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Taurine: A critical nutrient for future fish feeds

Guillaume P. Salze, D. Allen Davis

PII: S0044-8486(14)00629-2 DOI: doi: 10.1016/j.aquaculture.2014.12.006 Reference: AQUA 631469

To appear in: Aquaculture

Received date: 22 August 2014 Revised date: 3 December 2014 Accepted date: 4 December 2014

Please cite this article as: Salze, Guillaume P., Davis, D. Allen, Taurine: A critical nutrient for future fish feeds, Aquaculture (2014), doi: 10.1016/j.aquaculture.2014.12.006

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Taurine: A critical nutrient for future fish feeds

Guillaume P. Salze and D. Allen Davis

School of Fisheries, Aquaculture and Aquatic Sciences, Auburn University, 203 Swingle Hall, Auburn, AL 36849-5419, USA

Abstract

Taurine is a sulfonic acid found in high concentrations in animal tissues. In recent years, a number of studies have demonstrated the essentiality of dietary taurine for many commercially relevant species, especially marine teleosts. Consequently, the removal of taurine-rich dietary ingredients such as fishmeal may create a deficiency, of which symptoms include reduced growth and survival, increased susceptibility to diseases, and impaired larval development. These symptoms emphasize the systemic role of taurine in the animal’s physiology and provide few clues as to the underlying mechanisms of taurine function. In fact, a myriad of roles have been attributed to taurine in mammals, ranging from bile salt conjugation to membrane stabilization, osmoregulation, anti-oxidation, immunomodulation, calcium-signaling, and neuroprotection. This review describes the current knowledge of taurine physiology and metabolism in fish and requirement levels in relevant species, and highlights possible parallels with mammalian taurine metabolism. In addition, the effects of ingredient processing and feed ACCEPTED MANUSCRIPT manufacturing on taurine bioavailability are discussed. Finally, regulatory aspects are brought to the forefront: although the supplementation of taurine will be necessary to further reduce the use of ingredients such as fishmeal, taurine is not currently approved by the FDA in the USA for fish feeds.

Obtaining approval in the United States to utilize taurine in fish feeds can improve the environmental and economic sustainability of fish feeds nation-wide.

Keywords: Fishmeal replacement; taurine; regulations; requirement; biosynthetic pathway

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1 Introduction

Taurine (2-aminoethanesulfonic acid, CAS 107-35-7) is an organic acid which was first described from ox bile (Tiedemann and Gmelin, 1827). Taurine is a simple molecule, containing an acidic sulfonate group, a basic amino group, and two carbons in between. It is therefore an amino acid, albeit a β-amino acid: the amino group is bound to the carbon adjacent to the one holding the acidic group (i.e., the second carbon, β). This is in contrast to α-amino acids where the amino group is bound to the same carbon holding the acidic group (i.e., first carbon, α). There is also no tRNA encoding for taurine and its sulfonate group replaces the carboxyl group necessary for the formation of a peptide bond.

Consequently, taurine cannot be part of translated peptide chains, although there are naturally occurring, taurine-containing peptides (Bittner et al., 2005; Lähdesmäki, 1987). The amine group allows for quantitation by using the same methodology used for other amino acids (typically High Performance

Liquid Chromatography, HPCL) and analysis results are often reported together. Taurine exists naturally in animals including mammals, birds, fish, and aquatic invertebrates such as oysters and mussels.

Although plants contain less than 1% of the taurine levels found in animals, the most taurine-rich plants are algae, followed by fungi and other terrestrial plants (Kataoka and Ohnishi, 1986). High taurine levels naturally occur in seafood and meat, and many vertebrates can synthesize taurine. On the other hand, certain animals, includingACCEPTED species containing high MANUSCRIPTlevels of taurine, cannot metabolically synthesize taurine and require dietary sources for physiological processes. Taurine is the most abundant free amino acid in animal tissues, accounting for 25% of the free amino acid pool in liver, 50% in kidney, 53% in muscle and 19% in brain (Brosnan and Brosnan, 2006). In mammals, taurine is involved in a particularly wide variety of functions including constituent of bile, osmoregulation, cell membrane stabilization, anti- oxidation, and calcium signaling required in vertebrates for normal cardiac, skeletal muscle, nervous, and retinal function (Bouckenooghe et al., 2006; Huxtable, 1992).

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Approximately 5,000-6,000 tons of taurine (synthetic and purified from natural sources) were produced in the world in 1993, and were divided at 50% for pet food manufacturing, and 50% for pharmaceutical applications (Tully, 2000). An updated global production is difficult to estimate and would require a full market analysis. Three Chinese manufacturers each advertise a production of 15-

96,000 metric tons per year (source: Alibaba.com), although these numbers cannot be verified.

However, there is no doubt that today’s production is considerably higher than it was in 1993. Currently, global taurine production is destined to three main uses: cat food, infant formulas and the beverage industry for “energy” drinks. According to manufacturers, taurine products are crystalline powders more than 98.5% pure and conform to standards of the United States, Japan, and Europe. To our knowledge, all products are based on the 98.5% purity level, hence there is no food or feed grade taurine. Taurine can be produced either by extraction and purification from taurine-rich sources (Takahashi, 1986) or by chemical synthesis. The majority of taurine is produced by chemical synthesis because extraction is less efficient, more costly, and initial materials (e.g., bovine or ovine bile) are not available in sufficient amounts to meet the global market demand (Chen, 2014). To our knowledge, taurine can be chemically synthesized by five chemical processes: 1) amination of the isethionic acid resulting from the reaction of ethylene oxide and sodium bisulfite, 2) combination of aziridine and sulfurous acid, 3) reaction of methionine, vitamin E,ACCEPTED and cysteine, 4) formation MANUSCRIPTof salt from monoethanolamine and sulfuric acid, followed by reduction with sodium sulfite or sodium carbonate or 5) sulfonation of ethylene chloride by sodium bisulfite prior to reaction with anhydrous ammonia or ammonium cabonate. The fourth method

(monoethanolamine-based) results in 98.5% pure taurine, thus matching the purity level of commercially available taurine. This suggests that this method may be the most used for taurine production, although this is difficult to ascertain without a global survey of the industry.

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Novel methods also include the genetic modification of prokaryote or eukaryote cells to increase taurine biosynthesis (Turano et al., 2012). However taurine produced by such method is not currently available commercially.

2 Regulation and policies

Regulations of taurine use in people, pet, or animal feeds varies widely depending on the country under consideration. In the European Union the Observed Safe Level (OSL) is estimated to be 100 mg taurine per kg body weight per day for people, and synthetic taurine is considered efficacious in cats, dogs, and carnivorous fish diets (EFSA, 2012). In China taurine is authorized for fish feed in all species, and listed as a nutrition enhancer for children (GB-2760-2011 Food Safety National Standards for the

Usage of Food Additives) and maximum permissible values are given for some human food items such as jelly, milk, and energy drinks (GB14880-2012 Food Safety National Standards for the Usage of Nutrition

Enrichment). In Japan taurine is listed among “substances designated as having no potential to cause damage to human health” (Japanese Ministry of Health, Labor and Welfare). It is also designated as a feed additive which can be used in fish and other livestock, although quantities are not regulated

(Japanese Ministry of Agriculture,ACCEPTED Forestry and Fisheries, MANUSCRIPT Food and Agricultural Materials Inspection

Center). Finally, in Australia, feed supplements whose purpose is to ingredients supplying a nutrient required by the livestock do not require registration (Australian Pesticide and Veterinary Medicines

Authority, APVMA). As such, the use of the use of taurine is allowed without registration, for as long as the dose is limited to meeting the nutritional requirement. If included beyond this point, it is considered a veterinary chemical and thus requires registration to the APVMA. In the USA however, taurine is not listed by the Food and Drug Administration (FDA) as a food substance generally recognized as safe for human consumption and is considered a drug or additive (Code for Federal Regulations: 21 CFR 104.2,

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21 CFR 184, and 21 CFR 186). Taurine use is permitted as a nutritional supplement in chicken feeds up to

0.054% of the feed – no other farmed animal is listed in the FDA regulation (21 CFR 573.980). Thus, the current use of taurine as an additive in commercial fish and shrimp feeds is not permitted in the USA unless it is added indirectly via ingredients such as fishmeal or krill meal, which naturally contain taurine.

Alternatively, a “self-affirmation” procedure may be filed to the FDA, where an individual feed manufacturer gathers evidence supporting the use of taurine in feeds. However a successful request would only be valid for the petitioner, and would not be extended nation-wide.

