Rainbow trout (O. mykiss)0.05–0.25Semi-purifiedMLSMcLaren et al. (1947)
Rainbow trout (O. mykiss)≤0.25PurifiedWG, ACCCastledine et al. (1978)
Rainbow trout (O. mykiss)≤0.5PracticalWG, ACCCastledine et al. (1978)
Rainbow trout (O. mykiss)0.08PurifiedWG, MLSWoodward and Frigg (1989)
Rainbow trout (O. mykiss)0.05PurifiedACC, LPCWoodward and Frigg (1989)
Rainbow trout (O. mykiss)0.14PurifiedWMPCWoodward and Frigg (1989)
Lake trout (Salvelinus namaycush)≤0.1Semi-purifiedWG, SSPoston (1976)
Atlantic salmon (Salmo salar)≤0.3PracticalWG, MLS, LPCMæland et al. (1998)
Yellowtail (Seriola quinqueradiata)0.67–1.34PurifiedMLSShimeno (1991)
Common carp (Cyprinus carpio)1PurifiedWG, MLSOgino et al. (1970)
Common carp (C. carpio)1.0PurifiedWGGunther and Meyer-Burgdorff (1990)
Common carp (C. carpio)2.0–2.5PurifiedMLSGunther and Meyer-Burgdorff (1990)
Channel catfish (Ictalurus punctatus)≤1PurifiedWG, LPCLovell and Buston (1984)
Channel catfish (I. Punctatus)≤0.33PracticalWG, LPCLovell and Buston (1984)
Hybrid tilapia (Oreochromis niloticus x O. aureus)0.06PurifiedWGShiau and Chin (1999)
Tiger puffer (Takifugu rubripes)≤1PurifiedWGKato et al. (1994)
Shrimp (Penaeus monodon): juvenile2.0–2.4PurifiedWG, PERShiau and Chin (1998)
Shrimp (P. monodon): juvenile3.0–10.0PurifiedACC, LPCShiau and Chin (1998)
Shrimp (P. japonicus): larvae>4Kanazawa (1985)
Pacific salmon (Oncorhynchus spp.)1–1.5Halver (1972)
Atlantic salmon (Salmo salar): fry0.3PracticalWG, S, LPCMæland et al. (1998)
Catfish (Clarias batrachus): juvenile2.49Semi-purifiedWGShaik Mohamed et al. (2000)
Catfish (Clarias batrachus)2.54Semi-purifiedFERShaik Mohamed et al. (2000)
Catfish (Clarias batrachus)2.52Semi-purifiedPERShaik Mohamed et al. (2000)
Indian catfish (Heteropneustes fossilis): juveniles0.25Semi-purifiedWG, B, LPC, AACShaik Mohamed (2001)
Japanese seabass (Lateolabrax japonicas)0.046PurifiedWGLi et al. (2010)
Zebrafish (Danio rerio)0.51PurifiedWGYossa et al. (2013a)

Biotin deficiency and toxicity

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

Vitamin deficiency refers to a shortage in the supply of a vitamin to an organism in relation to the dietary requirement (hypovitaminosis) or a total absence of the vitamin in the diet supplied to that organism (avitaminosis) (Halver 2002; Combs 2008). For each vitamin, the findings of vitamin deficiencies share some characteristics and yet manifest some fairly specific signs and/or symptoms. The findings of deficiency are the result of many biochemical changes and the resulting physiological and functional disturbances (Lall 2000; Bender 2003; Combs 2008). According to Halver (2002), vitamin deficiency in fish was first reported in 1941, based on the demonstration that thiamine as well as dried brewer's yeast alleviated paralysis and restored the health of rainbow trout (Oncorhynchus mykiss).

Biotin deficiency is rare in farmed animals because biotin is found in a variety of feedstuffs used in animal feeds and the intestinal microflora may also release biotin in an absorbable form at the site of absorption (Combs 2008). However, biotin deficiency can be a problem in intensive farming of poultry (Bender 2003) and fish (Halver 2002). Generally, biotin deficiency is linked to either voluntary or inadvertent intake of an antinutritional factor such as avidin, or the consumption of an antibiotic-supplemented diet containing a marginal level of biotin (Combs 2008; Lall 2010; Yossa et al. 2011a,b, 2013b; Sarker et al. 2012).

