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Detailed product and ingredient information on Releira, the patent-pending, concentrated DHA supplement from Arenus. Research proven to support reproductive health in mares and stallions along with cognitive development in foals.

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Published by Arenus, 2017-12-01 14:10:25

Releira Whitepaper

Detailed product and ingredient information on Releira, the patent-pending, concentrated DHA supplement from Arenus. Research proven to support reproductive health in mares and stallions along with cognitive development in foals.

Keywords: releira,arenus,equine,horse,reproductive,omega-3,omega 3,dha,mare,broodmare,foal,stallion,supplement,health

WHITEPAPER


TABLE OF CONTENTS

I. Executive Summary����������������������������������������������������������������������������������������������������������������������������������3
II. Background�����������������������������������������������������������������������������������������������������������������������������������������������3

a. Fatty Acids: Omega 3 & Omega 6�������������������������������������������������������������������������������������������������3
b. DHA and Reproduction������������������������������������������������������������������������������������������������������������������3

Other Species�������������������������������������������������������������������������������������������������������������������������������3
Horses��������������������������������������������������������������������������������������������������������������������������������������������4
c. Other Omega-3 Findings����������������������������������������������������������������������������������������������������������������4
III. Ingredients – Description, Inclusion Rationale, Mechanism of Action����������������������������������������4
a. Flaxseed Meal���������������������������������������������������������������������������������������������������������������������������������4
b. Algal DHA�������������������������������������������������������������������������������������������������������������������������������������4-5
c. Vitamin C�������������������������������������������������������������������������������������������������������������������������������������������5
d. Vitamin D������������������������������������������������������������������������������������������������������������������������������������������5
e. Vitamin E�������������������������������������������������������������������������������������������������������������������������������������������5
f. Alfalfa Meal���������������������������������������������������������������������������������������������������������������������������������������5
g. Saccharin, Sorbitol and Flavoring������������������������������������������������������������������������������������������������5
IV. RELEIRA® Components – Feed Levels and Safety���������������������������������������������������������������������������6
a. Flaxseed Meal and Algal DHA������������������������������������������������������������������������������������������������������6
b. Vitamin C�������������������������������������������������������������������������������������������������������������������������������������������6
c. Vitamin D������������������������������������������������������������������������������������������������������������������������������������������6
d. Vitamin E�������������������������������������������������������������������������������������������������������������������������������������������7
e. Alfalfa Meal��������������������������������������������������������������������������������������������������������������������������������������7
f. Saccharin, Sorbitol and Flavoring�������������������������������������������������������������������������������������������������7
V. References�������������������������������������������������������������������������������������������������������������������������������������������� 7-8

Altera International, Ltd.

CONFIDENTIAL

Do not photocopy without the written permission of Altera International, Ltd. For discussion purposes only. Ref-
erences are for informational purposes. Altera does not necessarily agree with references cited or the conclu-

2 sions of the researchers.


I. EXECUTIVE SUMMARY 3

This whitepaper evaluates the efficacy and safety of the omega-3 fatty acids, alpha
linolenic acid (ALA) and docosahexaenoic acid (DHA), the primary active components in
RELEIRA® by Arenus. RELEIRA targets reproductive support of equines by supplying
omega-3 fatty acids to optimize the dietary fatty acid profile. In this whitepaper, the
formula components of RELEIRA are briefly discussed.

II. BACKGROUND

a. Fatty Acids: Omega-3 and Omega-6

Fats or oils have been generally used in equine diets to increase energy density, to
improve energetic efficiency, enhance body condition, or for metabolic adaptations that
increase the use of fat as a source of energy during exercise. Most of the supplemental
fat has been sources of omega-6 fats such as corn or soybean oil; but in recent years,
interest in the potential health benefits of the omega-3 fatty acids has grown and new
sources have included ALA from flaxseed meal or oil, and EPA and DHA from fish oil
[16]. Additionally, the desire for vegetarian and renewable sources of long chain omega-3
fatty acids (e.g., DHA) has led to the development of sustainable algal source such
as those used in RELEIRA. Research on omega-3 fatty acids relevant to reproductive
function is described below.