In other animals, taurine has been shown to be an essential dietary requirement for cats (Knopf et al., 1978; Sturman et al., 1977). The discovery of taurine deficiency in domestic cats led to profound changes in commercial cat feeds and markedly improved longevity of these animals. The most critical findings leading to the discovery of taurine deficiency in commercial cat feed were retinal degeneration and a reversible cardiomyopathy (Hayes et al., 1975; Pion et al., 1987). As a result, the Association of

American Feed Control Officials (AAFCO) lists taurine in its nutrient profile for cat food. The AAFCO is an

“association of local, state and federal agencies charged by law to regulate the sale and distribution of animal feeds and animal drug remedies” (aafco.org). For instance, cat feeds certified by the AAFCO must contain at least 0.1% and 0.2% (of dry-matter) taurine in extruded and canned food, respectively. ACCEPTED MANUSCRIPT In 1979 and 1981, taurine was added into two lists of International Food Standards of the CODEX alimentarius (FAO and WHO). The former (CAC/GL 10-1979) indicates that taurine is an acceptable nutrient for infant and young children foods, while the latter (Codex STAN 72-1981) revises the standards for infant formulas. There, the maximum permissible inclusion rate of taurine is set to 12 mg/100 kcal. No minimum rate is specified. Information on taurine toxicity is limited. The European

Food Safety Authority stated the No Observed Adverse Effect Level (NOAEL) was observed at 1,000 mg/kg body weight per day (EFSA, 2009). This is equivalent to 60,000 mg/day of taurine for a 60 kg

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adult. A large amount of taurine is used as a supplement in energy drinks. The popularity of energy drinks continues to grow, especially in the United States where sales increased exponentially between

2002 and 2006 (Reissig et al., 2009), reaching $12.5 billion in 2012. In 2013, the global market was worth

$27.5 billons. An energy drink contains an average of 1,000 mg of taurine per serving, with several popular brands containing 2,000mg (Higgins et al., 2010). In addition to the human and animal nutrition uses already mentioned, there is a growing interest for use in aquaculture diets.

3 Taurine in aquaculture

3.1 Biosynthesis pathways The description and quantitative characterization of the taurine biosynthetic pathways has been the subject of several decades of research, in spite of which some parts remain poorly characterized.

Jacobsen and Smith (1968) described and discussed five pathways for taurine biosynthesis (Error!

Reference source not found.). However, there is no convincing evidence supporting pathway V, since cystine disulfoxide is quite unstable and decomposes into cysteinesulfinate and cystine (Lavine, 1936), and previous studies supporting this pathway were rejected when the investigator subsequently realized that the measured cystine disulfoxide was in fact hypotaurine (Cavallini, 1956). Hence pathway V remains unsubstantiated.ACCEPTED Pathway IV sees taurine MANUSCRIPT biosynthesis by incorporation of inorganic sulfate, via phosphoadenosine phosphosulfate (PAPS) and cysteic acid. Although evidence shows that this pathway occurs in insects such as cockroaches, it was also shown that the initial conversion of inorganic sulfur to cysteine is actually performed by bacterial endosymbionts, and not by the insect itself (Block and Henry,

1961). In vertebrates, this pathway’s shortcomings were compellingly demonstrated by radioisotope tracing (Huxtable, 1981; Jacobsen and Smith, 1968; Knopf et al., 1978), in spite of which this pathway is sometimes referred to in more recent literature. Consequently it is now generally accepted that the

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non-bacterial conversion of inorganic sulfate to organic sulfur compounds (i.e., pathway IV) is insignificant. Likewise, it was hypothesized that taurine could be synthesized in vivo from its deaminated form, isethionic acid. However, no evidence for such reaction was found; rather it is the opposite reaction that occurs, at quite a slow rate (Huxtable and Bressler, 1972).

Over the years it became apparent that pathway I – the cysteinesulfinate-dependent pathway – was the main pathway for taurine biosynthesis in mammals. Consequently, it has been extensively studied and is reviewed in greater details (Huxtable, 1989). Nevertheless, two important points should be made about this pathway. First, the flux of cysteine sulfur to taurine is mainly determined by the highly regulated cysteine dioxygenase (CDO), although the oxidation of hypotaurine into taurine may also be enzymatically regulated (Vitvitsky et al., 2011). CDO activity is highly responsive to changes in substrate availability (e.g. through dietary changes), thus playing an important role in maintaining the steady-state intracellular cysteine levels (Stipanuk and Ueki, 2011). Second, cysteinesulfinate can be either transaminated into β-sulfinylpyruvate or decarboxylated into hypotaurine. The partitioning between the two is determined by the relative saturation constants Km of the two enzymes responsible for these reactions, aspartate aminotransferase (AAT) and cysteinesulfinate decarboxylase (CSD), respectively (de la Rosa and Stipanuk, 1985; Huxtable, 2000; Knopf et al., 1978). The Km of AAT is about 50 times higher than that of CSD, henceACCEPTED cysteinesulfinate is predominantly MANUSCRIPT converted to β-sulfinylpyruvate rather than to hypotaurine (Huxtable, 2000). In mammals this paradigm is tissue specific however: CSD activity is comparatively higher in hepatocytes compared to muscle, kidney or enterocytes (Stipanuk et al., 2006).

This explains the importance of the liver in taurine biosynthesis. In non-mammalian species, taurine biosynthesis pathways remain poorly described. There is indication that birds rely on pathway II: chickens convert cysteine to cysteic acid to taurine in the absence of hypotaurine formation (Chapeville,

1960; Simmonet et al., 1960). Insects also synthesize taurine using pathway II, although hypotaurine was found in some tissues, indicating that pathway I is also used (Whitton et al., 1995). In pathway III

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hypotaurine is produced from cysteamine, which can be seen as a decarboxylated cysteine. However, there is no evidence of cysteine decarboxylase activity (Huxtable, 1981). More likely, cysteamine is produced via coenzyme A turnover and pantetheine oxidation by cysteamine dioxygenase (Coloso et al.,

2006; Stipanuk and Ueki, 2011; Ueki and Stipanuk, 2009). Hepatic hypotaurine in cysteamine-fed rats was about 40% of that of cysteine-fed rats, while levels were about 7% in an unsupplemented group

(Stipanuk et al., 2006). Although the quantitative partitioning between pathway I and III has not been precisely quantified, such results suggest that pathway III could be biologically significant.

In fish, early studies revealed a lack of CSD activity in Labridae, Scombridae and Soleidae as well as

Rajidae (Bergeret and Chatagner, 1956; Goldstein et al., 1990; King et al., 1980a, b) or cysteic acid decarboxylase (CAD) activity in Gadidae (Blaschko, 1942). Making the assumption that the predominance of pathway I would be conserved in teleosts, Yokoyama et al. (2001) compared the CSD activity and hypotaurine production in several teleost and mammalian species: with the exception of opaleye, the fish species with the highest CSD activity were rainbow trout and tilapia: 0.61 and 0.56 nmol hypotaurine min-1 mg protein-1, respectively, which still remains an order of magnitude lower than that of rats and mice. Data indicate that both tilapia and rainbow trout benefit from dietary taurine supplementation (Gaylord et al., 2006; Gaylord et al., 2007; Gonçalves et al., 2011), thus suggesting that such levels of CSD activityACCEPTED are insufficient to provide MANUSCRIPT the necessary amounts of taurine for maximum growth. Likewise, low hypotaurine production observed in other teleost species suggest that dietary taurine is required by the animal, which was indeed later confirmed for Japanese flounder (Kim et al.,

2005a), red sea bream (Matsunari et al., 2008b), and yellowtail (Takagi et al., 2008). Intraperitoneal injection of cysteine elicited an increase in CDO activity (Yokoyama and Nakazoe, 1996), while the resulting cysteine sulfinic acid was subsequently equally split between hypotaurine and sulfate products

(Yokoyama et al., 1997), suggesting that taurine is produced along pathway I in rainbow trout. However, hypotaurine production was extremely low in common carp (Yokoyama et al., 2001), although this

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species is known for growing normally on taurine-free diets (Carvalho et al., 2004; Fontagné et al.,

2000). Additionally, Kim et al. (2008) found significant taurine biosynthesis capability in common carp.

This suggests that common carp relies on a different pathway than pathway I for taurine production, possibly pathway II, although the precise pathway remains to be ascertained. Similarly, Higuchi et al.

(2012) demonstrated that addition of the progestin 17α, 20β-dihydroxy-4-pregnen-3-one increased taurine production in eel testis via up-regulation of CDO, but not of CSD. This suggests that taurine is produced not through pathway I, but through pathway II. Consequently, one cannot systematically assume that all teleost rely on pathway I for the biosynthesis of taurine.

