METABOLISM AND NUTRITION

Centennial Review: Trace mineral

research with an emphasis
on manganese

Dedicated to Dr. Roland M. Leach, Jr.

1
Michael S. Lilburn

Department of Animal Science, The Ohio State University, Wooster, OH 44691, USA

ABSTRACT A century of publications in the Poultry in the synthesis of the epiphyseal matrix. The TM
Science journal is celebrated with Centennial papers. It research agenda today is considerably different with
is relevant, therefore, to explore trace mineral (TM) respect to all trace nutrients and is largely driven by gut
research with an emphasis on manganese and selected health, antibiotic free production, food safety and envi-
aspects of skeletal development. Some of the initial ronmental outcomes. A significant proportion of the
observations on the topic appeared in the earliest vol- published research over the last 2 decades has focused
umes of our journal. Published studies in the late 1920’s on the form (i.e., organic, inorganic) of a given TM rela-
and 1930’s confirmed the importance of the diet and tive to a given physiologic or production response under
unidentified organic (i.e., vitamins) and inorganic the pretext that modern commercial genotypes and pro-
nutrients (i.e., TM) relative to skeletal development. duction realities have changed considerably since the
The early nutrition research emphasized requirement last NRC publication (NRC, 1994). If one closely
studies, the search for unknown factors to alleviate rec- reviews the more recent scientific literature, however, it
ognized deficiencies, and lastly important nutrient inter- could be argued that the term “trace mineral require-
actions, especially in the gut. This review will discuss ment” is often a misnomer. Many of the TM levels rec-
TM research with an emphasis on manganese (Mn). ommended or in use today are not the result of
Some of the fundamental discoveries on the mechanisms quantifiable requirement studies but are often based on
underlying embryonic and post-hatch skeletal develop- efficacy comparisons with the different organic and inor-
ment led directly to research directed at the role of Mn ganic forms of commercially available TM.
Key words: embryo, manganese, perosis, proteoglycan, skeleton
2021 Poultry Science 100:101222
https://doi.org/10.1016/j.psj.2021.101222

INTRODUCTION or combinations of ingredients with curative properties

(i.e., rice bran, wheat germ). The early delineation of
An extensive treatise on post-hatch skeletal growth what we now know as essential vitamins (organic) and
was published by Latimer (1927). During the following TMs (inorganic) were often defined by their presence or
decades, there was considerable nutrition research on absence in the ash of curative ingredients. As will be
skeletal development in poultry with the goal of alleviat- noted later in this paper, Gallup and Norris (1939a)
ing the prevalent skeletal anomalies of that particular observed that while 50 ppm Mn would decrease the inci-
era. (i.e., perosis; rickets). At the time these early reports dence of perosis in New Hampshire chicks, only 30 ppm
were being published, essential vitamins and trace min- was needed by leghorn chicks. This was one of the first
erals (TMs) were still largely unknown. The design of a instances in which genotype differences were included in
given experiment to study a specific clinical problem the discussion on nutritional requirements.
often had treatments which were simply different levels Creek et al. (1960) would later show that body weight
was a determinant of the severity of perosis. In a paper
Ó 2021 The Authors. Published by Elsevier Inc. on behalf of Poultry considered to be one of the seminal publications on skele-
Science Association Inc. This is an open access article under the CC BY tal growth in poultry, Church and Johnson (1964)
license (http://creativecommons.org/licenses/by/4.0/).
Received March 4, 2021.
showed that within a genotype, body weight and bone
Accepted April 16, 2021. growth curves are very similar through 5 days post-
1
Corresponding author: [email protected]