Avidin is produced by the goblet cells in the epithelium of the oviduct of animals such as birds, reptiles and amphibians and is thereafter transferred to their egg white where it constitutes about 0.05% of the total protein (Bender 2003; Higdon 2003; Combs 2008). From an evolutionary standpoint, avidin probably serves as a bacteriostatic in egg white; consistent with this hypothesis is the observation that avidin is resistant to a broad range of bacterial proteases in both the free and biotin-bound form (Bender 2003; Combs 2008). The avidin molecule contains four subunits, each containing 128-amino acids which binds a molecule of biotin. The bond between biotin and avidin is the strongest non-covalent bond found in nature, with a dissociation constant of 10−15 M (Bender 2003; Kuramitz et al. 2003; Combs 2008). Native (undenatured) avidin in both the free and biotin-bound form is not sensitive to digestive proteases (Combs 2008) and therefore ingested avidin binds to dietary biotin (and probably any biotin from intestinal microbes) and prevents the intestinal absorption of biotin (Dakshinamurti 1994; Higdon 2003; Combs 2008; Lall 2010). The biotin–avidin complex is stable in a large pH range (Combs 2008), but heat (≥100°C) denatures avidin rendering it susceptible to digestive proteases and thereby unable to interfere with biotin absorption (Mock 1997; Halver 2002; Combs 2008). In animal nutrition, it is therefore advised to avoid feeding uncooked raw material containing egg white (NRC 1993, 2011; Halver 2002; Higdon 2003). Pure avidin isolated from eggs and dried egg white have been used as dietary supplements to induce an experimental biotin deficiency in cats, hamsters, pigs, rats and humans as well as in several fish species (Poston 1976; Castledine et al. 1978; Lovell & Buston 1984; White et al. 1992; Mæland et al. 1998; Lall 2010; Yossa et al. 2011a,b, 2013b; Sarker et al. 2012).

Stages of biotin deficiency

In mammals, non-specific findings such as anorexia, weight loss, malaise, insomnia and hyperirritability are the final results of the myriad processes that follow a reduction in the concentration of the metabolically active form of the vitamin in cells and tissues (Institute of Medicine 2000; Higdon 2003; Bender 2003; Combs 2008). The stages of vitamin deficiency have not yet been precisely elucidated in fish, but the process is gradual, typically requiring several months (Lall 2010). However, it is likely the pathogenesis in fish recapitulates the well-studied chain of events observed in mammals (Combs 2008). Vitamin deficiency in mammals begins with a reduction in vitamin stores in the body, accompanied by changes in vitamin concentration (marginal or subclinical signs), followed by observable deficiency signs, and finally morphological changes (e.g. findings on physical examination). During marginal deficiencies of each vitamin, there is a depletion in vitamin at the cellular level accompanied by metabolic disturbances, not yet observable abnormalities in function or morphology of the organism (Combs 2008). At this stage, detection of vitamin insufficiency is done using biochemical indicators such as the activities of the vitamin-dependent enzymes or the expression of the genes that are dependent to this vitamin (Combs 2008; Yossa et al. 2011a,b, 2013b; Sarker et al. 2012). Once detected, a vitamin supplementation can routinely restore normal health (Combs 2008). For all species, the earlier the diagnosis of vitamin deficiency the more effective the treatment is to control the nutritional deficiency diseases. If the marginal deficiency is not recognized and corrected, the progressive decline of vitamin status leads to gross deficiency signs, which are the results of the impairment of cellular metabolic processes specific to that vitamin (Lall 2010). Thereafter, functional and morphological changes appear in an organism (NRC 1993, 2011; Combs 2008; Lall 2000, 2010). This progressive decline of vitamin status could be associated with many causes such as abiotic and biotic factors. The abiotic factors include environmental conditions (e.g. water temperature), low content of the vitamin in feed, inadequate feed formulation or processing, prolonged feed storage, improper feeding and the presence of food contaminants or antinutritional factors in the diet or in the digestive tract of an organism (Lall 2000, 2010; Combs 2008). The biotic factors include physiological stresses, low feed intake, drug-induced anorexia, impaired digestion, impaired absorption, metabolic defects, increased metabolic demand due to infection, disease or egg production and excessive loss of vitamin (Lall 2000, 2010; Combs 2008).

Manifestation of biotin deficiency

The manifestation of vitamin deficiency follows pathogenic pathways that are shared by many other metabolic aberrations in an animal. Hence, the findings are not usually pathognomonic (Halver 2002; Combs 2008). In addition, every tissue or organ of an organism can be affected by a vitamin deficiency, although to a varying degree (Combs 2008), because of different rates of depletion and levels at which depletion impairs critical functions (Lall 2010). Thus, an optimal diagnosis of a vitamin deficiency should be based both on various findings such as zootechnical, haematological, biochemical, immunological and molecular impairments (Sauberlich & Machlin 1992).

