The Metabolism of Phosphorus, Copper and Molybdenum and Their Interrelationships In the Animal Organism By LEON SINGER A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA SeptemLer, 1949
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The Metabolism of Phosphorus, Copper and
Molybdenum and Their Interrelationships
In the Animal Organism
By
LEON SINGER
A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OFTHE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THEDEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
SeptemLer, 1949
ACKK0VL2D0JKSHTS
The author wishes to express his sincere appreciation to Dr.
George X. Deris and Dr. C. L. Comar for their aid in planning and their
suggestions In conducting this investigation. Without their assistance,
the completion of the investigation would hare been much more diffi-
cult. I also wish to thank Dr. Davis for his suggestions and assistance
in the preparation of this dissertation.
The technical assistance of Miss Katherlne Boney, Mrs. Mablc
Leonhardt, Mr. Jess Benson, Mr. Jack Peacock, and Mr. Max Jeter has
contributed Immeasurably to the success of this investigation. Mr.
Charles Bradley, Mr. Terry 01 sen, and Mr. John Melton have contributed
to the scope of the Investigation by their care In attending the small
experimental animals.
I also wish to thank Mrs. Betty Lucius for her aid in correcting
and typing this dissertation.
II
TAELE OF CCOTMOTS
Pay»e
Introduction 1
Review of Literature
Program of Experiment
.
25
General Experimental Procedure 27
Experiment 1
........
32
Experimental Procedure and Results ... 32
Discussion and Conclusions ••• ^2
Experiment 2
Experimental Procedure and ResultsDiscussion and Conclusions H
Experiment 3.
.....
51
Experimental Procedure and Results 51
Discussion and Conclusions ..... 52
Experiment I 55
Experimental Procedure and Results ........... 55Discussion and Conclusions • 6l
Experiment 5 65
Experimental Procedure and Results 65
Discussion and Conclusions ..... 67
Experiment 6..... 68
Experimental Procedure and Results .....Discussion and Conclusions • 68
Experiment ? 71
Experimental Procedure and Results . .
Discussion and Conclusions ............... 76
Experiment 8 , 83
sat
Page
Sxperiraentol Procedure and Results 83Discussion and Conclusions 83
Experiment 9 • 36
Bxperinental Procedure end Results .... 86
Discussion and Conclusions ............... 86
Experiment 10 .,.»,..,..*... * . 92
Rxperinantal Procedure and RoEulte »»»»...»».* 92Discussion and Conclusions ......»» 98
General Discussion and Conclusions ........ 100
Summary 110
Bibliography 11**
T\:T/;.. :
1. Composition of Rations 32
2. Copper and Molybdenum Content of Rations 32
3. Growth Studies of Rats Maintained on Simplified Rationetfith Varying Level e of Copper and Molybdenum .... 3^
4. Hemoglobin Values of 60-dry-old Rats Maintained on Simpli-
fied Rations V,Tith Varying Levels of Copper and
Molybdenum 39
5. F-ffect of Molybdenum on Rats Raised on i Lov CopperSimplified Ration 40
6. Mineral Accumulation in the Liver and Bone of AnimalsMaintained on Various Levels of Copper and Molyb-denum In the Simplified Ration Jfrl
7. Growth Studies of Rats Maintained on Commercial RationsSupplemented *'ith Varying Levels of Molybdenum ... h6
IT
Page
8, Hemoglobin Values of 80-day-old Rats Maintained on
Commercial Rations Vith Varying Levels of
Molybdenum **7
9. Mineral Accumulation in the Liver and Bone of Animals
Maintained on Commercial Rations Supplementedk'ith Tarying Levels of Mo?-ybd'»rua
10. Treatments and Rations Given Copper deficient Rat* ... 51
11. The Distribution of Labeled Copper in the Bovine .... 56
12. Excretion of Labeled Copper Administered to the Bovine . 60
13. Blood Study of Cattle Administered Labeled Copper ... 62
lit. Effect of Molybdenum and Phosphorus on the Accumulation
of Ingested Copper in the Tisr.ues of the Rat ... 66
15. The Distribution of Labeled Copper Administered to the
Rabbit 69
16. The Distribution 01 Labeled Molybdenum Administered to