3.2 Discovery of an essential nutrient A nutrient is required in the diet if endogenous production from precursors is absent or insufficient to meet physiological needs. As interest in taurine gained traction in the early 2000s in fish, limited knowledge was available for the hundreds of fish and invertebrate species being grown as food in aquaculture. The ability to synthesize taurine may exist for several freshwater fish species including cyprinids, but this may not be conserved across the class Actinopterygii as many predatory marine species have not demonstrated the ability for taurine synthesis (Yokoyama et al., 2001). Interest first arose in nutrition of marine finfish larvae and early juveniles: several reports noted the superior growth and survival of larvae whenACCEPTED fed on zooplankton such MANUSCRIPT as mysids or copepods, compared to larvae fed on traditionally enriched rotifers and Artemia (Conceicao et al., 1997; Luizi et al., 1999; Næss et al., 1995;

Park et al., 1997; Shields et al., 1999; Takeuchi et al., 2001; van der Meeren and Naas, 1997). Helland et al. (2003) and Aragao et al. (2004) later compared the biochemical composition of copepods with that of

Artemia and noted that taurine was the most abundant free amino acid (after glycine) in the former, while being found at lower levels in the latter. Stemming from this observation, several studies subsequently described marked improvement in growth and survival of larvae as well as juveniles when feeding taurine-supplemented feeds (Brotons Martinez et al., 2004; Chatzifotis et al., 2008; Chen et al.,

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2004; Kim et al., 2005a; Kim et al., 2005b; Lunger et al., 2007; Matsunari et al., 2005; Pinto et al., 2010;

Rossi Jr and Davis, 2012; Salze et al., 2011; Salze et al., 2012; Takagi et al., 2008), as well as in shrimps

(Shiau and Chou, 1994). Because fishmeal is a significant source of essential minerals, it was hypothesized that growth reduction in low-fishmeal diets were due to a low mineral bioavailability, and that taurine acted as an organic acid, improving the bioavailability of minerals (Baruah et al., 2007;

Khajepour and Hosseini, 2012; Vielma et al., 1999). However, replacement of 53% of dietary fishmeal – and taurine – led to a significant decrease in growth in yellowtail, despite diet acidification by citric or formic acid and improved phosphorous retention (Sarker et al., 2012). This demonstrated that taurine does not exert its actions solely as an acid, and together with aforementioned studies, this strongly indicates that taurine is an essential dietary nutrient in many species.

One of the criticisms of aquaculture has been the need for using significant amounts of fishmeal and other marine protein sources from wild caught fisheries in prepared diets for the cultured species. As a consequence, commercial food producers have been trying to substitute fishmeal using alternative nitrogen and protein sources such as feather meal and soy products (Jirsa et al., 2011; Li et al., 2009).

However, such alternative ingredients are often devoid or contain very low concentrations of taurine compared to fishmeal, thus yielding diets similar to low taurine feeds used in terrestrial animal agriculture (Spitze et al.,ACCEPTED 2003). A successful dietary MANUSCRIPT formulation using these alternate protein sources for salmonid diets may not offer the same success when rearing marine predatory species such as cobia Rachycentron canadum (Lunger et al., 2007), red sea bream Pagrus major (Takagi et al., 2006b), or yellowtail Seriola quinqueradiata (Takagi et al., 2008). When S. quinqueradiata and P. major were fed a taurine-deficient diet they developed “green liver syndrome” and exhibited poor growth performances compared to animals receiving taurine-rich diets (Takagi et al., 2005; Takagi et al., 2006b).

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Taurine deficiency explains the reduction in growth performance when including high levels of taurine-poor ingredients in fish feeds. By supplementing plant-based diets with taurine, growth performance was restored (Chatzifotis et al., 2008; Lunger et al., 2007).

3.3 Estimation of dietary requirement It should be re-stated here that a requirement is the amount of a nutrient the animal needs to obtain to achieve a specific target (e.g., maintenance, maximum growth, health status, etc.). In other words, it is a characteristic intrinsic of the animal and is independent of the diet matrix (ingredient combinations). The diet matrix, possibly in interaction with other environmental parameters, may affect the nutrient’s bioavailability and thus the necessary dietary content to meet the animal’s requirement.

However, diet matrix alterations should largely not affect the nutritional requirement of the animal. On the other hand, diseases, life stage, and reproductive cycle may affect nutritional requirements.

Therefore the expression “conditional requirement” refers to such biological changes as opposed to the use of certain feedstuffs. In the case of taurine, the use of various protein sources ranging from semi- purified products such as casein and gelatin (Matsunari et al., 2008a; Qi et al., 2012), to plant proteins (Aksnes et al., 2006b; GaylordACCEPTED et al., 2007), to ethanol MANUSCRIPT-washed fishmeal (Kim et al., 2005b) that were devoid of or highly reduced in taurine clearly demonstrated the essentiality of this nutrient in susceptible species.

The effects of diet matrix and other environmental parameters on taurine bioavailability and metabolism have received limited attention. However, seemingly contradicting studies highlight the importance of such interactions. For example, taurine supplementation in rainbow trout fed a fishmeal- free diet improves growth and feed efficiency (Gaylord et al., 2006; Gaylord et al., 2007).

Supplementation also increased serum taurine levels, while methionine supplementation did not

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produce such an increase nor did it increase CDO or CSD activities (Gaylord et al., 2007). This strongly suggests that taurine is an essential nutrient in this species. In contrast, Yokoyama and Nakazoe (1992) showed an increase in muscle taurine when feeding rainbow trout with a casein-based diet supplemented with methionine or cystine. Likewise, Yamamoto et al. (2012) showed that plant-based diets supplemented with a taurine-free amino acid mix resulted in increased whole-body taurine, suggesting significant taurine biosynthesis activity. Dietary taurine levels were 0.34% (dry matter basis) in the fishmeal control diet and below detection limits in the fermented soy diets (unpublished, Dr.

Takeshi Yamamoto personal communication). However, the best-performing plant-based diet was still out-performed by the fishmeal-based control diet; it is not known whether dietary taurine supplementation would have fully restored growth performance. Comparisons based on of thermal-unit growth coefficient (TGC) using reported data (Gaylord et al., 2006; Gaylord et al., 2007; Yamamoto et al.,

2010; Yamamoto et al., 2012) reveals a stark difference between the respective growth potential of the

American (TGC = 0.250) and Japanese (TGC = 0.150) strains. Such a difference in growth potential may reflect the different genetic selection programs in the two countries: taurine biosynthesis may have been unintentionally selected against, resulting in the American strain requiring dietary taurine while the Japanese strain does not. A strain with lower biosynthesis capacity would be more susceptible to nutrients and/or environmentalACCEPTED conditions, which MANUSCRIPT therefore may dictate whether supplementation is necessary or not (Gaylord et al., 2007).

3.3.1 Juvenile stage Once recognized as an essential nutrient, quantitative requirement levels of dietary taurine must be determined in various species. Table 1 summarizes the studies conducted in juvenile fishes, the main protein sources used in the experimental formulations and their taurine content, and the authors’ conclusion, in terms of quantitative requirement, or whether supplementation is recommended. The table provides a comparison among species and leads to the conclusion that the response to dietary

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taurine seems to be species specific. Much of the research effort has been conducted on marine carnivorous species such as cobia, Japanese flounder, red seabream, or yellowtail, with results demonstrating that dietary taurine is required by some species. More recent studies have indicated requirements for a number of other species. For example, in a feeding trial with Florida pompano

(Trachinotus carolinus), the supplementation of taurine to diets containing plant proteins in combination with about 14% meat & bone meal with blood (MBM) or 14% poultry by-product meal (PB) resulted in enhanced pompano growth and survival (Rossi Jr and Davis, 2012, In press). A complete dose-response study later revealed that taurine requirement in pompano was 0.54-0.65% (Salze et al., 2014a). Recent research on white seabass (Atractoscion nobilis) has determined the dietary requirement for taurine at

0.99% using combined datasets from two trials (Jirsa et al., 2014). In similar studies with California yellowtail (Seriola lalandi), practical diets low in fishmeal were utilized to determine limiting amino acids: lysine, methionine and taurine supplements were all evaluated, and a significant response was observed with the removal of the 0.20% taurine supplement. A second trial using graded levels of taurine (0.32-1.50% dietary taurine) was also conducted. There was no response to these diets, suggesting that 0.32% dietary taurine was adequate to meet the requirement (Jirsa et al., In Press).

Although almost all studies in marine species conclude that taurine is an essential nutrient, the paradigm is not nearlyACCEPTED as clear in freshwater species: MANUSCRIPT taurine supplementation did not benefit growth in channel catfish and common carp, while some data suggest that rainbow trout require dietary taurine

(see discussion in section 3.3 above). It is also difficult to draw distinctions based on feeding habits: indeed data available in tilapia species suggests that taurine is limiting in plant-based diets for Nile tilapia (Gonçalves et al., 2011), while taurine biosynthesis levels in red hybrid tilapia suggest that its requirement can be met by endogenous production (Divakaran et al., 1992). Similarly, observations in

Atlantic salmon are in conflict whether taurine is truly essential in this species (Table 1), although this could potentially be explained by life stage and transition to marine life: exposure of isolated gill, kidney

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or heart tissue to hyperosmotic conditions upregulated the expression of taurine transporter mRNA, while dietary taurine regulates taurine transporter expression in smolts but not in parr (Zarate and

Bradley, 2007). The effect of fish size was shown in turbot (Qi et al., 2012) where 6.3g fish required

1.15% dietary taurine whereas 165.9g fish only required 0.64%. This is however the only study which specifically looked at the effect of fish size on the quantitative taurine requirement. There is limited data in other species, there is no compelling evidence of a similar trend in other species where different sizes have been studied (Atlantic salmon, red sea bream, yellowtail S. quinqueradiata; Table 1). Overall, it appears that the essentiality of taurine does not follow broad ecological boundaries and instead is species-specific.