1
2 LILBURN

hatch after which the inherent variability within a popu- (Drummond, 1916; Osborne and Mendel, 1918). These
lation increases. They noted that in both Barred Rock defined diets became the research tool used in establish-
and Leghorn chicks, long bone development was greatest ing the importance of many essential micronutrients
from 0 to 3 weeks and overall skeletal maturation was (i.e., Vitamin A; Hart et al., 1920; 1924) and in the
accelerated in the heavier, Barred Rock chicks. The criti- determination of which micronutrients/ingredients were
cal importance of the first 3 weeks post-hatch, especially effective in alleviating major nutritional deficiencies
in commercial broiler genotypes, was subsequently con- (i.e., cod liver oil and rickets; Dunn, 1924). Numerous
firmed by Williams et al. (2000) and Applegate and Lil- reports from this era used BW as a primary metric for
burn (2002). studying nutrient and ingredient interactions and many
It has been well documented that genetic selection has of these studies included notations on skeletal issues,
been largely responsible for the improved growth and often referred to as “leg weakness” (Hart et al., 1920,
carcass traits in commercial broilers (Reddy, 1996; 1922; Johnson, 1925). There were also those research
Havenstein et al., 2003a,b). Yair et al. (2017) more groups that questioned the applicability of synthetic
recently reported that post-hatch differences in genetic diets in studies relative to optimizing the growth and
growth potential may also be reflected in embryonic development of chicks reared in artificial or confined
skeletal traits, using reciprocal matings between fast environments (Hogan et al., 1925, 1928; Hogan and
and slower growing strains to experimentally equalize Shrewsbury, 1930). It was during this time that McCar-
egg size. Commercial selection programs in broiler and rison (1927) reported some of the first observations on a
turkey genotypes have not only changed their growth dietary requirement for manganese (Mn) in rats.
and carcass characteristics but also the relationships
between the latter 2 traits and the physiology of growing
lone bones (Leach and Nesheim, 1965; Leblanc et al., Ingredient and Macromineral Interactions
1986; Kestin et al., 1992; Leterrier and Nys, 1992; Pitsil-
lides et al., 1999; Williams et al., 2004). Changes in car- Norris et al. (1930; 1931) described a “nutritional
cass conformation and the potential for carryover effects paralysis” of the lower skeleton and noted that dietary
on ambulation in commercial broilers have also contrib- supplementation with meat scrap, menhaden fish meal,
uted to an increased incidence of bacterial chondronec- and dried whale meat did not alleviate this condition
rosis in the tibia and femur (Wideman and Prisby, 2013, and speculated that possibly a third, unidentified essen-
Wideman et al., 2014, Wideman, 2016). The resulting tial vitamin in milk was involved. At the time, vitamin
lameness from these bacterial challenges have both eco- B (polyneuritis) and vitamin G (pellagra) were recog-
nomic and animal welfare consequences. In addition to nized trace factors found in milk and milk products.
the aforementioned genotype changes, nutrition and Hart et al. (1930b) dismissed the idea of an unknown
management approaches have also changed consider- vitamin and countered that the “nutritional paralysis”
ably over the years, largely the result of the paradigm described by Norris had been observed several years ear-
shift to antibiotic free production and the advent of lier in chicks which had consumed “ample quantities of
third party welfare audits of production facilities. milk”. Chicks with “range paralysis” were sent from the
The citations often referenced in the published litera- Ontario Agricultural College (Professor Graham) to the
ture and/or recent reviews on TM supplementation will University of Toronto for bone structure analysis (histol-
often include publications from the 1960’s and 1970’s. A ogy), Ca and P determination (bone, serum) and bone
critical review of the literature, however, shows that phosphatase levels (Hall and King, 1931). The authors
papers published 20-30 years earlier paved the way for reported that histology, serum and bone measurements
the subsequent discoveries on the essentiality of key were similar with the only abnormal findings being a
TM. The perceived lack of appreciation for the founda- “subluxation, bowing and rotation” of the bones. The
tion papers underlying our present understanding of TM symptoms described in the Norris and Hart reports were
was the motivation for the writing of this review. It similar to the “range paralysis” described by Hall and
seemed appropriate to include this as a Centennial paper King (1931) and later Wilcke et al. (1933). As the inci-
for Poultry Science given that the initial research dis- dence of these long bone anomalies became more com-
cussed herein was conducted and subsequently pub- mon, Titus (1932) suggested that there appeared to be a
lished in some of the earliest issues of the journal. consistent pattern of adverse skeletal events which he
lumped together, coining the term “perosis.” The individ-
Development of Defined Diets ual sequential events included an initial enlargement of
the hock with hemorrhages in surrounding tissues, cur-
The initial, underlying research which established the vature of the tibia, and finally a slipping of the gastroc-
dietary requirements for many trace nutrients occurred nemius tendon from the underlying articular cartilage,
during a time when unidentified factors were starting to hence the term “slipped tendon.” He acknowledged that
be recognized as being important dietary cofactors. It is this sequence of individual pathologies was similar to
important to note that during this earlier research what had been previously described by Payne (1930).
period, there was a considerable focus on the develop- Milby (1934) later reported that the “slipped tendon”
ment of synthetic or defined diets which largely used was a major causal factor in the structural bending of
chicks as the experimental animal model the bone (i.e., bowed legs) and hypothesized that the
 MANGANESE NUTRITION IN POULTRY 3
degree of tibial curvature was related to the severity of corn with 5 to 10% rice bran or 20% wheat gray shorts
the deformity. would reduce the percentage of slipped tendons. At the
In an interesting series of experiments reported by 25th annual PSA meeting, Branion (1933) reported that
McFarlane et al. (1931), individual animal protein sour- chicks fed a nutritionally adequate diet containing corn
ces (meat meal, buttermilk powder, fish meal, gelatin, as the only cereal resulted in considerable bowing of the
cod liver meal, casein plus yeast derivatives) were incor- long bones with a high proportion of slipped tendons,
porated into otherwise defined diets to compare their similar to what was observed by Hogan et al. (1925).
efficacy in supporting chick growth. All the diets were The incidence of the condition decreased with dietary
standardized to 18% CP and none of the “animal pro- inclusion of wheat germ or oat hulls/germ and the posi-
tein” sources alone would support acceptable chick tive effects of wheat germ were later confirmed by
growth without accompanying “leg weakness.” Visible Graham et al. (1934), contrary to what had previously
deficiency symptoms associated with individual protein been reported by Bethke et al. (1931). This latter point
sources varied with the age of the chicks. The basal diet emphasizes some of the contradictions in the early litera-
with fish meal was similar to that of ture that may have been simply the result of the vari-
Plimmer et al. (1927) who had successfully reared chicks ability due to sourcing of the ingredients used in the
with no reported skeletal issues. One noted difference early research. It is also interesting to note that in stud-
between the 2 reports, however, was the use of dextrin ies conducted almost 60 years later (Halpin and
as a carbohydrate source by McFarlane et al. (1931) Baker, 1987), the not as yet defined neutral detergent
whereas Plimmer et al. (1927) had used white rice. fiber fraction in common ingredients was reported to be
McFarlane et al. (1931) subsequently included white a significant modulator of Mn absorption.
rice (~50%) in a basal diet replacing dextrin and this
improved growth and markedly decreased leg issues and
mortality. These authors limited their conclusion to The Move Beyond Bone Mineralization
some component of “rice protein” in eliciting or facilitat-
ing the beneficial response. The results of McFarlane The recognition that previously unknown dietary fac-
et al. (1931) supported previous observations by tors could be influencing skeletal development was based
Hogan et al. (1925) who reported considerable improve- largely on secondary observations in studies which
ments in chick growth through maturity when corn emphasized the roles of Ca, P, and the Ca:P ratio in
starch was replaced by polished rice in semi-purified bone mineralization (Hart et al., 1930a). There was a
diets. growing consensus that the total mineral content (Ca,
The published results of McFarlane et al. (1931) P) and source of minerals (i.e., bone meal) in the diet
increased research interest relative to identifying which were positively related to the incidence of perosis with
ingredients or ingredient fractions could potentially no effects on bone morphometry or ash content
reduce the incidence of “leg weakness”. (Hall and King, 1931; Herner and Robinson, 1932;
Bethke et al. (1931) reported that wheat middlings with Holmes et al., 1933). Payne et al. (1932) reported that a
germ and wheat germ alone improved growth but did mix of minerals including calcium phosphate and cal-
not cure perosis whereas dried pork and beef liver were cium carbonate resulted in the same incidence of perosis
effective. The annual meeting of the Poultry Science as steamed bonemeal. Parkhurst and McMurray (1933)
Association (PSA) became an increasingly important observed that perosis was negligible if meat and bone
forum for the sharing of data and these presentations meal levels were low or calcium carbonate was the pri-
became the basis for much of the early published litera- mary source of calcium. Milby (1933) ran a statistical
ture. At the 23rd annual PSA meeting, 3 papers were analysis with single and multiple correlations using pub-
presented on the “slipped tendon and hock disease.” lished data available at the time (Mussehl et al., 1927;
Hunter et al. (1931) reported that oats and oat fractions Hunter and Funk, 1931; Payne et al., 1932; Titus, 1932).
alleviated the condition in leghorn pullets while The correlation (r = 0.630) between percentage slipped
Titus and Ginn (1931) observed a similar effect with tendons and total dietary P was significant and as good
dietary inclusion of 10% rice bran. Buckner et al. (1931) a predictor as the combination of all the factors tested
discussed and contrasted the slipped tendon condition (dietary Ca, protein, P, bone ash). Insko et al. (1934)
with deformed metatarsal bones resulting from supple- observed that simply widening the Ca:P ratio did not
mentation with different combinations of magnesium increase the incidence of slipped tendons but when bone
carbonate and tricalcium phosphate. Titus (1932) meal was used to increase P levels as part of the ratio
reported on a “chance observation” that showed the adjustment, there was an increased incidence, support-
effectiveness of rice bran in reducing the incidence of ing the correlation analysis by Milby (1933). At the 27th
perosis with subsequent experiments suggesting that 6% PSA meeting (1935), Hammond (1935) noted that die-
rice bran was the minimum effective supplementation tary inorganic P vs. organic or total P had the highest
level. It is possible that a small amount of rice bran in correlation with the incidence of perosis and there was a
with the white rice may have contributed to the benefi- negative correlation between perosis and Ca. It is inter-
cial effects previously attributed to McFarlane et al. esting to note that the form of P in the diet (inorganic,
(1931). Sherwood and Couch (1933) repeated the organic) reported by Hammond (1935) was several years
Titus (1932) experiments and reported that replacing before some of the initial reports in the literature on the
4 LILBURN