b. DHA and Reproduction

Other Species

There is evidence in a number of species that suggests DHA or other omega-3 fatty acids
may favorably affect reproduction in both females and males. Experimentally, in female
rodents, for example, incorporation of omega-3 appeared to enhance ovulation [23].
Several studies in cattle and other mammals have shown that altering the omega-6
to omega-3 ratio may alter the number and size of ovarian follicles, ovulation rate,
progesterone production by the corpus luteum, and timing of luteolysis and gestational
length. In males, recent work has focused on sperm production. Experiments in fowl
have demonstrated clear effects of dietary polyunsaturated fatty acids (PUFAs) on both
the sperm membrane phospholipid composition and on fertilizing ability [1].
Recently, a study pointed out that omega-3 PUFAs “may benefit fertility in cattle and
reduce the risk of preterm labor in women. In both cases, current evidence to support
this is inconclusive” [26]. Additionally, it has been suggested that omega-3 fatty acid
supplementation may be useful to support full term pregnancy in women with recurrent
and spontaneous preterm births [22].
In humans, DHA is required for normal brain and visual development. It is important for
pregnant women to build body stores of DHA to ensure optimal development of the
fetus and child [11]; DHA crosses the placenta and is present in breast milk. Thus, it is
plausible, though not yet proven, that DHA status—or at least adequate ALA status—
could possibly be of benefit to the unborn foal.
Spermatozoa require a high PUFA concentration to provide their plasma membrane
with the necessary fluidity that is essential for fertilization. However, their high PUFA
concentration makes spermatozoa particularly vulnerable to attack by reactive oxygen
species, and lifestyle factors promoting oxidative stress have clear associations with
reduced fertility [26]. This suggests that adequate antioxidant status is important in
protecting spermatozoa and improving semen quality. In a recent study, vitamin C
supplementation in infertile men was found to improve sperm count, sperm motility and
sperm morphology [4].


Horses

Omega-3 and omega-6 balance can affect eicosanoid biochemistry. Eicosanoids control complex bodily functions
including reproduction. A shift toward more omega-3’s may lead to the production of fewer eicosanoids that
negatively affect inflammation and reproduction [12]. Oral supplementation of mares with RELEIRA® demonstrated
a significant reduction in uterine inflammation following insemination with frozen semen [5]. It has also been
shown that supplementing mares with DHA (RELEIRA®) in late gestation and early lactation increases DHA levels
in their foals [3].
Further, reproductive performance in stallions has been shown to benefit from DHA supplementation [7].
While supplemental DHA may improve the motion characteristics of cool-stored stallion semen, it may be most
beneficial for stallions suffering from marginal fertility whose sperm do not tolerate the rigors of cooling and
storage. Trials with a greater number of horses are warranted.

c. Other Omega-3 Findings

It is interesting to note that other trials with promising findings have been carried out with omega-3
supplementation in horses. Examples include:

• Improved vascular compliance with LC-PUFAs has been reported, which might assist exercise-induced hy
pertension and associated pulmonary hemorrhage [20]. Vascular compliance is the ability of a blood vessel wall
to expand and contract passively with changes in pressure, and is an important function of large arteries and
veins;
• Omega-3 supplementation has been reported to lower heart rate in exercising horses, which could possibly
delay fatigue [18];
• Increased stride length in exercising horse has also been reported with omega-3 supplementation [28], as has
decreased inflammatory markers in arthritic horses [14].
• Horses with chronic lower airway inflammation (RAO and IAD) supplemented with ALEIRA® by Arenus, con
taining DHA, MSM and a mushroom matric, showed significant improvement in clinical signs [17].
• Exposure to DHA (RELEIRA®) during the perinatal period may improve long-term memory and enhance learn
ing ability in young horses [2].

III. INGREDIENTS

DESCRIPTION, INCLUSION RATIONALE,
AND MECHANISM OF ACTION

a. Flaxseed Meal

The flaxseed meal in RELEIRA is a high-quality source for omega-3 fatty acids. ALA is important in supporting
essential fatty acid status of the animal. This particular flaxseed meal also helps to stabilize the added DHA in
RELEIRA.

b. Algal DHA

The feed grade fatty acids in RELEIRA are derived from algae and a vegetarian source of DHA. DHA supports a
healthy immune response, cognitive development, visual acuity and cardiovascular health. As discussed, DHA
may improve some aspects of sperm quality and could possibly support DHA status of the unborn foal.
The long chain omega-3 fatty acids may influence reproductive function by contributing to the membrane fluidity
of sperm that is essential at fertilization, by enhancing the motility of cooled sperm: in mares, long chain omega-3
fatty acids may influence reproduction possibly via eicosanoids (prostaglandin family), which can influence luteal
function [7, 8, 26]. Additionally, placental transfer of long chain fatty acids may improve the DHA status of the
unborn foal, thereby supporting proper in utero development.
According to the International Society for the Study of Fatty Acids and Lipids (ISSFAL), the ability in humans to