3.3.2 Larval stage Table 2 compiles results obtained with supplementing larval diets with taurine. Only one study took a graded dose approach (Matsunari et al., 2013), but since best performances were observed in the group receiving the highest dose of dietary taurine, estimation of a quantitative requirement was not possible. Larval studies have been conducted exclusively with marine carnivorous species. Larval rearing of these species has been particularly challenging considering their small size. To date formulated diets ACCEPTED MANUSCRIPT for first-feeding larvae remain inadequate (resulting in very low growth and survival), and rearing typically relies on the production of zooplankton such as rotifers and Artemia. These live preys are enriched using commercial products to increase the content of essential nutrients such as amino acids and long chain, highly unsaturated fatty acids (i.e., EPA and DHA). With the exception of red sea bream and white seabass, all other species appear to benefit from taurine supplementation through enrichment of the live prey: improvements were seen in growth and survival rates, as well as in morphological development and activity of digestive enzymes (Table 2).

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3.4 Meeting the requirement – Ingredient content, delivery and bioavailability of taurine As is the case with many other nutrients, dietary taurine requirement can be met by using a purified form, synthetic, and/or ingredients which naturally contain taurine. It is noteworthy that many studies describing a taurine requirement (Table 1) were able to do so using crystalline taurine. Indeed since taurine is almost always found in free form in natural ingredients, purified/synthetic taurine is well utilized by animals. This strongly supports the suitability and efficacy of crystalline taurine toward meeting dietary requirements of various species. Alternatively, a number of ingredients also contain some taurine. Spitze et al. (2003) provided an extensive survey of taurine concentration in various ingredients relevant to animal feeds, ranging from terrestrial animal meat, dairy, seafood, as well as some plants and fungi. They show that levels vary greatly between types of ingredients (e.g., 112 mg/kg in yeast vs. 3201 mg/kg in fishmeal, as-is basis). Choices in the ingredient matrix will therefore influence the taurine level provided through practical ingredients, which in turn will influence the amount of purified taurine to be added, if necessary, in order to meet the requirement. This could explain the positive response of fishes to low-fishmeal feeds with supplemented attractants (Espe et al., 2007;

Kader et al., 2012; Kolkovski et al., 2000; Suresh et al., 2011): indeed, often-used attractant products include fish solubles, krill meal and squid meal, which contain significant levels of taurine (Spitze et al., ACCEPTED MANUSCRIPT 2003).

There can be large variations in taurine content of a given ingredient: for example, the taurine content of poultry-by-product meal, a commonly-used protein source, ranges from 1894-5352 mg/kg on a dry-weight basis (Spitze et al., 2003). Significant variations are also seen in other major ingredients such as fishmeal and other animal meals. Several factors may explain this variation. In the case of animal by-products, this may be caused by differences in source animals, such as cut (white or dark meat) and breed. In the case of wild-caught animals such as menhaden or anchovies for fishmeal production,

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seasons are known to influence the fish diets and therefore their composition (Bragadóttir et al., 2004;

Hannachi et al., 2011; Mairesse et al., 2006). Ingredient processing is also critical in explaining variations in taurine content. Since taurine is water-soluble, the greatest losses occur when the water-soluble fraction is separated. Therefore boiling without retaining the cooking water results in a drastic reduction of the ingredient’s taurine content, while grilling results in more modest loss (Gormley et al., 2007;

Spitze et al., 2003). The influence of processing was clearly seen when stickwater or fish hydrolysates were added back to a dietary formulation (Aksnes et al., 2006a; Aksnes et al., 2006b; Kousoulaki et al.,

2009): the graded addition of soluble fraction(s) effectively resulted in an increase in dietary taurine content, to which fish growth rate was positively correlated. Consequently, fishmeal – or other animal protein sources – produced by processes where there is full, partial, or no recovery of soluble fractions will contain variable levels of taurine; lower levels will have to be compensated for in compound feeds.

As a free, water-soluble molecule, taurine is particularly susceptible to leaching. However, duration of water contact before ingestion is typically very short when feeding healthy juvenile fishes; hence the amounts of leached taurine remain negligible. More importantly, a nutrient must be available to the animal in order to meet the requirement, lest the nutrient remains unutilized and excreted. The Maillard reaction is the non-enzymatic browning reaction between an amino acid and a reducing sugar, which yields a non-bioavailableACCEPTED amino acid-sugar complex. MANUSCRIPT Taurine has been reported to be susceptible to the

Maillard reaction when heat and water are present such as during autoclaving of infant formula (Yeung et al., 2006) and casein-based cat diets (Kim et al., 1996), during sterilization of milk (Saidi and

Warthesen, 1990), and also during air-drying at 35oC of squid (Tsai et al., 1991). Because conditions during extrusion could favor Maillard reaction on taurine, recent trials compared its stability in extruded and cold-pelleted feeds and subsequently evaluated its bioavailability to rainbow trout O. mykiss

(Gaylord et al., 2014) and red drum S. ocellatus (Gatlin et al., 2014). There was no change in taurine content between pre- and post-extrusion, indicating that no taurine is lost due to the extrusion process.

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There was also no significant loss after 214 days of storage. In rainbow trout there was no effect of pellet type (extruded or cold-pelleted) on growth performance, feed efficiency, and taurine content of filet. In red drum however, reduced muscle taurine levels in fish fed the extruded compared to cold- pelleted diets suggest that taurine bioavailability is reduced by the extrusion process, presumably due to a Maillard reaction. Rainbow trout has been shown to benefit from dietary supplementation in all-plant diets, although it does not appear to have a requirement as high as seen in other marine carnivorous species (Gaylord et al., 2007). This may explain why rainbow trout was not affected by the reduction of taurine bioavailability in the extruded feed.

Being water-soluble, taurine is absorbed by the intestinal epithelium through a specific, Na+/Cl— dependent taurine transporter (TauT). In mammals, some compounds were identified to specifically inhibit the uptake of taurine in the intestine: β-amino acids such as β-alanine and hypotaurine (Roig-

Perez et al., 2005) or lysophosphatidylcholine, present in sesame seeds (Ishizuka et al., 2000; Ishizuka et al., 2002). Results suggest that interactions at the taurine transporter level are the cause of the decreased uptake. By interfering with the epithelial absorption of the nutrient, these substances can be classified as anti-nutritional factors. TauT was described in mammals (Bedford et al., 2000), chicken (Kim et al., 2006), common carp and tilapia (Takeuchi and Toyohara, 2000), S. senegalensis (Pinto et al.,

2011), and mussels (HosoiACCEPTED et al., 2005); hence it isMANUSCRIPT likely that such anti-nutritional action of substances such as β-amino acids would be conserved in fish. Results suggest an interaction between taurine and other anti-nutritional factors, as illustrated by the restorative effects of cholyltaurine on saponin- and lectin-induced enteritis (Iwashita et al., 2008; Iwashita et al., 2009). However, this area of research has so far received little attention, and a deeper understanding of the interactions between these anti- nutrients (alone or in combination) with taurine – and other nutrient – bioavailability and metabolism would be invaluable to refine requirement estimates and the necessary supplementation levels depending on the feed matrix (NRC, 2011).

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In larval rearing, where feed items are both smaller and stay in the water column for much longer periods of time than in juveniles, leaching is a primary concern. The delivery of water-soluble nutrients is usually achieved by including them in the enrichment medium of live prey such as rotifers and Artemia.

However, the low drinking and nutrient retention rates of live prey causes wastage of large amounts of the nutrient. Efficiency of delivery can be markedly improved by encapsulating the nutrient in hydrophobic carriers such as wax spray beads before being added to the enrichment of live prey such as rotifers and Artemia (Hawkyard et al., 2011; Langdon et al., 2008). Doing so allowed Hawkyard et al.

(2014) to reduce by 80-times the amount of taurine required to achieve the same level of live prey enrichment compared to a traditional enrichment bath method, while maintaining larval growth and survival. This suggests that this delivery method is adequate to meet the larvae’s taurine requirement.

However, larvae fed wax spray beads-encapsulated taurine had a lower body taurine content than larvae fed rotifers enriched with dissolved taurine, indicating that the availability of encapsulated taurine is reduced. Digital images suggest that wax spray beads can be digested by rotifers, although the proportion of digested beads is likely a function of the lipids used to produce them. Liposomes were also successfully used as carrier systems to enrich live prey with hydrophilic or hydrophobic nutrients (Barr and Helland, 2007; Monroig et al., 2007; Ozkizilcik and Chu, 1994; Pinto et al., 2013; Saavedra et al., 2009), with results suggestingACCEPTED high availability of theMANUSCRIPT carried nutrient. However, a direct comparison of digestibility of beads produced with different lipid types has not yet been conducted.