effects of phytate on P digestibility in poultry fed vege- between the Mn content of ingredients and the overall
table based diets (Common, 1939; Lowe et al., 1939). incidence of leg abnormalities including perosis. These
Wilgus et al. (1935) discussed how monosodium phos- authors also warned, however, of potential toxicity
phate and steamed bone meal were causative factors for issues when high levels of Mn (1.0 % MnCO3) were
perosis while among the practical ingredients, wheat included in the diet. Clifcorn et al. (1938) developed a
germ was effective in reducing the incidence, again in defined diet devoid of grains and grain byproducts and
support of earlier published data (Branion, 1933; this diet was subsequently used by Wiese et al. (1938) to
Graham et al., 1934). Schaible et al. (1935) supported determine which rice bran fractions and levels of supple-
the growing consensus that bonemeal and calcium phos- mental Mn might be effective in reducing the incidence
phate predisposed chicks to perosis whereas 5% added of perosis. Insko et al. (1938) fed diets with low or high
oyster shell (calcium carbonate) decreased the incidence. Ca and P levels in combination with 0 or 30 ppm supple-
This paper was also one of the first to discuss the concept mental Mn (MnSO4). At both 4 and 8 weeks of age, the
of acid/base balance and the source of protein as being diet with 30 ppm Mn was the only effective treatment in
predisposing factors, particularly in diets high in total reducing both average percentage bowed legs and
mineral content. These authors also observed that slipped tendons. In a subsequent experiment, the combi-
some chicks were hatched with a malady similar to pero- nation of 30 ppm Zn, Al, and Fe was tested alone or in
sis or acquired it early in life if the diet was low in total combination with Mn and only diets with supplemental
minerals. Mn proved to be effective, contrary to the moderately
positive effects of Zn and Al reported by Wilgus et al.
(1937b). Gallup and Norris (1938) subsequently
The Importance of Manganese observed that the slipped tendon and condyle issues
observed with Mn deficiency were accompanied by a
In their paper initially describing “nutritional paraly- measurable increase in tibia thickness and decreased
sis,” Norris et al. (1930) commented that one goal of tibia length. Caskey et al. (1939) later reported that
their research was to establish a defined reference diet wing bones in addition to the long bones were similarly
that could subsequently be used for Ca and P require- affected by Mn deficiency and hypothesized that Ca and
ment studies. At the seventh World’s Poultry Congress, P metabolism were dependent upon adequate dietary
Wilgus et al. (1939) discussed the happenstance observa- Mn.
tion that an impurity present in a particular source of
monocalcium phosphate prevented rather than exacer-
bated the incidence of perosis (Wilgus et al., 1937a). Manganese Interactions in the Intestine
The impurity was subsequently shown to be manganese
(Mn) and shortly thereafter it was reported to be a The late 1930’s was a focused period with respect to
major dietary factor predisposing chicks to the onset of research interest in mineral interactions within the intes-
perosis if fed Mn deficient diets (Wilgus et al., 1936; tine relative to their digestibility and subsequent bio-
Wilgus et al., 1937b). It was suggested that 35 ppm Mn availability. Schaible et al. (1938) published an
was needed to minimize perosis and this was one of the extensive review of the existing literature on Mn and
first actual requirements published for a TM (Wilgus perosis which included analytical values for the Mn con-
et al., 1936; 1937a). Wilgus et al. (1937a) later reported tent of multiple ingredients/forages. This review also
that supplementing Zn and Al would also moderately included 2 interesting references on the location of Mn
reduce the incidence of perosis but a combination of Mn, within different plant species and its importance to plant
Fe, and Al was the most effective dietary treatment, par- and potentially animal metabolism (McHargue, 1914;
ticularly in diets with minimal levels of Ca and P. These 1922). The location of Mn within the plant could help
authors subsequently suggested that the preventive explain the subsequent observations that the bran frac-
effects of different cereal grains were a function of their tions from rice and wheat were beneficial at reducing the
Mn content. At the 1936 PSA meeting, Heller and Pen- incidence of perosis. Schaible et al. (1938) developed
quite (1936) presented several years of data on diet/skel- high mineral (32% corn; 6% bonemeal; 37 ppm Mn) and
etal weakness and confirmed the link between high low mineral (67% corn; 11 ppm Mn) diets which induced
mineral levels and perosis. They noted that after encour- perosis and hypothesized these diets either decreased
agement from Wilgus to include supplemental Mn in Mn solubility/availability in the gut (bonemeal) or
subsequent studies, they too were able to confirm the resulted in a frank Mn deficiency (high corn diet). When
beneficial effect of Mn (Heller and Penquite, 1937). 30 ppm Mn from different salts was added to the low
These authors also observed that 15% rice bran was not mineral, high corn diet (11 ppm Mn), 41 ppm total Mn
effective in reducing perosis in one particular study but minimized perosis, which was close to the 35 ppm sug-
in a follow-up experiment, the dietary inclusion of the gested as being adequate (Wilgus et al., 1937b). They
ash from 70 lb of rice bran was as effective as 0.02% also suggested that nutrient requirements derived from
MnCO3 or 0.02% MnCl2 in reducing perosis, thus sup- experiments with either a high proportion of corn or
porting the earlier data from Titus (1932) and increased mineral levels be reconsidered if these diets
Sherwood and Couch (1933). Heller and Penquite (1937) were atypical when compared with practical type diets.
concluded there appeared to be a positive relationship Wilgus and Patton (1939) would later support the