4 convert ALA to DHA at levels that confer physiological benefit is insufficient. DHA status in the body, according to


ISSFAL, is most effectively raised by consuming pre-formed DHA [6]. This bolsters the
rationale for inclusion of DHA in the reproductive and respiratory formula.

c. Vitamin C

Vitamin C is a water-soluble antioxidant also necessary for collagen and norepinephrine
production, and for normal cellular immunity. Vitamin C supports natural killer (NK) cell
and lymphocyte activities, for example [27].
Although horses are able to synthesize vitamin C in their liver, supplemental vitamin
C may bolster overall vitamin C status. In humans, vitamin C supplementation has
been shown to improve sperm quality [4]. Presumably this effect is due to antioxidant
activity, as spermatozoa contain high levels of long-chain PUFAs, which are vulnerable to
oxidation.

d. Vitamin D

Vitamin D is supplied for its immune modulating effect, as it may suppress inflammation.
In turn, it may enhance placental immune function and support general reproductive
performance.
The enzyme (1α-hydroxylase) that activates vitamin D is expressed by human placental
tissue. Some researchers have described how induction of the vitamin D-activating
enzyme in early gestation might provide a mechanism by which vitamin D can influence
fetal-placental development [9].
Although there are no equine-specific studies in regards to the above functions of
vitamin D, it is plausible that this fat soluble vitamin has similar effects in horses.

e. Vitamin E

Vitamin E is added as an antioxidant and is supplied at up to twice the National
Research Council (NRC) requirement (for a 500 kg horse) because of the high levels of
polyunsaturated fatty acid in the product. The level of polyunsaturated fatty acid may
increase the requirement for vitamin E [16].
In humans, it has been suggested that high intake of long-chain polyunsaturated fatty
acids may raise the requirement for vitamin E somewhat, as these fatty acids are
vulnerable to oxidative damage [24]. As the primary fat-soluble antioxidant, vitamin E is
incorporated into cellular membranes where PUFAs are located and protects them from
peroxidation, for example, in spermatozoa.

f. Alfalfa Meal

Alfalfa meal is a palatant included to ensure that the product appeals to horses.

g. Saccharin, Sorbitol and Flavoring

Saccharin and sorbitol are sugar-free sweeteners to improve taste. Flavor is added to
provide an appealing aroma for the horse.

5


IV. RELEIRA® COMPONENTS

FEED LEVELS AND SAFETY

a. Flaxseed Meal and Algal DHA

The level of flaxseed meal included in the reproductive product is limited by practicality of the formula, but helps
delivers a large amount of n-3 fatty acids (minimum 7.2 g total n-3 per serving) that supports the
n-3:n-6 balance.
Feed grade fatty acid delivers at least 2.0 g DHA in a single serving of RELEIRA. This value is approximately
200% of the suggested minimum human serving (on metabolic BW equivalency basis). The amount of total
omega-3s and DHA contribute to favorably modifying the omega-6 to omega-3 ratio. A study [12] tested 10, 20
and 40 g of a long-chain PUFA supplement per day in mares and found a dose response. With the 40 g level,
DHA concentrations were up to ten times higher than control animals. Others have also examined the effects
on long-chain PUFA concentrations at high levels of supplementation, such as 18 g of combined EPA and DHA
[13]. All these studies were of short duration with extremely high DHA supplementation levels of up to ten times
the human equivalent Recommended Dietary Intake or up to six and a half times the equivalent Recommended
Allowance in dogs set by the NRC [15]. Chronic supplementation with lower levels, ensuring a constant, sufficient
pool of omega-3s is not only more economical, but also could prevent potential negative side effects of extreme
omega-3 supplementation.
It should be pointed out that little is known about the naturally occurring concentrations of omega-3 fatty acids
in horses, the amount of omega-3 fatty acids required to influence circulating fatty acid levels, or what an optimal
omega-6 to omega-3 ratio should be [12]. There is also no clear ‘optimal’ ratio established for humans, but ratios
as low as 2.5:1 are considered beneficial compared to those of 10:1 and higher [21].
Safety: There is no safety concern with the dose of fatty acids supplied by RELEIRA. However, it should be
noted that most equine studies with omega-3 in the literature are short term (less than 3 months), and therefore
the effects of long-term feeding are not well known. Additionally, the forage-based diet typically consumed by
free-roaming horses delivers significantly greater amount of omega-6 fatty acids as compared to omega-3. It is
possible that horses could derive some health benefits from a greater omega-6 to omega-3 ratio than the one
often recommended for humans [12].
Flaxseed meal may contain lignans, which have weak estrogenic and anti-estrogenic activity in humans. However,
it appears that the intake of lignans associated with common supplemental flaxseed levels is safe for horses. One
study examined the effects of one pound of high quality flaxseed per 1000 pounds of body weight per day on the
common dermatologic ailment “sweet itch” in horses [19], and reported beneficial effects of flaxseed with no
negative side effects. According to the study’s author, “flaxseed is a common additive to many equine diets.”