3.5 Understanding the roles of taurine Taurine has been attributed a wide diversity of roles in mammal physiology – yet specific knowledge of taurine function(s) in teleost is acutely limited. In teleost species where taurine has been identified as an essential nutrient, poor growth and reduced survival are consistently observed during taurine deficiency. However such symptoms are uninformative to the roles of taurine. In some fish species, taurine deficiency has also been characterized to cause green liver syndrome, reduced hematocrit

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values and high mortality typically associated with reduced disease resistance. Green liver syndrome is attributed to both a decrease in the excretion of bile pigments and hemolytic biliverdin overproduction as a result of dietary taurine deficiency (Kim et al., 2007; Sakai et al., 1990; Sarker et al., 2012; Takagi et al., 2005; Takagi et al., 2010, 2011). Taurine also appears to play a role in hemolytic suppression through its effects on osmoregulation and biomembrane stabilization in fish (Takagi et al., 2006a). Because of taurine's role across numerous biological processes, a range of physiological problems and histological changes have been reported when taurine is reduced in the diet or is not present in adequate amounts.

3.5.1 Effects on growth Growth depression is one of the most obvious and commonly observed signs reported during taurine deficiency episodes. However, growth depression is a symptom common to a myriad of conditions, and therefore is not sufficient to diagnose a taurine deficiency. Growth is the result of the deposition into tissues of nutrients that are available after metabolic expenditure for maintenance, digestion, etc. It is known that some free amino acids have an appetite-stimulating effect (Ina and

Matsui, 1980; Kasumyan and Doving, 2003). If taurine had such an effect, an increase in feed consumption would explain the observed increase in growth. However, taurine supplementation is often accompanied by an improvement in feed efficiency. Moreover, taurine had only limited stimulating effect in red sea breamACCEPTED (Fuke et al., 1981) and acted MANUSCRIPT as a deterrent in marbled rockfish Sebasticus marmoratus (Takaoka et al., 1990). Thus taurine must promote growth by another mechanism. The osmoregulatory effect of taurine has been highlighted in fish and other species (Huxtable, 1992; Takagi et al., 2006a). In fish, indirect osmoregulatory action was suggested by an increase in skin thickness and condition in fish fed taurine-supplemented diets (Kato et al., 2014). Also, since other α-amino acids such as glycine and arginine can also participate in cellular osmoregulation in fish (Li et al., 2009), it could be hypothesized that taurine spares these amino acid which then become available for protein synthesis or energy production. However, no study undertook to elucidate this question.

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When observing growth depression during taurine deficiency, reduced feed and protein efficiencies are generally reported (Aksnes et al., 2006b; Chatzifotis et al., 2008; Enterria et al., 2011; Kim et al.,

2005a; Kim et al., 2003; Matsunari et al., 2008b). Additionally, a limited number of studies report changes in body composition in response to dietary taurine levels: although due caution should be exerted when comparing studies using different species, diet matrices, and husbandry conditions, there is a general trend of decreasing body lipid content in response to limiting levels of dietary taurine (Espe et al., 2012a; Lunger et al., 2007; Qi et al., 2012; Salze et al., 2014b; Yun et al., 2012). However, the opposite trend have been observed in different species such as Atlantic salmon (Espe et al., 2012a; Espe et al., 2012b) and rodents (Tsuboyama-Kasaoka et al., 2006). Evidence also suggests differences between fish sizes: 166-g turbot (Psetta maxima) fed a taurine-deficient diet had significantly reduced body lipid, protein, and dry matter; whereas, 6.3-g individual had increased body ash and a tendency to decreased body crude protein without significant changes in body lipid or moisture (Qi et al., 2012).

While the disruption of nutrient deposition explains the reduced feed and protein efficiencies, the underlying mechanism of such disruption by taurine deficiency – explaining the above discrepancies – remains elusive. Bañuelos-Vargas et al. (2014) observed significant decreases in key enzymes of intermediate metabolism (amino acid catabolism and gluconeogenesis) in the liver of totoaba juveniles when fed 30-60% soy proteinACCEPTED concentrate in replacement MANUSCRIPT of fishmeal. Taurine supplementation fully restored the enzyme activities to the levels seen in fishmeal control diet. This suggests a significant role of taurine in modulating metabolism and nutrient utilization. One possibility posits that taurine acts as a signaling molecule. This is seen in the digestive tract of rats, where dietary taurine induces gastric acid secretion by binding to γ-aminobutyric acid (GABA) receptors (Huang et al., 2011). Similarly, taurine stimulated alkaline phosphatase activity and collagen synthesis in cultured osteoblasts via activation of extracellular signal regulated protein kinase (ERK) pathway (Park et al., 2001; Yuan et al., 2007), although the transporter in this case is taurine-specific (Yuan et al., 2006). Additionally, taurine was

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found to inhibit bone resorption by osteoclasts (Koide et al., 1999). Taken together, this suggests a direct role of taurine in bone metabolism and would partially explain the hindered growth observed during taurine-limiting conditions. Evidently additional research is necessary to elucidate such mechanisms in fish.

3.5.2 Lipid digestion and formation of bile salts The biological activities of taurine in the formation of bile salts, which are essential for the intestinal digestion and absorption of lipids, are well-documented (Bouckenooghe et al., 2006; Huxtable, 1992).

The term “bile salt” combines the conjugated bile acids and bile alcohols, which are both derived from cholesterol through complex pathways (Norlin and Wikvall, 2007; Russell, 2003). This origin results in an initial hydrophobicity; the amphipathic property necessary for miscellar solubilization of dietary lipids is acquired via the conjugation of the salt by esterification with sulfate for bile alcohols, or by N- acylamidation with glycine, taurine, or a taurine analogue for bile acids. As small molecules, bile salts present the highest known chemical structure diversity in vertebrates, and the composition of bile is species-specific. With over 30,000 known fish species, the composition of fish bile illustrates this diversity (Hofmann et al., 2010). Nevertheless, in teleost virtually all described bile acids conjugations occur with taurine, and most species of aquaculture interest only secrete C24 bile acids cholic acid and chenodeoxycholic acid.ACCEPTED Noteworthy exceptions include MANUSCRIPT fishes such as sturgeons and paddlefish, where proportions of C27 bile alcohol are found, and cyprinids where 5α-cyprinol sulfate is the main bile salt

(Hofmann et al., 2010). Also, bile acids of gilthead sea bream Sparus aurata and red sea bream P. major may conjugate with D-cysteinolic acid, which is structurally similar to taurine and thought to originate from the diet (Goto et al., 1996; Une et al., 1991). Once conjugated, the hydrophilic moiety prevents passive re-absorption by the enterocytes; rather, most conjugated salts are actively absorbed in the distal intestine, thus maintaining adequate concentrations in most of the intestine. After re-absorption bile salts are routed to the liver where they will be recycled to the gallbladder – a process termed

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enterohepatic circulation. During their transit in the intestine, bile salts may undergo some modifications by the intestinal microbiota (Hofmann et al., 2010). The diversity of possible modifications, whose functional significance remains unclear, is beyond the scope of this review.

However, both bile acids and alcohols may be deconjugated by intestinal bacteria, and while bile acids can be passively re-absorbed in this form, bile alcohols cannot. Thus, excessive deconjugation can impair lipid digestion, and presumably result in significant loss of cholesterol in species where bile alcohols constitute a significant proportion of bile salts. Empirical evidence shows that taurine supplementation increases bile salt content in several teleost species (Kim et al., 2007; Kim et al., 2014), although it appears to be independent from dietary lipid levels (Kim et al., 2008). Dietary protein source (fishmeal, conventional soybean meal, or processed soybean meals), however, affects the amount of bile in the chyme (Nguyen et al., 2011) as well as the composition of bile, as demonstrated with rainbow trout by

Murashita et al. (2013) where the ratio of taurocholic acid to taurochenodeoxycholic acid varied from

0.89 to 11.90. The practical significance of the latter result remains to be elucidated, perhaps in light of recent findings of other properties of bile salts such as signaling, osmosensing, or hormonal actions

(Hylemon et al., 2009; Keely et al., 2007; Lefebvre et al., 2009). Yamamoto and coworkers (2007) noted that rainbow trout benefits from 1.5% bile salt supplementation in a fishmeal-free, soy- and corn-based diet: growth, lipid digestibility,ACCEPTED and distal intestin eMANUSCRIPT morphology were improved. However, in species more sensitive to taurine deficiency such as P. major, taurocholic acid supplementation was insufficient to fully recover growth and bile salt content while taurine supplementation did (Matsunari et al.,

2008b). This indicates that taurine supplementation does benefit lipid digestibility but its benefits are multifaceted and expand beyond this single function.