Cattlo 72
17. The Accumulation of Labeled Molybdenum in the Liver of
the Bovine •••.»••.» ..... 75
18. Absorption and Rotontion of Labeled Molybdenum in the
Blood of the Bovine 77
19. l&eretlon Studies of Labeled Molybdenum Adninistorodto Cattle 79
20. Effect of Phosphorus on Excretion of Ingested Molyb-
denum by the Mature Rat » • M
21. Tissue Distribution of Labeled Phosphorus Administeredto a Calf • 87
22. Excretion Studies of Labeled Phosphorus Administeredto the Bovine 89
V
23. Accumulation of Labeled Phosphorus in *h« Bloo*. ofthe Bovine When Aduinictered Orally ......... 90
2h. Effect of Molybdenum and Copper on Accumulation of
Ingested Phosphorus In the Tinsue* of the Rat • • . . 93
25. Effect of Dietary Molybdenum on Mmimulation of Tngented
Phosphorus In the Tissues of the Eat 95
26. Effect of Fasting and Non-Fasting Rats on the Accumu-
lation of Ingested Phosphorus in Select TJstties ... 96
1. fc-fiphic Representation of Average Weight* ef F«oale
Rats Maintained on simplified Rations With Varying
Levels of Copper and Molybdenum 35
2. Graphic Representation of Average Weights of Hale BatsMaintained on Simplified Rations With Varying Levels
of Copper and Molybdenum .......•••..*.. 36
3. Typical Copper Deficient Rat After Three Weeks ..... 38
h. Typical Copper Deficient Rat After Five to Six Weeks i • 38
5. Formal Rat (Left) and Rat With Severe MolybdemaiToxicity (Right) ........ 38
6. Response of Pantothenic Acid on the Graying Producedby Copper Deficiency 53
7* Response of Pantothenic Acid on the Cray CopperDeficient Rat 53
8. Comparison of a Typical Copper Deficient Rat and anAnimal Showing Response to Pantothenic Acid 53
•
9. Graphic Representation of the Effect of Phosphorus onthe Hxcretion of Ingested Molybdenum by the RatDuring a 228-Eour Trial ..... 85
iiraoiwcTioi
Naturally occurring nutritional abnormalities due to mineral de-
ficiencies and excesses hare been reported in Florida, in other state*,
and in various parts of the world. Extensive investigations have "been
aade of the diseases as they affect livestock and laboratory animals. In
the study of copper deficiency in cattle, the existence of a relationship
between Molybdenum, phosphorus, and oopper has been noted, and the in-
fluence of these elements upon each other in body metabolism and their
relationship to the general health, breeding, reproduction, and growth
of livestock has been the object of this investigation.
In many soils of Florida, oopper is borderline in regard to the
nutritional requirement. In the muck or peat soils of the Everglades and
the sm-iller peat deposits throughout the state, copper fertilization is
necessary to produce truck crops (3, 69)* Cattle graced on the pastures
of these areas have frequently shown symptoms of abnormal mineral-copper
metabolism. The analysis of some of these pastures have given copoer
values ranging between two and one-half and four parts per million, where-
as other non-peat borderline areas have been reported with as high as seven
parts per million of copper. The molybdenum content of some forage from
these muck and peat areas has been far in excess of the levels found In
normal forage (3*0 • Cattle growers have found that it has been necessary
to use oopper supplements on these copper deficient or high molybdenum
soils as top dressing for pastures, in mineral mixtures, or as drenches
in order to use more efficiently areas in which cattle production has al-
most been an impossibility.
The symptoms which hays, in general, resulted from continued
grazing of cattle on these pastures, without regard to corrective meas-
ures, include severe diarrhea, low hemoglobin, emaciation, loss of weight,
rough skin, fading of the haircoat, coarseness of the halrcoat, tendency
for sores to heal slowly, swelling of the *nds of the long hones of the
legs of calves, beading of the ribs, fragile bones and ribs, swelling of
the joints, and generally, a picture of the early stage of rickets (31*).