 MANGANESE NUTRITION IN POULTRY 5
hypothesis that insoluble Ca phosphates (i.e., steamed observed that wheat germ was also effective in reducing
bone meal) could precipitate Mn from solution and elicit perosis and this group subsequently reported the bene-
a deficiency in diets marginal in Mn. The partitioning fits of an organic component in concentrated extracts of
and subsequent availability of Mn from the liquid and wheat germ distinct from Mn (Van der Hoorn et al.,
solid phases of the intestinal digesta as affected by Ca 1938). Wiese et al. (1938) confirmed previous reports
and P was subsequently described in great detail by that rice bran and supplemental Mn were both effective
Bandemer and Schaible (1942) and Schaible and Ban- at minimizing perosis but autoclaved rice bran was
demer (1942). These authors also observed that the con- much less effective. They suggested rice bran contained
centration of Mn in bones from deficient chicks was a “labile organic factor” which was effective alone or
lower than in normal chicks which supported the conclu- facilitated Mn function. Hogan et al. (1940) confirmed
sions by Gallup and Norris (1938) who had hypothesized that Mn alone was not sufficient but was completely
that Mn was required for normal bone development. effective in combination with an alcohol extract of dried
Within their extensive technical bulletin, liver. From a species comparison standpoint,
Schaible et al. (1938) wanted to test the hypothesis that Jukes (1939) reported that a basal diet containing 0.1%
Mn deficiency induced via macromineral interactions in MnSO4 eliminated perosis in leghorn chicks but higher
the gut or Mn deficient grains was the primary causal dietary levels (0.4% MnSO4) or Mn injections were not
effect of perosis. These authors injected previously cali- effective in turkey poults. The observation in poults was
brated solutions of Mn (0.8% MnSO4.H2O) on alternate supported by Ringrose et al. (1939) and Jukes (1940a,b)
days beginning at a week of age and this completely subsequently reported that a basal diet with supplemen-
eliminated perosis. There were 2 similar papers pub- tal Mn and 0.1% choline was essential for growth but
lished at approximately the same time that corroborated the same diet with 0.2% choline was needed to reduce
these observations (Lyons et al., 1938; Caskey and Nor- perosis. A diet with 25% soybean meal was also noted as
ris, 1939). Lyons et al. (1938) showed clearly that Mn having anti-perosis properties in poults (Funk and
injection but not Zn, Al, or Fe was effective at improving Kempster, 1940) and this was attributed to the levels of
BW with almost a complete absence of perosis and lecithin and choline at this level of soybean meal inclu-
reduced “leg bowing.” In the study by Caskey and Nor- sion. The effectiveness of choline in turkeys was con-
ris (1939), 15 ppm dietary Mn reduced perosis in chicks firmed by Evans et al. (1942, 1943). Jukes (1941a,b,c)
fed a control diet (1.0% Ca, 0.5% P) whereas 140 ppm subsequently went on to report some of the first experi-
Mn was still not completely effective when chicks were ments in poultry on the potential dietary interrelation-
fed diets with increased mineral levels (3.0% Ca, 1.5% ships between choline, betaine, and methionine.
P). In a subsequent study, intraperitoneal injection of Cravens et al. (1944) observed embryonic anomalies
Mn (10 mg) completely eliminated perosis whereas associated with biotin deficiency that they referred to as
20 mg significantly reduced growth. They also cited pub- “chondrodystrophy.” The deficient embryos, however,
lished rat data in which the negative effect of high solu- were reported to have clinical symptoms more similar to
ble Mn intake was negated if the diet was sufficiently those observed by Landauer and Dunn (1926) than
high in P (Becker and McCollum, 1938) and also noted what was described with Mn deficiency by Lyons and
that 1,100 ppm dietary Mn did not have any noticeable Insko (1937a).
effects on growth (Gallup and Norris, 1939a). From the perspective of genetics, Serfontein and
Wilgus and Patton (1939) hypothesized that insoluble Payne (1934) suggested there was a genetic predisposi-
Ca phosphate in ingredients such as steamed bone meal tion for perosis with “straight legs” and “crooked legs”
might be precipitating Mn in the gut and thereby elicit- used as the selection criteria as they best represented the
ing a deficiency when Mn levels were marginal, similar observed clinical symptoms. Gallup and Norris (1939a)
to the conclusions by Schaible et al. (1938). Similar mac- noted that in New Hampshire chicks, 50 ppm Mn could
romineral − Mn relationships would be reinvestigated significantly reduce but not eliminate perosis whereas a
and confirmed by Wedekind and Baker (1990a) approxi- lower level (30 ppm Mn) was effective in leghorn chicks.
mately 50 years later. One seemingly obvious contributing factor to the geno-
type responses were the differences in growth and skele-
tal development in leghorn vs. heavier broiler type
Perosis and Predisposing Factors Other chicks and years later, Creek et al. (1960) would report
than Manganese that body weight was an important criterion relative to
the severity of perosis.
Over the course of the 1930’s, even as numerous stud-
ies demonstrated the benefits of Mn supplementation, it
was still not 100% effective in experiments with Mn defi- Manganese, Laying Hens, and Embryonic
cient diets and chicks that were predisposed to the onset Skeletal Growth
of the anomaly. Hogan and Shrewsbury (1930) reported
that symptoms of perosis could be alleviated by dietary One of the first written accounts on the avian skeleton
inclusion of wheat or wheat midds but the ash from was a description of different stages of embryonic bone
these ingredients was ineffective, suggesting that the growth (Johnson, 1883). Fell (1925) published a charac-
curative factor(s) was organic. Branion (1933) later terization of cellular changes during embryonic bone
6 LILBURN