It should also be noted that the majority of taurine studies in fish have been conducted using soy- based diets (e.g., soy protein concentrate, soybean meal). Soy products are known to reduce lipid absorption and cholesterolemia in mammals (Anderson and Bush, 2011; El Khoury and Anderson, 2013)

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as well as in fish (Kortner et al., 2013). Because Kortner et al. (2013) worked with Atlantic salmon Salmo salar, the enteritis developed by soy-fed fish likely explains the observation. However, hypocholesterolemia was also observed in S. quinqueradiata fed soy proteins (Nguyen et al., 2011) although soy does not cause enteritis in this species. Certain protein hydrolysates have been shown to effectively bind bile salts at their hydrophobic core or anionic acid group (Howard and Udenigwe, 2013).

Consequently, the bound bile salts are not available for lipid solubilization and cannot be re-absorbed, thus leading to increased excretion of lipids and bile. This could partially explain why the removal of the high molecular fraction of soy proteins resulted in the partial recovery of intestinal bile acid in yellowtail when compared to fish fed a fishmeal-based control feed, although plasma cholesterol remained low

(Nguyen et al., 2011). Unfortunately, dietary cholesterol composition was not reported, thus it is difficult to discriminate its contribution to this results which may simply reflect dietary levels. Maita et al. (2006) reported similar results, where plasma cholesterol of yellowtail fed soybean-based diets was restored to that of fishmeal-fed fish only when supplemented with both taurine and cholesterol. Although there was an increase in total bile acid content in the anterior intestine in response to the removal of the high molecular fraction, it remained unchanged in the posterior intestine, suggesting that the amount of excreted bile acid was not affected (Nguyen et al., 2011). The soy-based diets were not supplemented with taurine, and despiteACCEPTED a slight increase in liver taurineMANUSCRIPT content in response to the lower molecular weight of soy protein, the improvement was quite minor and levels remained about half of that in fish fed the fishmeal control diet. There are many interacting factors contributing to the absorption of lipids, including micellar formation under favorable concentrations of phospholipids and bile salts, the level of bound bile salts by dietary peptides due to the peptide content in hydrophobic or cationic amino acids, and the type of bile salt which can be more or less susceptible to binding (Howard and Udenigwe, 2013).

Consequently, it remains difficult to draw a definitive conclusion as to the mechanism of reduced lipid absorption in fish fed soy proteins and the role of taurine in this context.

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3.5.3 Health and immunity In mammals and humans, evidence designates taurine as a potent regulator of proinflammatory and immune response. Taurine has been linked to a number of health benefits, including tissue repair (Gupta et al., 2006; Kingston et al., 2004; Motawi et al., 2007; Sahin et al., 2011; Seki et al., 2005; Shiny et al.,

2005; Takatani et al., 2004; Tong et al., 2006; Zhang et al., 2008; Zhang et al., 2010), alleviation of metal toxicity (Aydogdu et al., 2007; Bosgelmez and Guvendik, 2004; Bosgelmez et al., 2008; Gulyasar et al.,

2010; Gurer et al., 2001) and bacterial lipopolysaccharide hepatotoxicity (Kim and Kim, 2002). Many of these actions result from two, cascading mechanisms. The first is through neutralization of oxidative species, the product of which regulates inflammatory reactions via modulation of leukocyte gene expression (Redmond et al., 1998; Schuller-Levis and Park, 2004). In this proposed mechanism, hypochlorous acid (HOCl) is produced during the leukocyte’s (usually neutrophil granulocyte) respiratory burst via the myeloperoxidase pathway. HOCl is a cytotoxic oxidant used to kill pathogens, but it is equally toxic to the host’s cells. Taurine reacts with HOCl to produce the stable oxidant taurine chloramine (Tau-Cl), thereby reducing the oxidative stress. The second mechanism is through Tau-Cl which modulates the inflammatory response by inhibiting the production of proinflammatory mediators

TNF-α, PGE2, and nitric oxide, as well as regulating the proliferation of lymphocytes and activity of macrophages and granulocytes and monocytes, and production of interleukins 6 and 8 (Park et al., ACCEPTED MANUSCRIPT 2002a; Wang et al., 2009). It is still unclear whether such mechanism exists in fish.

In fish the relationship between methionine and cataract formation is well known in fish (Cowey et al., 1992; Simmons et al., 1999); however, taurine has no protective role against this condition (Bjerkas and Sveier, 2004). Nevertheless, there is a growing – albeit very fragmented and sometimes conflicting – body of data suggesting that taurine plays a role in fish health and immunity. Taurine has been, in some cases including humans (Sirdah et al., 2002), associated with decreased hematocrit. Decreased hematocrit was observed in S. quinqueradiata (Takagi et al., 2006a), where taurine-deficient fish

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exhibited hemolytic anemia and significantly reduced hepatic and plasma taurine concentrations, as well as reduced serum osmolality and osmotic tolerance of erythrocytes. Contrarily, taurine deficiency did not result in significantly decreased erythrocyte count, hemoglobin concentration or hematocrit in P. major (Takagi et al., 2011), although there was a numerical decreasing trend. Positive health effects were also found in grass carp: although taurine has no effect on growth in this species, Yang et al. (2013) showed that lower hemolysis rate was correlated with acute hypoxia tolerance. Thus, it may still be beneficial to supplement taurine in grass carp or other non-carnivorous species based on health aspects despite a lack of a growth response with low taurine diets.

Very few studies have assessed the possible link between dietary taurine and disease resistance in fish. Maita et al. (1998) observed that S. quinqueradiata fed fishmeal-free diets grew as well as those fed a fishmeal control diet, but were more susceptible to mortality from bacterial infections. In a second study, the same research group observed that taurine supplementation of a fishmeal-free diet reduced mortality to similar levels as fish fed a fishmeal control diet after an artificial bacterial challenge (Maita et al., 2006). Whether the improvement in disease resistance conferred by dietary taurine is due to enhanced leukocyte activity, reduction of inflammation-induced oxidative stress, or another mechanism remains unclear; nevertheless, these findings support the hypothesis that taurine has immunoregulatory properties in fish. ACCEPTED MANUSCRIPT

3.5.4 Taurine as an antioxidant One of the most commonly cited benefits of taurine is its antioxidative action, often associated with the cytoprotective characteristics. In addition to the aforementioned reaction with HOCl, taurine has been shown to reduce lipid peroxidation levels (Aydogdu et al., 2007; Bosgelmez and Guvendik, 2004;

Nandhini et al., 2005; Zhang et al., 2004). However, the data on direct measurements of scavenging

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activity indicated that taurine is a weak scavenger for various radicals such as hydrogen peroxide, oxygen superoxide, or peroxynitrite (Aruoma et al., 1988; Mehta and Dawson, 2001; Shi et al., 1997).

Rather, taurine likely modulates the production of reactive oxygen species in the first place, whether indirectly such as with Tau-Cl, or directly. An example of the latter is seen in mitochondria: when cultured in taurine-poor medium, cardiomyocytes suffer from oxidative stress caused by a disruption of the mitochondria electron transport chain, leading to the generation of superoxide anions (Chang et al.,

2004; Parvez et al., 2008). Re-introduction of taurine in the medium restores the electron transport chain integrity, thereby decreasing the production of superoxide anions (Jong et al., 2012). A likely mechanism for this is the modification of mitochondrial tRNA with taurine at the wobble anticodon; without the taurine modification, translation of mitochondrial proteins (including subunits of enzymes from the electron transport chain) is severely impaired (Umeda et al., 2005).

In fish, the relationship between taurine and oxidative stress was hypothesized in jaundiced S. quinqueradiata (Sakai et al., 1998). Taurine supplementation also led to a restored catalase activity and reduced lipid peroxidation levels in T. macdonaldi (Bañuelos-Vargas et al., 2014). Finally, it has also been shown in T. carolinus maintained on a taurine-deficient diet for 16 days: a significant decrease in hepatic mitochondrial protein content and mitochondrial activity was reported to be strongly correlated with a decrease in taurine contentACCEPTED (Salze et al., 2014b). MANUSCRIPT

3.5.5 Liver function Taurine is known to be mainly synthesized in the liver (Huxtable, 1989; Yokoyama et al., 2001), although it is also produced in the brain (Pasantes-Morales et al., 1980). Thus unsurprisingly, much of the empirical data gathered so far in fish strongly suggest that the liver is the most-impacted organ in the event of a deficiency. Hepatic taurine levels are very responsive to dietary levels (Espe et al., 2012a;

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Matsunari et al., 2008b; Park et al., 2002b; Takagi et al., 2008), and may plateau at high dietary levels

(Matsunari et al., 2006). Green liver syndrome is arguably the most specific symptom of taurine deficiency in fish, though it has not been reported in all species. Takagi et al. (2005) established a link between green liver and taurine deficiency in S. quinqueradiata, and reported anemia, increased levels of bile pigments, and histological observations of hemosiderin deposits in the spleen. It was later found that the green liver originated from the accumulation of biliverdin: as taurine deficiency increases hemolysis, the released hemoglobin is catabolized into biliverdin in P. major (Takagi et al., 2006b; Takagi et al., 2011). However, while the occurrence of green livers is linked to elevation of pigment production in P. major, evidence suggests that this issue doubles with a reduced excretion of bile pigment from the liver to the bile in S. quinqueradiata without hepatobiliary obstructions (Takagi et al., 2005; Takagi et al.,

2008). Though reporting the presence of a parasitic mucosporozoa in the bile duct (coincidental, as it was never reported in other findings of green liver), Watanabe et al. (1998) reported low phospholipid, total cholesterol and free cholesterol levels of the blood, indicating abnormal liver function as part of the characterization of green liver syndrome in Seriola quinqueradiata, with similar observations made in P. major (Goto et al., 2001a).