The manifestation of biotin deficiency is highly variable among animal species, and fish species in particular (Combs 2008; Cammalleri et al. 2009). Signs of biotin deficiency that have been generally observed in fish include abnormal swimming, hyperirritability, reduced growth, increased mortality, abnormalities in skin, intestine, kidney, liver and gill tissues, lesions of the colon, reduced food consumption and utilization, neurological disorder, muscle atrophy and changes in skin colouration (Ogino et al. 1970; Poston 1976; Castledine et al. 1978; Woodward & Frigg 1989; Robinson & Lovell 1978; Lovell & Buston 1984; Gunther & Meyer-Burgdorff 1990; Mæland et al. 1998; Shiau & Chin 1998, 1999; Shaik Mohamed et al. 2000; Shaik Mohamed 2001; Halver 2002; Li et al. 2010; Yossa et al. 2011a,b, 2013a,b; NRC 2011). Reduced activity of biotin-dependent enzymes and an accumulation of hepatic glycogen are also well-documented signs of biotin deficiency in fish (Shiau & Chin 1998, 1999; Mæland et al. 1998; Shaik Mohamed et al. 2000, Shaik Mohamed 2001; Halver 2002; Li et al. 2010). It has been generally accepted that the activities of liver pyruvate carboxylase and acetyl CoA carboxylase are the best indicators of the biotin status in fish, as these activities are reduced in biotin-deficient individuals (Arinze & Mistry 1971; Robinson & Lovell 1978; Lovell & Buston 1984; Mæland et al. 1998; Shiau & Chin 1998, 1999; Shaik Mohamed et al. 2000; Shaik Mohamed 2001; Halver 2002; Li et al. 2010). It is also argued that the whole-body biotin content may reflect the vitamin status of the fish (Shiau & Chin 1999; Yossa et al. 2011a,b, 2013a,b). However, the whole-body biotin measurement includes biotin that might be produced by intestinal microflora which might be found in fish gut, as well as bound-biotin which is not readily bioavailable. Because of these methodological biases, the use of whole-body biotin content as an indicator of the biotin status is questionable. The removal of the gut, could allow a better estimation of the “body” biotin content.

Recently, biotin was also found to affect the expression of genes coding for some biotin-dependent carboxylase in a few fish species (Yossa et al. 2011a; Sarker et al. 2012).

Biotin toxicity

Vitamins are supplemented in diets to prevent deficiency signs without causing any adverse effects or toxicity, which is often referred to as vitamin tolerance or upper safe levels. Maximum tolerable levels of vitamins for animals have been published (NRC 1987). The supply of excess quantity of a specific vitamin to an animal may cause a disease, which is referred to as hypervitaminosis. Hypervitaminosis of water-soluble vitamins including biotin is rare. Studies conducted on poultry and swine indicate that they can tolerate 4 to 10 times their requirement for this vitamin (NRC 1987).

Hypervitaminosis has been reported for fat-soluble vitamins such as vitamins A and D (Hilton 1983). High dietary intakes of vitamin A may cause toxic effects in certain fish (Atlantic salmon, Japanese flounder, Paralichthys olivaceus, tilapia, Oreochromis niloticus) and the main toxic effects are associated with bone malformation (Dedi et al. 1995, 1997; Ørnsrud et al. 2002, 2013; Saleh et al. 1995). The sensitivity to hypervitaminosis A appears to be species specific and life stage dependent in fish, which has also been shown for mammals (Nau et al. 1994). This difference in toxicity between water- and fat-soluble vitamins is due to the fact that excess water-soluble vitamin is excreted by the fish, while excess fat-soluble vitamin is accumulated in the lipid fraction of the fish body (Olivia-Teles 2012; Ørnsrud et al. 2002, 2013; Halver 2002). Since biotin is not retained in the body, the maximum tolerable limit or toxicity of this vitamin may not be a concern for fish and other animals (NRC 1987).

Conclusion and future perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References

From all the information above, it is clear that biotin is essential for growth, development and welfare, as well as reproduction in animals in general and fish in particular. However, there are many areas of biotin nutrition, both applied and fundamental, that still need to be explored in order to fully explain the mechanisms through which biotin acts in fish, especially in reproduction, disease resistance and gene expression. In the future, the parameters used in biotin nutrition studies in fish should include haematological parameters, histopathology of the gills, liver and kidney, gonad development, gamete quality and quantity, fecundity and larvae survival, in addition to standard parameters which are growth, survival, biotin-dependent enzyme activity and biotin content of tissues. Dietary biotin requirement levels should also be determined for each of these parameters, as well as at every life history stage of aquatic animals. Moreover, the effect of biotin on the expression of genes encoding the enzymes that are involved in biotin metabolism such as biotinidase, holocarboxylase synthetase, acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase, as well as in biotin transport such as SMVT should be investigated in fish. Finally, experiments should be conducted in order to examine the possible production and the potential contribution of intestinal microflora to biotin supply in different fish species and at different life history stages and under different environmental conditions.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. General properties of vitamins and biotin
  5. Biotin sources and bioavailability
  6. Biotin absorption, transport and storage
  7. Biotin metabolism and metabolic function
  8. Biotin in molecular biology
  9. Biotin in cell cycle and reproduction
  10. Biotin requirement
  11. Biotin deficiency and toxicity
  12. Conclusion and future perspectives
  13. References
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