development followed many years later by a detailed and there was no evidence of notable differences in brain
description of the ontogeny of embryonic bone formation histology. This condition was similar to the loss of coor-
and associated morphology (Pechak et al., 1986a,b). dination observed by Shil and McCollm (1943) in young,
Byerly et al. (1933) observed that embryos from hens Mn deficient rats and it was subsequently linked to
fed diets with different non-animal proteins included a impaired otolith development in the inner ear
number of “short boned individuals.” They subsequently (Hurley and Everson, 1959; Asling et al., 1960;
reported that these embryonic skeletal anomalies could Everson et al., 1959; Shrader and Everson, 1967).
be alleviated with the supplementation of either wheat Erway et al. (1970) would later show that mice with
germ/whey or wheat germ/liver to the hen diet ataxia born from Mn deficient dams had partial or com-
(Byerly et al., 1935). The observation of shortened and plete absence of the otolith bodies of the inner ear and
thickened embryonic long bones was confirmed by they noted this was also true for ataxic chicks.
Gallup and Norris (1937) and Lyons and Insko (1937a, The recognized essentiality of Mn for normal embry-
b). In the latter reports, hens fed a Mn deficient diet onic development ushered in a research era which
(5.5 ppm) had a significantly reduced hatch percentage emphasized the understanding of those mechanisms
(< 10%) and a number of embryos with shortened and underlying the dietary requirements for Mn and other
thickened long bones. This condition was referred to as TM. There have been several reviews over the last 25+
“chondrodystrophy,” so named after the mammalian years that have discussed different aspects of TM nutri-
condition known as Chondrodystrophia foetais tion and storage (Richards and Steele, 1987;
(Landauer and Dunn, 1926; Hutt and Greenwood, 1929). Richards, 1997; Miles, 2001; Torres and Korver, 2018).
If eggs from hens fed a deficient diet were injected with With respect to Zn and Mn, Bellairs et al. (1972) showed
Mn prior to incubation, embryonic development was that a granule subfraction in the yolk was the primary
normal and injections of Zn or Fe were without effect. storage site in the egg and this supported previous obser-
Following the reports by Lyons and Insko (1937a,b), vations for Mn by Gallup and Norris (1939b) and later
the terms chondrodystrophy and perosis began to be confirmed for Mn and Zn by Grau et al. (1979). Phosvi-
used interchangeably even though they were embryonic tin, derived from vitellogenin, is a major component of
and post-hatch skeletal anomalies, respectively. yolk granules and as a phosphoprotein, contains a high
Schaible et al. (1938) subsequently confirmed that there proportion of phosphate groups. It is not surprising,
were no differences between controls and diets with therefore, that yolk granules would be rich in TM.
>39 ppm Mn. Review papers by Naber (1979) and Angel (2007) are
Gallup and Norris (1939b) suggested that 53 ppm Mn often cited in the current literature to support the
was adequate for normal fertility and hatchability and hypothesis that the hen diet is not an effective way to
dry yolk Mn (mg/100 g) increased linearly when dietary increase egg/yolk TM levels. Naber (1979), however,
Mn was increased to 500 and 1,000 ppm, respectively. included Mn in a list of nutrients that could be positively
These authors also noted that while hatchability was affected by diet while Zn was on the list referred to as
significantly decreased in hens fed Mn deficient diets, having no data available. Stahl et al. (1988) subse-
the chicks that did hatch were not predisposed to quently showed that Zn supplemented as the inorganic
develop perosis if subsequently fed a Mn adequate diet. sulfate would significantly increase egg concentrations
Caskey et al. (1939) confirmed that Mn supplementation and even very high levels (1861 ppm) did not affect egg
to both hens and chicks was needed for normal long bone size or production.
(tibia, femur, metatarsus) and wing bone (humerus, In commercial practice today, nutritionists can choose
radius, ulna) growth. These authors were also careful to between “inorganic” TM (i.e. sulfates) or “organic” che-
differentiate between the specific need for Mn in skeletal lates. Mabe et al. (2003) fed hens diets with 0, 30, and
development vs. the broader Mn requirement for body 60 ppm supplemental Zn and Mn as either an inorganic
weight. Caskey and Norris (1940) subsequently showed sulfate or amino acid chelate. There was a stepwise
that these embryonic skeletal effects in afflicted chicks increase in yolk Mn with increasing level of supplemen-
were not reversed with a Mn adequate diet post-hatch. tation but no difference between the 2 Mn sources. The
These studies were soon supported by studies linking amino acid-Zn chelate increased yolk levels with 30 ppm
Mn deficiency with skeletal issues in swine (Miller et al., supplementation and while 60 ppm resulted in an addi-
1940) and albino rats (Barnes et al., 1941). The observa- tional incremental increase from both sources, there was
tions on reproduction and embryonic development in no difference between them. With respect to Cu,
chicks came several years after Mn was deemed essential Elvejem et al. (1929) did not see any changes in yolk Cu
for normal reproduction in both male and female rats levels with dietary supplementation. Many years later,
(Kemmerer et al., 1931; Orent and McCollum; 1931; Guclu et al. (2008) also observed no significant differen-
Daniels and Everson, 1935). ces in yolk Cu from hens fed 150, 300, or 450 ppm die-
The studies by Byerly et al. (1935), Lyons and tary Cu which, it should be noted are levels well above
Insko (1937a) and preliminary observations by the NRC (1994) recommendation of 8 ppm.
Norris and Caskey (1939) included descriptions of chicks Dewar et al. (1974) was among the first to describe the
from Mn deficient hens exhibiting head retraction or pattern of TM transfer from the egg to the embryo. In
“ataxia.” Caskey et al. (1944) reported that the incidence that study, hens were fed a basal diet containing Zn (72