b. Vitamin C

Supplemental vitamin C may potentially augment endogenous ascorbic acid production, although horses do not
have any dietary requirement for vitamin C. The serving provided by RELEIRA is equal to approximately two times
the human body weight equivalent serving.
Safety: Though horses synthesize vitamin C, this supplemental level of vitamin C does not pose a safety concern.
Daily servings of 20 g (approximately 44 mg of ascorbic acid/mg body weight) have been administered to horses
over a period of eight months with no apparent ill effects [16].

c. Vitamin D

Supplemental vitamin D in this product represents approximately two times the NRC recommendation to support
healthy immune function.
Safety: NRC indicates that 300 IU per 100 pounds of body weight is adequate for horses, though horses exposed
to sunlight may not require supplemental amounts. The presumed upper safe limit is 44 IU/kg (2.2 lbs) of body
weight, which would be about 22,000 IU for a 500 kg horse. In humans, recent research indicates that levels
beyond the current RDA are beneficial and safe [25, 10]. The form of vitamin D most commonly supplemented is
D3, the form included in RELEIRA.

6


d. Vitamin E 7

Vitamin E is added to RELEIRA to support antioxidant status and is formulated to deliver
up to two times NRC recommended levels because of the high amount of omega-3
fatty acids in the formulas. Additionally, this supplementation level ensures adequate E
concentrations even as the product nears the end of its shelf life.

Safety: This level does not pose safety concerns. The NRC maintenance requirement
is 1 IU/kg body weight, and the NRC states that the upper safe level is 1000 IU/kg DM
(equal to about 10,000 IU for a 500 kg horse).

e. Alfalfa Meal

Alfalfa meal is a common component of a normal horse ration and is safe to feed to
gestating horses.

f. Saccarin, Sorbitol and Flavoring

These sweeteners and flavors are approved for use in animals and do not pose safety
concerns.

V. REFERENCES

[1] Abayasekara DR, Wathes DC. Effects of altering dietary fatty acid composition on prostaglandin
synthesis and fertility. Prostaglandins Leukot Essent Fatty Acids. 1999; 61: 275-287.

[2] Adkin AM, Muniz AV, Mortensen CJ, Warren LK. Maternal fatty acid supplementation influences
memory and learning ability in yearling and 2-year-old horses. J Equine Vet Sci. 2015; 35: 418-436.

[3] Adkin AM, Warren LK, Mortensen CJ, Kivipelto J. Maternal supplementation of docosahexaenoic
acid and its effect on fatty acid transfer to the foal. J Equine Vet Sci. 2013; 33: 321-399.

[4] Akmal M, Qadri JQ, Al-Waili NS, Thangal S, Hag A, Saloom KY. Improvement in human semen quality
after oral supplementation of vitamin C. J Med Food. 2006; 9(3): 440-442.

[5] Brendemuehl JP, Altman J, Kopp K. Influence of dietary algal N-3 fatty acids on breeding induced
inflammation and endometrial cytokine expression in mares bred with frozen semen. J Equine Vet
Sci. 2014; 34(1): 123-124.

[6] Brenna JT, Salem N, Sinclair AJ, Cunnane SC. alpha-Linolenic acid supplementation and conversion
to n-3 long-chain polyunsaturated fatty acids in humans. Prostaglandins Leukot Essent Fatty Acids.
2009; 80(2-3): 85-91.

[7] Brinsko SP, Varner DD, Love CC, Blanchard TL, Day BC, Wilson ME. Effect of feeding a DHA-
enriched nutriceutical on the quality of fresh, cooled and frozen stallion semen. Theriogenology. 2005;
63(5): 1519-1527.