In the past a number of observations have indicated that copper deficiency
may result in bone changes and abnormalities. There appears to be a
definite retardation of normal phosphorus deposition in the bones of ani-
mals grated on some of the affected pastures. The cells of the periosteum,
as a result of inadequate phosphorus deposition, regress so that the union
with the bone matrix is destroyed and an actual separation may result.
Davis (34) has also indicated that there is am erosion of the joints which
develops into an arthritic-like condition. This condition is generally
associated with a low phosphorus intake and results in a stiffness of the
lege of the animal. This Is accompanied by inflammation and pain. Seem-
ingly a high molybdenum content of the ration accentuates a copper de-
ficiency, which is in turn apparently related to a possible phosphorus de-
ficiency. Copper deficiency also results in poor breeding efficiency with
small calf crop yield. Another effect has been the death of seme animals,
apparently from heart failure, as indicated by the suddenness of death and
the lack of gross clinical symptoms.
In the present investigation, rats have been used to study the ef-
fect of copper and molybdenum. In varying amounts in the ration, upon
- 2 -
growth, hemoglobin values, pigaentation of the hairooat, and the pro-
ctuctlon of bone abnormalities, and their effect on reproduction. The
deposition of copper and molybdenum in the liver and molybdenum in the
bone has been investigated. The distribution of cooper, molybdenum and
phosphorus in selected tissues and the excretion of each element ad-
ministered alone, in combination with the others, and under specific
feeding trial conditions, have been studied in the bovine and laboratory
tf&M&i v the of Mmf ftMNMtttft liVM Ml of H ptt\ nolybd»nun ml
phosphorus.
REVIEW OF LITERATURE
Although the essentiality of copper in nutrition has been recog-
nized for a relatively short time, the discussion of its occurrence in
nature can he traced as far hack as 1817 to the work of Meissner (130) (
who established the fact that copper is actually a constituent of plants.
In 1847 Harless (81) detected copper in the Marine animals, Klidene and
Hallar promatla. and demonstrated that it did not exist as a free salt,
hut rather in combination with hlood proteins. In 1920 Rose and Bodansky
(159) reported that copper is a normal and possibly an essential constitu-
ent of marine fish tissue. A review of the early historical development
of the biological significance of copper has been presented by Elvehjem
(56).
While the earlier workers considered the presences of copper in
animal tissue to be of no significant Importance except in the lower ani-
mals, where it occurred as hemocyanin, McHargue (120) in 1925, stated
that copper is a necessary constituent of the blood of all animal life
and probably performed important functions in the absorption and transfer
of oxygen in the respiratory process. The high accumulation of copper in
the fetuses of mammals was accepted as strong evidence that copper has
many important functions in the development of the enbryo and in early
growth after birth. This has been confirmed by other investigators (20,
30, 111, 117, l*f3, 1^5, 160). In humans it has been observed that the
mjirtWi oontent of copper in the liver is found at birth. There is a
rapid decline of copper after the second month of life (20).
Other workers (30, 98, 101, 121, 138, 152, 188) have established
- 4 -
the necessity of copper for the mobilization of iron from the tissues
and for the utilization of iron in the formation of hemoglobin. The
action of copper in iron metabolism and its role in hemoglobin regenera-
tion has been given extensive investigation. McHargue et al (121) in
1928 were among the first to show that young anemic rats required copper
for the formation of hemoglobin. In 1928 Hart et al (82) found that
copper in minute amounts is capable of supplementing ferric chloride,
which in itself was ineffective in the regeneration of hemoglobin. These
results were interpreted as indicating the necessity of copper for the
effective utilisation of iron for hemoglobin formation. Elvehjem and
Hart (57) in 1929 presented a further demonstration of the supplementing
action of copper to iron on the regeneration of hemoglobin. Cunningham
(30) in 193i confirmed the effect of copper in promoting the utilisation
of Iron in hemoglobin formation. In the same year Drabkin and co-workers
(U6) questioned the specificity of copper in hemoglobin synthesis. The
essentiality of copper for hemoglobin formation has been confirmed by
When the labeled molybdenum was injected into the bovine, there
was evidence of considerable activity in the various parts of the stomach,
the intestinal tract, and their contents. It seems probable that the
presence of this activity in the stomach must be accounted for by the
passage of the injected molybdenum into the large quantities of saliva,
which are secreted by the bovine, and its movement into the upper regions
of the digestive system. The presence of activity in the Intestines and
their contents is in part due to the activity present in the upper regions
of the digestive system and also to the activity which is probably present
in the intestinal secretions, bile and pancreatic Juices.