of ataxia ranged from 2.3 to 11.7% (3 separate hatches) ppm), Mn (81 ppm), and Cu (22 ppm). Individual
 MANGANESE NUTRITION IN POULTRY 7
mineral concentrations (ug/g dry embryo) decreased pre- subsequently led to the development of additional in ovo
cipitously from ED5 to ED10 of incubation followed by a viral vaccines and one for coccidiosis (Thaxton, 1994;
continual but less dramatic decrease between ED10 and Reynolds, 1998; Evans et al., 2002).
ED18 d. The authors calculated the transfer efficiency The near universal acceptance and benefits associated
from the egg to the embryo at 69.8% (Cu), 50.7% (Zn) with in ovo vaccine delivery has generated considerable
and 36.2% (Mn) and noted that the latter value for Mn research interest in the potential for in ovo delivery of
was considerably lower than the 61.5% reported by nutraceuticals and other physiological modulators
Gallup and Norris (1939 c). They also noted that (Tako et al., 2004; Uni and Ferket, 2004; Uni et al.,
Gallup and Norris (1939b) fed a hen diet with 200 ppm 2012). The aforementioned decline in yolk TM through
Mn. Yair and Uni (2011) confirmed that the yolk is a pri- ED17 of incubation was the impetus for studies on late
mary storage depot for Zn, Mn, and Cu but they also term in ovo mineral supplementation. Yair and
observed considerable Zn (37%) and Cu (23%) storage Uni (2011), using in ovo supplementation at ED 17,
in the albumen vs. only 3% for Mn. These authors were successful at eliciting small but significant increases
reported a progressive decline in yolk content (ug or mg/ in yolk sac Fe, Zn, and Cu levels (ug) at ED20 and Hatch
yolk) between ED 0 − ED 11, a somewhat accelerated (ED21) and considerably greater increases in Mn at the
decline from ED 11- ED 17 with very little additional latter 2 time points. Yair et al. (2013), using the same in
disappearance from ED 17 through hatch. Total con- ovo treatments, observed a consistent increase in tibia
sumption (disappearance) between set and hatch was Mn from ED 19 through 7 d post-hatch with no effects
94.2% (Zn), 86.7% (Mn) and 95.5% (Cu). More recently, on Zn. There were no consistent treatment effects on
Hopcroft et al. (2019) reported similar patterns of yolk tibia or femur length or weight from ED 19 through 54 d
disappearance or uptake from ED0 to ED 17.5 although post-hatch, structural properties of cortical bone (corti-
their reported baseline level of Mn (ug/yolk) was cal area, medullary area, crosssectional thickness) or
reached at ED 13.5. These authors also reported consid- indices of mineralization (cortical bone ash, bone min-
erable differences in the yolk content of Zn, Mn, and Cu eral density). It should be noted that cortical bone sam-
vs. what was observed by Yair and Uni (2011) and they ples from the midshaft region have ash values that are
emphasized the importance of the maternal diet when considerably higher than if the “whole bone” was sam-
comparing different reports on TM dynamics during the pled. These authors conducted a subsequent study
course of incubation. With respect to hen age and which included both an inorganic and an organic TM
source of dietary TM, Favero et al. (2013) observed treatment with vitamin D3 in the mix of enrichment
significant hen age effects on yolk/albumen Zn, Mn, nutrients (Yair et al., 2015). There were no differences
and Cu concentrations similar to what was reported between TM sources and both Enrichment treatments
by Kienholz et al. (1964) for Zn. The TM in hen diets significantly increased Cu, Zn, and Mn yolk content to
were supplemented as inorganic sulfates or amino levels much higher than those reported earlier by
acid chelates and there were no diet (source) effects Yair and Uni (2011). There were again, no Enrichment
on Mn or Cu concentration nor any diet by age inter- effects on BW, tibia weight or length and no differences
actions for any of the minerals. There was a signifi- in the structural properties of cortical bone before or
cant hen age effect on tibia length, dry weight and post-hatch. At 38 d but not 10 d post-hatch, organic
percentage ash at hatch but no TM source effects or TM/ vitamin D3 Enrichment increased cortical bone ash
age by source interaction. 1.2% and 1.4% over 2 non-enriched control treatments,
respectively, with no effects on bone mineral density.
Cortical bone structure is a critical area with respect to
Embryonic In Ovo Modulation “leg problems” associated with rapid growth in modern
broilers (Williams et al. 2000, 2004; Rawlinson et al.,
In the poultry industry, innovation often takes the 2009) and in ovo TM supplementation alone did not
form of a unique process that is often facilitated by appear to modulate this. Oliveira et al. (2015) adminis-
established industry practices. The development of in tered 2 levels of TM in ovo at ED17 and there were also
ovo injection technology is one example of this because no significant treatment effects on selected tibia traits
the concept and ultimately commercial application were at hatch. The percentage bone ash was significantly
compatible with the manual transfer of eggs to a increased in the high TM treatment but neither treat-
“hatcher” at approximately 18 days and post-hatch vac- ment changed the proportion of TM in the bone ash
cination for Mareks disease in the hatchery. The manual from Enriched chicks.
vaccination alone was time consuming, labor intensive, In writing this review, it became apparent that in the
and always had the potential for additional chick stress early days of poultry nutrition research on TM and skel-
prior to placement (Gildersleeve et al., 1993). The avian etal development, the Norris lab at Cornell was a consis-
immunology research and agricultural engineering tent source of published research and future scientists.
underlying the feasibility of in ovo vaccination resulted Over the last 25 years, it is safe to say the same could be
in numerous patents prior to its successful introduction said for the Uni lab and Hebrew University with respect
to the industry (Miller, 1984; Sharma and to advancing our understanding of embryonic and post-
Burmester, 1984; Hebrank, 1987). In addition to its con- natal intestinal development and the potential for in ovo
tinued use for Mareks vaccination, research nutrition.
8 LILBURN