3.5.6 Reproduction and development To date there is onlyACCEPTED one study reporting on theMANUSCRIPT effects of taurine supplementation in broodstock diet on reproductive performances in fish (Matsunari et al., 2006). This study was conducted with S. quinqueradiata broodstock fed diets containing 40% fishmeal and 24% soybean meal for 5 months prior to receiving a human chorionic gonadotropin injection followed by stripping and artificial fertilization.

The control group, which was fed a diet containing 0.17% taurine, did not produce any mature eggs and thus had no reproductive output. In contrast, two taurine-supplemented groups (0.73% and 1.23% dietary taurine, respectively) were successfully spawned, with a marked improvement in egg quality in fish fed the 1.23% taurine diet: there were increases in buoyancy, fertilization, and hatching rates,

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although egg diameter and oil globule diameter were not significantly different. Although it is unclear whether the soybean meal used for these diets contained any anti-nutritional factors, this study clearly shows that taurine plays a major role in maturation in this species. However, the mechanism explaining the role of taurine remains unclear as the oocyte taurine content did not vary among treatments. In rat testis, taurine has been shown to stimulate testosterone secretion both in vivo and in vitro (Yang et al.,

2010), although once again, such an effect has not been demonstrated in fish. Benefits of dietary taurine also have been reported in birds, where supplementation of up to 0.05% (500 mg kg-1) significantly improve egg laying rate without affecting the egg weight or shell characteristics, although egg taurine and cholesterol contents were positively and negatively affected, respectively (Wang et al., 2010).

However, egg weight is reduced in laying White Leghorn hens when dietary taurine exceeds 0.25%, although other laying performance variables were not affected (Yamazaki and Takemasa, 1998).

The role of dietary taurine in fish embryonic and larval development is another area where many questions remain, as the available data are more limited than for juvenile fish. The essentiality of dietary taurine has been established for a number of teleost larvae, all marine species (Table 2). All studies report increases in larval taurine content in response to dietary supplementation, and positive effects are seen in terms of growth as well as survival through weaning from live prey onto an artificial diet.

Positive effects were alsoACCEPTED seen on digestive enzyme MANUSCRIPT activity in R. canadum (Salze et al., 2012): specific activities of amylase and trypsin, in particular, were higher in the taurine-supplemented larvae until 20 days-post-hatch (dph), presumably improving nutrient availability in these individuals. Pepsin activity also was higher in taurine-supplemented larvae, although the time of onset of pepsin activity was not altered by dietary treatment. Benefits to morphological development and metamorphosis have also been attributed to dietary taurine in R. canadum and S. senegalensis (Pinto et al., 2010; Salze et al.,

2011). As it is for the other observed effects of taurine, the mechanisms underlying these effects on larval growth, survival and development remain obscure. Certainly, the roles previously discussed above

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could partially explain these results. In mammals, taurine deficiency has been linked to retinal degeneration, central nervous system abnormalities and growth depression (Lima et al., 2001; Liu et al.,

2012; Stapleton et al., 1997). Should these effects be conserved in fish, they may partially explain the observed benefits of taurine supplementation in fish larvae.

4 Summary

Taurine is a structurally simple nutrient, yet to which a myriad of complex roles are attributed.

Some data on physiological and metabolic mechanisms explaining these roles is available in mammals, but they are particularly limited in fish, especially in broodstock and larvae. Nevertheless, an increasing number of species have been identified as having a clear, true requirement for dietary taurine.

Deficiencies are characterized by depressed growth, low survival, increased susceptibility to diseases, as well as impaired development in larvae. Moreover, taurine deficiency may manifest itself through a green liver syndrome in some species. None of these effects are fully explained, although some initial hypotheses have emerged. However, as the state of knowledge of taurine physiology in fish remains fragmented and limited, additional research is evidently necessary to elucidate the mechanisms by which taurine exerts its actions

It is abundantly clearACCEPTED that as taurine-rich ingredients MANUSCRIPT are removed from practical diet formulations, taurine supplementation will be required to optimize production in susceptible species. This will however require the registration of taurine as an approved ingredient for inclusion in fish feeds by the

FDA, as the European Union and China have already done. Doing so will allow manufacturers to produce feeds in the United States with lower fishmeal content while promoting fish growth and health, thereby improving aquaculture environmental and economic sustainability.

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Acknowledgments

The authors are particularly grateful to Drs. Ryan J. Huxtable, Delbert M. Gatlin III, and T. Gibson

Gaylord for their helpful comments during manuscript preparation. Part of the development of this review was supported by the United Soybean Board and the Alabama Agricultural Experiment Station

(Hatch) funds.

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Figure legend

Figure 1: Pathways of taurine biosynthesis. Adapted from Jacobsen and Smith (1968), Huxtable

(1981), and Stipanuk et al. (2006). Five pathways were originally described, although pathway IV is only relevant in bacteria and pathway V remains unsubstantiated, as is the in vivo transamination of isethionic acid. Pathways I and II are the likely predominant pathways in teleosts, depending on species.

In mammals AAT activity is notably higher than that of CSD, resulting in a majority of cysteine sulfinic acid being transaminated. AAT: aspartate aminotransferase; ADO: 2- aminoethanethiol dioxygenase;

CDO: cysteine dioxygenase; CSD: cysteinesulfinate decarboxylase; CAD: cysteic acid decarboxylase;

PAPS: phosphoadenosine phosphosulfate.

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Table 1: Summary of species and critical responses to taurine in juvenile (and adult) teleosts

Initial Main Dietary taurine Primary Recommended Species weight protein content, % diet2 response supplement (% Reference (g) source1 (source) criteria diet) Atlantic 0.8, 1.0, 1.3, 1.4, SPC, CGM, (Kousoulaki salmon 137 1.5, 1.8, 3.9 Growth R FM et al., 2009) Salmo salar (FM, stickwater) Pea/soy 0.2-0.3 (Espe et al., 2 Growth NR PC, FM (FM, krill, crystal) 2012a) Cobia FM repl. 0.13-0.55 Rachycentron 9.8 Growth, FE by YP (FM, crystal) (Lunger et canadum 0.5 al., 2007)

FM repl. 28 0.0-0.5 Growth, FE by YP Common 0.16, 0.34 Growth, feed (Chatzifotis dentex 40 FM, SBM 0.2 (FM, crystal) intake, FE et al., 2008) Dentex dentex Dolphin fish (Divakaran et Coryphaena Various Enzyme activity R al., 1992) hippurus Growth, Florida survival, pompano 0.0, 0.5 4.4 SBM, PBM protein and R Trachinotus (crystal) energy carolinus (Rossi Jr and retention Davis, 2012) Growth,

survival, 0.07, 0.35, 0.64, 6.25 SBM protein and 0.5-0.75 0.85 (crystal) energy retention Japanese flounder 0.18, 1.02 0.4 FM Growth 1.0 Paralichthys (FM, crystal) (Kim et al., olivaceous ACCEPTED MANUSCRIPT 2003)

0.18, 1.02 15 FM Growth NR (FM, crystal) 0.67, 1.10, 1.59 Growth, FE, (FM, Squid, krill, (Kim et al., 0.2 FM whole body 1.5 crystal) 2005a) taurine

Growth, 0.06, 0.56, 1.6 0.3 wFM feeding (crystal) (Kim et al., behavior 1.66 2005b) Growth, 0.06, 0.56, 1.6 3.7 wFM feeding (crystal) behavior

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0.13, 0.17, 0.32, Growth, FE, bile 0.7 wFM 00.6-1.6 0.63, 1.55 (crystal) salts, FE (Kim et al., 2007) 0.13, 0.17, 0.32, Growth, FE, bile 9.6 wFM 1.6 0.63, 1.55 (crystal) salts, FE

0.06, 0.56, 1.60 0.3 wFM Growth, FE 1.5 (crystal) (Kim et al., 2008) 0.06, 0.56, 1.60 3.7 wFM Growth, FE 0.6-1.6 (crystal)