The excretion of 4?.60 percent of the total injected dose in the
first five days indicates that there is a rapid elimination of the dose
by the bovine. This is further emphasized by the elimination of approxi-
mately 71 percent of the oral dose in a similar period by two other ani-
mals. Fairhall et al (62) have reported that the excretion and absorption
of inert molybdenum are rapid. Copper sulfate, in this investigation, did
not appreciably affect the total activity eliminated, but did Increase the
108 -
percent In the feces. Copper appears to decrease the absorption of
molybdenum. The data further Indicate that copper results In a slight
inhibiting effect on the accumulation of molybdenum in the liver and
a decreased level in the blood. Simultaneous administration of phos-
phorus did not appear to affect the total amount of activity excreted
by the rat during an experimental trial, but did increase the absorp-
tion from the intestinal tract. The data of Hollands et al (1*12)
indicate that molybdenum is principally eliminated in the urine of the
rat. This is in agreement with the experiments with the rat, but is
contrary to the results of studies with the bovine.
The most rapid absorption of molybdenum by the liver occurs in
the first W hours after dosage. There is, however, a small amount of
the total dose accumulated in the liver. The removal of molybdenum from
the blood of the injected animal is rapid during the first hour after
injection. Approximately 78.52 percent of the dose was removed from the
bloodstream during this period. The peak of molybdenum in the blood
occurs within 46 to 70 hours after oral dosage. The plasma contributes
70 percent of the activity.
109 -
SUMMARY
The effects of levels of copper and molybdenum in the simplified
rations (copper ranging from one to parts per million, and molybdenum
from less than one to 80 parts per Billion) and in the commercial rations
(copper ranging from 31.4 to ^3,6 parts per million, and molybdenum from
80 to 160 parts per million added) hare been investigated with the rat.
The relation between molybdenum toxicity and the dietary level of copper
has been demonstrated. The following observations were made:
(1) Molybdenum toxicity is characterised by severe diarrhea, weak-
ness, loss of weight, and a rough haircoat. It may also result in de-
generation of the liver, a retarded skeletal development with poor calci-
fication of the bone, a severe laorimatlon, and death to the animal.
(2) In molybdenum toxicity, the indications are that mortality
among the female rat is greater than among the male animals. There is
evidence of high accumulation of molybdenum in the bone and liver.
(3) Copper deficiency is characterized by anemia, retarded growth,
graying of the haircoat of black and piebald rats, a failure in repro-
duction, and a reduction in the level of copper in the liver.
(4) Copper exerts a therapeutic effect in overcoming, in part,
the effects of high molybdenum levels in the ration.
(5) High levels of molybdenum (80 to 160 parts per million) in a
high copper (31*4 to 43.6 parts per million) commercial ration did not
appear to appreciably affect the hemoglobin value of the rat.
(6) The graying induced by copper deficiency in the black and
piebald rat responded to supplements of pantothenic acid or copper. Copper
- 110 -
deficiency appeara to accentuate the requirement of the rat for panto-
thenic acid.
The radioactive isotope*. Mo**, P32 and Cu^, hare been used to
determine the fate and interrelationships of these elements in the aniaal
organism. The data indicate the following observations!
(1) The distribution of the elements in select tissues of experi-
mental animals under normal and special conditions is demonstrated.
(2) The liver and kidney are the principal storage organs for
copper. Phosphorus and molybdenum are primarily stored in the hone, al-
though there are high accumulations in the liver. All three elements are
widely distributed.