Manganese, Cartilage Matrix, and had to be quite small. In a subsequent study by

Endochondral Bone Growth Parker et al. (1955), radiolabeled Mn, Ca, and P was
administered to Mn deficient chicks and there were no
When Gallup and Norris (1938) conducted experi- differences in the quantity or location of labelled Ca or P
ments with Mn adequate and deficient diets, samples in the tibia. Deficient chicks, however, accumulated
were collected from chicks of the same sex, age, similar more labelled Mn with the highest concentration being
body weights and with no visible signs of perosis. The detected in the epiphyseal region, near the site of active
deficient chicks had noticeably shorter and thicker bones mineralization. These authors also reported that while
at 24 d with no visual differences in calcification. There bone mineralization was similar in both deficient and
was a short sentence near the end of the paper that normal bones, the deficient bones were structurally
would later prove to be very insightful: “Partial deple- weak and more prone to shattering when cut.
tion of the bones in manganese resulted in deformities at Frost et al. (1959) would subsequently report abnormal
the joints and at the ends of the bones.”These observa- epiphyseal cartilage formation in Mn deficient rats. For
tions were subsequently confirmed by Shils and McCol- more detailed discussions on chondrocytes, cartilage and
lum (1943) and Amdur et al. (1945) in rats and mice, endochondral bone formation in chicks, we would direct
respectively. In the latter report, rats fed the deficient readers to the following references (Leach and
diet had similar body weights, small but significant Gay, 1987; Roach and Shearer, 1989; Roach, 1997).
reductions in tibia length, bone density and a reduction In embryos with the inherited “micromelia” skeletal
in femur strength. Ellis et al. (1947) pair-fed rabbits anomaly, the shortened long bones had an increase in
either normal or Mn deficient diets to equalize intake percentage bone ash and decreased bone matrix which
and the deficiency decreased body weight as well as the led Asmundson (1942) to hypothesize that matrix syn-
length, density and percentage ash in the humerus. thesis and mineralization were independent traits.
Kay (1930) reported that in humans, plasma phos- Wolbach and Hegsted (1952) noted that the pattern of
phatase was associated with bone disorders, particularly epiphyseal cartilage replacement via vascular penetra-
rickets while Wiese et al. (1939) would later hypothesize tion in chicks is different than what occurs in mammals.
that phosphatase activity might be involved in the etiol- When these authors fed Mn or choline deficient diets,
ogy of perosis. They fed chicks a perosis inducing diet there were noticeable changes including reduced cellular
developed by Clifcorn et al. (1938) and observed that proliferation and the presence of abnormal matrix. The
blood and bone phosphatase activities were elevated at reported changes in the matrix had no effect on bone
hatch and then declined to a steady state from 4 to 7 d mineralization and they suggested that either Mn or
post-hatch. The decrease in phosphatase occurred more choline deficiency resulted in similar lesions associated
quickly with Mn deficiency and remained elevated in with the onset of perosis (Wolbach and Hegsted, 1953).
chicks fed a supplemented diet (50 ppm Mn). A diet The incidence of slipped tendons in commercial practice
with added calcium phosphate (3%) but not calcium lac- continued, however, after it was accepted that Mn was a
tate reduced both blood and bone enzyme levels and causative factor in nutritional perosis. Thomas and Low-
these responses were negated with supplemental Mn. ther (1976) compared commercial “field” broilers with
Using preps of bone phosphatase for in vitro studies, Ca slipped tendons with age matched experimental birds
and P ions both depressed enzyme activity although the fed Control or Mn deficient diets. There were no differ-
negative effect of P was far greater. These effects were ences in proximal tibia histology in the “slipped tendon”
reversed with supplemental dietary Mn. In a subsequent commercial or Control birds but Mn deficiency resulted
report, Wiese et al. (1940) observed that the phospha- in fewer proliferative cells and a disorganized columnar
tase concentration was proportionately greater than structure. There were no differences in the Mn content
enzyme activity in normal bones (+ Mn) suggesting a of epiphyseal cartilage sampled from Control and
role for Mn in both enzyme synthesis as well as activa- “slipped tendon” field broilers which was contrary to the
tion. Combs et al. (1942) would later report that suggestion by Wise et al. (1973) that all conditions
reduced phosphatase activity in chicks associated with resulting in “slipped tendons” had a common underlying
Mn deficiency was correlated with reduced ash content mechanism.
in the tibia. Their observation that enzyme activity was The PhD dissertation of Leach (1960), a student of
much higher in the epiphyseal region vs. midshaft of Norris, focused on TMs, specifically manganese, and the
long bones supported the visual observations of development of the epiphyseal growth plate in chicks.
Gallup and Norris (1938). The reduction in phosphatase The dissertation research supported the hypothesis that
activity observed in Mn deficient chicks was not Mn deficiency specifically affected the matrix mucopoly-
observed in deficient rats (Wachtel et al., 1943). saccharide (proteoglycan) fraction in epiphyseal carti-
Mohamed and Greenberg (1943) administered labeled lage. Leach and Muenster (1962) would subsequently
Mn56 to both normal and Mn deficient chicks with pero- show that Mn but not choline deficiency significantly
sis. Only the deficient chicks injected with labelled Mn affected the proteoglycan composition of the matrix. Mn
had any accumulation in the bones and oral administra- deficiency decreased the total hexosamine content of
tion of the tracer was not detected in the bones of either epiphyseal cartilage, largely due to a reduction in the