0.2, 0.8, 1.4, 1.9 (Park et al., 0.9 FM Growth 1.4 (FM, crystal) 2002b) Korean Growth, FE, rockfish 0.07, 0.5, 0.87, 1.32, tissue (Kim et al., 13.5 wFM R Sebastes 1.71 (crystal) composition, 2014) schlegeli bile salts Red drum AA, fish 0, 1.5, 3.0 (Patterson et Sciaenops Growth R? muscle (FM, crystal) al., 2012) ocellatus Taurine Red sea bream FM, 0.7, 1.1, 1.9 Growth, green (Goto et al., 260 probable cause Pagrus major SBM,CGM (FM, krill, crystal) liver 2001b) of green liver 0.95, 2.58, 4.72 Growth, green (Takagi et al., 153 SPC R (crystal , FM, krill) liver 2006b) Casein, 0.02, 0.92 2.3 gelatin, Growth, FE, FI (crystal) FM >0.5 (Matsunari et al., 2008a) Casein, 0, 0.4, 1.0, 1.6 2.5 Growth, FE, FI gelatin (crystal)

Casein, 0, 0.10, 0.29, 0.47, (Matsunari 4.7 Growth, FE 0.5 ACCEPTEDgelatin 0.65 (crystal) MANUSCRIPT et al., 2008b) 0, 0.56, 1.24, 1.84, Growth, FE, (Takagi et al., 580 SPC 0.5 2.82 (crystal) green liver 2010) Growth, FE, 0.0, 0.98, 2.1 green liver, (Takagi et al., 72 SPC R (crystal) bile, osmotic 2011) tolerance Sea bass (Brotons 0.28,0.37,0.45,0.54 Growth, diet Dicentrarchus 0.8 FM, SBM 0.2 Martinez et (FM, crystal) selectivity labrax al., 2004) Summer Flounder FM repl. 0, 1.5, 2.0 (Lightbourne, 34 Growth R Paralichthys by SBM (FM, crystal) 2011) dentatus

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Growth, body composition, FM, SBM, 0, 1 (Enterria et 34 PER, R CGM (FM, crystal) al., 2011) formulation cost Intermediary Totoaba metabolism, (Bañuelos- 0.2, 0.3, 0.5, 1.3, 1.5 Totoaba 7.5 FM, SPC oxidative R Vargas et al., (FM, crystal) macdonaldi status, growth, 2014) FE, PER Growth, Turbot SBM, 0.11, 1.14 (Yun et al., 5.8 cholesterol, R Psetta maxima WGM, FM (FM, crystal) 2012) enzymes Growth, FE, 6.3 1.15 Casein, 0.16, 0.64, 1.15, body (Qi et al., Gelatin, 1.66 composition, 2012) FM (FM, crystal) taurine tissue 166 0.64 levels 0.39, 0.86, 1.3, 1.8, Yellowtail 2.3 (Matsunari Seriola 0.5 FM Growth, FE R (FM, krill, squid, et al., 2005) quinqueradiata crystal) Growth, FE, 0.073, 0.25, 2.14 mortality, (Takagi et al., 240 SBM R (crystal) hematocrit, 2005) green liver Growth, feed utilization, 0.3, 3.39, 5.28, 7.16 (Takagi et al., 250 SBM survival, R (crystal) 2006a) hematocrit, green liver Anemia, SPC, SBM, 0.09, 0.8 disease (Maita et al., 200 CGM, R (crystal) resistance, 2006) meat meal ACCEPTED MANUSCRIPTcholesterol FM, SBM, 0.17, 0.73, 1.23 (FM, Reproductive (Matsunari ~6100 R CGM crystal) performance et al., 2006)

Yellowtail SPC, FM, 0.20, 0.45 11.9 Weight gain, FE Seriola lalandi CGM (crystal, FM) (Jirsa et al., R 0.32, 0.62, 0.82, In Press) SPC, FM, 3.5 1.18, 1.5 (crystal, Weight gain, FE CGM FM) White Seabass 0.06, 0.17, 0.27, SBM, SPC, Atractoscion 4 0.38, 0.49, 0.57 FM nobilis (crystal, FM) (Jirsa et al., Growth, FE 0.99 0.27, 0.49, 0.69, 2014) SBM, SPC, 3.7 0.86, 1.2, 1.67 FM (crystal, FM)

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Rainbow trout SPC, CGM, 0.27, 0.85, 1.45 (Gaylord et Oncorhynchus 18.4 SBM, Growth, FI 0.85 (crystal) al., 2007) mykiss WGM FM, SBM, NR (basal diet 0, 0.5, 1.0, 1.5 CGM, Growth, FE, contains 0.2% (FM, crystal) WGM protein and taurine) (Gaylord et 26.8 SPC, SBM, energy al., 2006) 0, 0.5, 1.0, 1.5 CGM, retention 0.5 (crystal) WGM SBM, SPC, 0.03-0.17 Growth, feed Somewhat (Aksnes et 149 CGM (FH) utilization correlated al., 2006a)

0.07, 0.27 (Boonyoung 6.9 SPC, FM Growth NR (FM, crystal) et al., 2013) Nile tilapia Plant 0, 0.2, 0.4, 0.6, 0.8 (Gonçalves Oreochromis 0.3 Growth R proteins (crystal) et al., 2011) niloticus 270 Red hybrid Taurine (Divakaran et days NR tilapia3 biosynthesis al., 1992) old Channel 0, 0.084, 0.168, Catfish (Robinson et 200 AA, casein 0.252 Growth NR Ictalurus al., 1978) (crystal) punctatus Common Carp 0.6, 0.95,2.72 (Kim et al., 4.8 wFM Growth, FE NR Cyprinus carpio (crystal) 2008) 1 In decreasing order of inclusion in the formulation; 2 Underlined values indicate supplemented levels; 3 Oreochromis mossambicus female x O. macrochir male; AA: amino acid mix; CGM: corn gluten meal; FE: feed efficiency; FI: feed intake; FH: fish hydrolysate; FM: fishmeal; wFM: washed fishmeal; PBM: poultry by-product meal; SBM: soybean meal; SPC: soy protein concentrate; WGM: wheat gluten meal; YP: yeast protein; R= required; NR=not required;

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Table 2: Summary of species and critical responses to taurine in larval teleosts

Diet/live Primary Recommended prey Dietary taurine Species response supplement (% Reference (enrichment content, % diet criteria diet) method) Ro: 0.11-0.19%, dm Ro/Ar (DHA, Ar: 0.63%, dm Growth, (Yamamoto Amberjack Chlorella), R WZ: 0.58-0.83%, survival et al., 2008) Seriola dry diet, WZ dm dumerili Ro (DHA Growth, (Matsunari Chlorella, 0.15-0.72%, dm survival, larvae R et al., 2013) dTau) composition Ro: 0.00-0.09%, as- Growth, Cobia Ro/Ar (Com, is survival, (Salze et al., Rachycentron R dTau) Ar: 0.09-0.20%, as- morphological 2011) canadum is development Ro: 0.00-0.09%, as- Ro/Ar (Com, is Digestive (Salze et al., R dTau) Ar: 0.09-0.20%, as- enzyme activity 2012) is Gilthead Ro (Com, seabream Ro: 0.88-1.41% of (Pinto et al., eTau), Ar Growth NR Sparus ΣeAA 2013) (Com) aurata Japanese flounder (Chen et al., Ro (dTau) Ro: 0.09-0.45%, dm Growth R Paralichthys 2005) olivaceous Red Sea (Chen et al., bream Ro (dTau) Ro: 0.11-0.32%, dm Growth R 2004) Pagrus major Senegalese Ro, (Com, 0.77-0.93 Growth, sole (Pinto et al., eTau), Ar (FH, FM, cuttlefish metamorphosis R Solea 2010) (Com) meal, crystal) success senegalensis Northern ACCEPTED MANUSCRIPTGrowth, rock sole development (Hawkyard et Ro (eTau) Ro: 0.04-0.18%, dm R Lepidopsetta stage, larval al., 2014) polyxystra taurine content Yellowtail Survival, (Rotman et Seriola Ro (dTau) Enriched R Growth al., 2012) lalandi White Seabass Survival, (Rotman et Ro (dTau) Enriched ? Atractoscion Growth al., 2012) nobilis Ar: Artemia spp; Com: commercial enrichment product; dm: dry-matter basis; dTau: crystal taurine dissolved in enrichment medium; eTau: encapsulated taurine fed to prey for enrichment; FH: fish hydrolysate; FM: fishmeal; NR: not required; R: required; Ro: rotifer; Tau: taurine; WZ: wild zooplankton; ΣeAA: sum of essential amino acids.

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Highlights

 In susceptible species, dietary taurine must be supplemented when using taurine-poor

ingredients in feeds

 However, taurine is currently not listed as an approved ingredient for animal feeds in the

USA

 Taurine is involved in bile salt formation, membrane stability, immunomodulation, anti-

oxidation and mitochondrial function, and calcium-signaling

 The roles of taurine and its mechanisms in fish remain poorly described

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