(3) There is a similarity in the accumulation of phosphorus raid
molybdenum in the tissues.
Phosphorus and copper are apparently poorly absorbed. Molyb-
denum appears to be rapidly absorbed and eliminated. It is largely elimi-
nated in the feces of the bovine and in the urine of the rat. Phosphorus
and copper are principally eliminated in the feces. Approximately 98.5
percent of the orally administered copper eliminated by the rat and the
bovine is in the feces. Intravenously injected copper is apparently re-
tained in the body for a considerable time.
(5) The highest level of orally administered phosphorus in the
blood of the bovine occurs in the first 2k hours and molybdenum in 46
to 70 hours. Injected copper is rapidly removed from the bloodstream in
the first five minute* and molybdenum during the first hour.
(6) The liver and kidney are vitally concerned with the removal
- Ill -
of excess copper from the blood. The rabbit at the end of six hours
accumulated approximately 19.0 percent of the total injected dose in
the liver and 3«° percent in the kidney*
(7) The young rat accumulated approximately threefold the acti-
vity of p32 in select tissues and tenfold in the bone, in comparison
to that accumulated by the mature animal.
(8) There is a relatively high accumulation of activity in the
digestive system of the bovine five days after the labeled molybdenum
was injected into the Jugular vein.
(9) Copper in the mature rat had little effect on phosphorus
accumulation, molybdenum shoved a tendency to increase accumulation in
select tissues, and copper and molybdenum together reduced accumulation
in the lung, liver, and kidney. In the young animal, molybdenum and
copper resulted in approximately a 50 percent decrease in the accumulation
of phosphorus in the bone. Animals maintained on a high dietary level
of molybdenum had a lowered accumulation of p32 in the select tissues,
failure to fast animals before dosage decreased absorption.
(10) Molybdenum appears to decrease the accumulation of copper in
many tissues of the bovine, with the exception of the liver; however. In
the rat there is a reduction of accumulation in the liver and kidney.
Phosphorus administered simultaneously causes an even greater decrease
in these tissues.
(11) Copper did not affect the total activity of Mo99 eliminated
by the bovine, but apt/eared to decrease absorption, inhibit accumulation
in the liver, and decrease the level in the blood. Phosphorus did not
- 112 -
appear to affect total activity excreted by the rat; however, it in-
thft absorption of molyodenuin.
The accueulation of molybdenuri in the hone and lire? of the
animal in experiments of longer duration may prove to be signi-
ficant factors in health, condition, and reproduction. Copper appears
to be related to unknown enzyne systems, involving hair pigmentation
and pantothenic acid, and cellular respiration. The toxic action of
molybdenum may be tee to competition between nolybderam and phosphorus
for deposition or interference in enzyme systems tfiich are necessary
for bone formation. The therapeutic effect of copper does not appear
to be accounted for by the formation of Insoluble complex compound*
.
113 -
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125
BlCXHtAMIICAL ITEMS
Leon Singer wi born August 15, 1918, at Gainesville, Florida.
He received the degree of Bachelor of Science in Agriculture from the
University of Florida in May, 19^3. He has received all of his gradu-
ate training at the University of Florida,
While in residence as a graduate student from 1940 to 19^2, he
was employed at the Florida Agricultural Erperiment Station as a
laboratory assistant in the Biochemical Laboratory of the Agronomy
Department, After four years of service in the United States Army, he
was discharged with the rank of captain. In November, 19^6, he was
employed as Assistant in Nutrition in the Animal Industry Department
of the Florida Agricultural Experiment Station. He resigned this posi-
tion in February, 19^7, to accept a grant-in-aid fellowship from the
Nutrition Foundation, Inc. While in residence, he has been a Graduate
Research Assistant at the Nutrition Laboratory of the Florida Agricul-
tural Experiment Station. He is a member of Phi Sigma honorary biologi-
cal fraternity.
This dissertation «u prepared under the direction of the
Chairman of the candidate's Supervisory Committee and has been approved
by all members of the Committee. It was submitted to the Graduate
Council and was approved as partial fulfilment of the requirements for