control or deficient chicks. These authors concluded galactosamine fraction. Both the total hexosamine and
that the Mn requirement for normal bone development galactosamine matrix levels responded in a dose
 MANGANESE NUTRITION IN POULTRY 9
response manner to incremental Mn supplementation to this would increase TM intake in the absence of
a deficient diet. Leach (1968) would later observe that increased dietary content.
the reduction in size of the epiphyseal growth plate was 3. The emergence of commercially available organic TM
the result of a reduction in matrix formation rather than and the differences in bioavailability compared with
decreased cell proliferation. While choline deficiency was traditional inorganic salts (Richards et al., 2010).
effective at inducing a perosis like condition, there were 4. The use of modern molecular tools that have identified
no differences in the concentration of total hexosamines, potentially new mechanistic roles for selected TM
specifically galactosamine, in cartilage taken from con- (Liu et al., 2015; Lu et al., 2016).
trol or choline deficient chicks. Stock and Latshaw (1981)
took a somewhat different research approach with incre-
mental supplementation of manganese, choline or biotin Suffice it to say, both the organic and inorganic seg-
to a basal control diet. Supplementation of each trace ments of the TM market each include multiple products
nutrient increased total hexosamines above what was with their own individual pros and cons. With respect to
observed for the basal diet in both articular and epiphy- inorganic TM, one of the first comparison studies was
seal cartilage though the determination of individual Gallup and Norris (1939a) who reported that all 5 inor-
proteoglycans was not reported. ganic Mn sources tested (MnCl2, MnSO4, KMnO4,
Chondroitin sulfate is the primary proteoglycan in MnCO3, MnO2) were equally effective in decreasing the
epiphyseal cartilage. It contains 2 galactose residues incidence of perosis in diets with 50 ppm Mn.
along with a xylose to form a trisaccharide that links Hennig et al. (1966), as cited by Watson et al. (1971),
linear polysaccharide chains with a serine residue on subsequently showed that whole body uptake of 54Mn
a core matrix protein. Leach et al. (1969) showed from 54MnCl2 was greater than either 54MnSO4 or
54
that 2 enzymes involved in the galactose transfer to MnO2 in chicks dosed with the various isotopes.
the initial trisaccharide (galactosyl-transferase) and Watson et al. (1970, 1971) determined the solubility of
subsequent chain elongation with repeating disac- different MnO sources compared with reagent grade
charide units (polysaccharide polymerase) require MnSO4 (100%). The MnO solubilities in 0.4% HCl were
Mn as an essential co-factor. Liu et al. (1994) later 30 to 50% (Watson et al., 1970; n = 2 sources) and 2.7
showed that proteoglycan monomers from normal to 87.2% (Watson et al., 1971; n = 5 sources). Any dif-
cartilage were almost exclusively chondroitin sulfate ferences in BW or bone ash between MnSO4 and individ-
(92%) and keratan sulfate (8%). In Mn deficient car- ual MnO sources, however, were not a function of
tilage, however, this fraction was significantly solubility differences. In both reports, MnSO4 was used
reduced (75%) with the appearance of a second frac- in a dose response assay and the regression of bone ash
tion (25%) with a reduced carbohydrate content. or total bone Mn on intake showed the latter to be the
The authors suggested this could represent either best assessment of bioavailability. Subsequent studies
smaller or fewer side chains associated with the core by Black et al. (1984) and Henry et al. (1989) confirmed
protein. Leach and Gross (1983) also studied the that bone Mn could be an effective tool for bioavailabil-
effect of dietary Mn on the organic matrix of egg- ity studies. Reagent grade MnSO4 and MnO were used
shells. There were morphological changes in the in both of the aforementioned studies with maximum
mammillary cores associated with Mn deficiency con- levels set at 2,100 ppm and 4,000 ppm Mn above a basal
comitant with a reduction in the hexosamine and diet (~ 100 ppm Mn). There were considerable differen-
hexuronic acid concentrations. levels. They also ces in bone Mn bioavailability estimates for MnO (91%,
observed that the polysaccharide chains in normal Henry et al., 1989; 65.6%, Black et al., 1984) which
eggshells were different than those extracted from emphasizes the variability that exists even among well
cartilage proteoglycans. designed studies. Edwards and Baker (1999) reported
bioavailability estimates for analytical grade ZnSO4 and
ZnO were similar and only slightly higher than 2 feed
The Inorganic − Organic Trace Mineral grade sources. An additional 2 feed grade ZnO sources
Debate were also tested, however, and their bioavailability esti-
mates were less than 50% which supported an earlier
Actual TM deficiencies have largely disappeared in
report by Wedekind and Baker (1990b).
commercial practice and more recent literature often
It is beyond the scope of this review to discuss the
cites one of the following reasons for continued TM
chemistry and bioavailability differences of organic and
research:
inorganic TM sources. Readers are directed to
1. The almost 30 years since the last NRC requirement Cao et al. (2000) who did an excellent job discussing this
report was published (NRC, 1994). topic for multiple organic Zn sources and zinc sulfate. As
2. The significant genetic gains in traits of economic noted by Cao et al. (2000), not all organic TM have the
importance and the concomitant pressure on skeletal same characteristics when exposed to varying pH envi-
development (Williams et al., 2000, 2004; Yair et al., ronments within the intestine and these individual
2017). Rarely is it mentioned, however, that indirect responses often become a talking point for a company’s
selection for feed intake has been a primary driver in marketing efforts. These authors did report that bio-
the genetic gains in BW (Chambers et al., 1981) and availability estimates of multiple organic Zn TM when
10 LILBURN

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