[8] Cheng Z, Robinson RS, Pushpakumara PG, Mansbridge RJ, Wathes DC. Effect of dietary
polyunsaturated fatty acids on uterine prostaglandin synthesis in the cow. J Endocrinol. 2001; 171(3):
4 6 3 - 473.

[9] Evans KN, Bulmer JN, Kilby MD, Hewison M. Vitamin D and placental-decidual function. J Soc
Gynecol Investig. 2004; 11(5):263-271.

[10] Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007; 85:
6 -18.

[11] House SH. Schoolchildren, maternal nutrition and generating healthy brains: the importance of
lifecycle education for fertility, health and peace. Nutr Health. 2009; 20: 51-76.

[12] King SS, AbuGhazaleh AA, Webel SK, Jones KL. Circulating fatty acid profiles in response to three
levels of dietary omega-3 fatty acid supplementation in horses. J Anim Sci. 2008; 86: 1114-1123.

[13] Kruglik VL, Kouba JM, Hill CM, Skjolaas-Wilson KA, Armendariz C, Minton JE, Webel SK. Effect
of feeding protected n-3 polyunsaturated fatty acids on plasma and milk fatty acid levels and IgG
concentrations in mares and foals. Proc 19th Equine Sci Soc. 2005; 135-36.

[14] Manhart DR, Scott BD, Eller DM, Honnas CM, Hood DM, Cloverdale JA, Gibbs PG. Effect of n-3
PUFAs on markers of inflammation in arthritic horses. Proc 20th Equine Sci Soc. 2007; 11-12.

[15] National Research Council. Nutrient requirements of dogs and cats. National Academies Press,
2006.

[16] National Research Council. Nutrient Requirements of Horses, 6th Ed; National Academies Press,
2007.

[17] Nogradi N, Couetil LL, Messick J, Stochelski MA, Burgess JA. Omega-3 fatty acid supplementation


provides an additional benefit to a low-dust diet in the management of horses with chronic lower
airway inflammatory disease. J Vet Intern Med. 2015; 29(1): 299-306.
[18] O’Connor CI, Lawrence LM, Lawrence AC, Janicki KM, Warren LK, Hayes S. The effect of dietary fish oil supplementation on
exercising horses. J Anim Sci. 2004; 82(10): 2978-2984.
[19] O’Neill W, McKee S, Clarke AF. Flaxseed (Linum usitatissimum) supplementation associated with reduced skin test lesional area
in horses with Culicoides hypersensitivity. Can J of Vet Res. 2002; 66(4): 272-277.
[20] Portier KB, de Moffarts B, Fellman N, Kirschvink N, Motta C, Letellierw C, Ruelland A, van Erck E, Lekeux P, Couder J. The effects
of dietary N-3 and antioxidant supplementation on erythrocyte membrane fatty acid composition and fluidity in exercising horses.
Equine Vet J Suppl. 2006; 36: 279-284.
[21] Simopoulos, AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases.
Exp Biol Med. 2008; 233(6): 674-688.
[22] Spong CY. Prediction and prevention of recurrent spontaneous preterm birth. Obstet Gynecol. 2007; 110(2 Pt 1): 405-415.
[23] Trujillo EP, Broughton KS. Ingestion of n-3 polyunsaturated fatty acids and ovulation in rats. J Reprod Fertil. 1995; 105: 197-203.
[24] Valk EE, Hornstra G. Relationship between vitamin E requirement and polyunsaturated fat intake in man: a review. Int J Vitam Nutr
Res. 2000; 70: 31-42.
[25] Veith R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, Holick MF, Hollis BW, Lamberg-Allardt C,
McGrath JJ, Norman AW, Scragg R, Whiting SJ, Willett WC, Zittermann A. The urgent need to recommend an intake of vitamin D
that is effective. Am J Clin Nutr. 2007; 85: 649-650.
[26] Wathes DC, Abayasekara DR, Aitken RJ. Polyunsaturated fatty acids in male and female reproduction. Biol Reprod. 2007; 77: 190-
201.
[27] Wintergerst ES, Maggini S, Hornig DH. Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Ann Nutr
Metab. 2006; 50(2): 85-94.
[28] Woodward AD, Nielson BD, O’Connor CI, Webel SK, Orth MW. Dietary long chain polyunsaturated fatty acids increase plasma
EPA and DHA concentrations and trot stride length in horses. Proc 19th Equine Sci Soc. 2005; 101-106.

©2010 Altera International, Ltd. All rights reserved

8 ®RELEIRA, ARENUS and are registered trademarks of Altera International, Ltd. and are registered in the United States and other countries.


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