Pathology of aging rats : a morphological and experimental study of the age-associated lesions in aging BN/Bi, WAG/Rij and (WAG x BN) F1 rats

230 Pages·1979·0.22 MB·English

by  Joe D Burek

Pathology
of
Aging Rats
A Morphological and Experimental Study of the Age-Associated
Lesions in Aging BN/Bi, WAG/Rij and (WAG x BN) F1 Rats
Author:
Joe D. Burek, D.V.M.
Toxicology Research Laboratory
Health and Environmental Research
Dow Chemical U.S.A.
Midland, Michigan
From the Institute for Experimental Gerontology of the Organization for Health
Research TNO, Rijswijk, The Netherlands. Publication supported by National In-
stitute on Aging, Public Health Service, National Institutes of Health, U.S. Depart-
ment of Health, Education and Welfare, Washington, D.C. and Health and Envi-
ronmental Research, The Dow Chemical Company, Midland, Michigan.
Boca Raton London New York
CRC PressC isR anC im Pprrinets osf, thIenc.
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Library of Congress Cataloging in Publication Data
Burek, Joe D
Pathology of aging rats.
Bibliography: p.
Includes index.
1. Age factors in disease. 2. Diseases — Animal
models. 3. Rats — Diseases. 4. Rattus norvegicus.
I. Title.
RB210.B87 619’ .93 78-15489
ISBN 0-8493-5649-0
A Library of Congress record exists under LC control number: 78015489
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THE AUTHOR
Joe D. Burek, D.V.M., is Research Specialist, Toxicology Research Laboratory,
Health and Environment Research, The Dow Chemical Company, Midland, Mich-
igan and advisor in rodent pathology and laboratory animal medicine, Institute for
Experimental Gerontology TNO, Rijswijk, The Netherlands.
Dr. Burek received his B.S., D.V.M., and M.S. degrees from Michigan State
University in 1968, 1969, and 1970, respectively. He subsequently received postdoc-
toral training in pathology and laboratory animal medicine at the U.S. Army Med-
ical Research Institute of Infectious Disease, Frederick, Maryland, and the Johns
Hopkins University School of Medicine, Baltimore. He is a Diplomate of the Amer-
ican College of Veterinary Pathologists and the American College of Laboratory
Animal Medicine.
Dr. Burek is a consulting member of the European Late Effects Project Group;
a member of the Program Committee of the American College of Laboratory Ani-
mal Medicine. His professional affiliations include the American College of Veteri-
nary Pathologists, the American College of Laboratory Animal Medicine, the
American Veterinary Medical Association, and the Midwest Association of Veteri-
nary Pathologists.
ACKNOWLEDGMENTS
I am indebted to many people who made it possible for this work to become a
reality. Therefore, I wish to express my sincere gratitude to: Professor Dr. C. F.
Hollander for introducing me into the field of aging research, for providing me with
the needed support to finish this study, and for his collaboration and friendship;
Dr. P. Zwart for his support and comments; Dr. C. Zurcher for helping me for-
mulate many ideas through our lengthy discussions; Dr. M. J. Van Zwieten for his
encouragement and criticisms; Ms. A. Nooteboom for her technical assistance and
support; Mr. A. A. Glaudemans for the preparation of the photomicrographs; Dr.
S. P. Meihuizen for his assistance with the electron microscopy; Mr. W. Krause for
the preparation of the charts and figures; Ms. K. Richards and Ms. D. Euser-Gaan-
derse for their help in the final preparation of the thesis; The technical and scientific
members of the staff of the REPGO-TNO Institutes for all of their assistance; The
National Institute on Aging, National Institutes of Health, U.S. Department of
Health, Education and Welfare, Bethesda, Maryland and The Dow Chemical Com-
pany, Midland, Michigan for their financial support.
TABLE OF CONTENTS
Part 1: Introduction
Chapter 1
Introduction .......................................................................... 3
I. Purpose ........................................................................ 3
II. Definition of an "Old" Rat ....................................................... 3
Ill. Lesions of Aging Rats ............................................................ 4
IV. Factors that can Influence Life Span Studies ......................................... 4
V. Introduction to the Chapters ...................................................... 5
Part II: Background Information
Chapter 2
Background of the Animals and the Rat Colony ........ : ................................... 9
I. Background of the Rats ........................................................... 9
II. Colony Husbandry .............................................................. 9
A. Germ-free Colony ......................................................... 10
B. Specific Pathogen-free Breeding and Stock Colony ............................. 10
C. Aging Colony ............................................................ 12
III. Diet. .......................................................................... 13
IV. Breeding Performance and Preweanling Mortality ................................... 13
V. Weights of Aging Rats ........................................................... 14
VI. Protocol for Sick or Dead Rats .................................................... 14
VII. Necropsy Procedure ............................................................. 16
VIII. Selection of Necropsied Rats ...................................................... 17
Part III: Results and Discussion
Chapter 3
Longevity Studies ................. ....................................................2 1
I. Longevity of Cohorts of Aging Rats ............................................... 21
A. Cohorts of Virgins ........................................................ 21
B. Cohorts of Retired Breeders ................................................2 1
II. Longevity of the Necropsied Rats ..................................................2 3
III. Discussion .....................................................................2 5
Chapter4
Age-associated Pathology ..............................................................2 9
I. Introduction ...................................................................2 9
II. Organs and Organ Systems .......................................................2 9
A. Thyroid Gland ...........................................................2 9
1. Nonneoplastic Lesions ............................................... 29
2. Neoplastic Lesions .................................................. 29
a. Medullary Thyroid Carcinoma ..................................2 9
b. Follicular Cell Tumors ......................................... 34
3. Discussion ......................................................... 36
B. Parathyroid Gland ........................................................ 38
1. Nonneoplastic Lesions ............................................... 38
a. Interstitial Fibrosis ............................................ 38
b. Cystic Parathyroid Glands ..................................... 39
2. Neoplastic Lesions .................................................. 39
a. Parathyroid Adenomas ........................................ 39
3. Discussion ......................................................... 39
C. Adrenal Gland ........................................................... 41
1. Nonneoplastic Lesions .............................................. .41
a. Foci of Cellular Alteration in the Adrenal Cortex ................. .41
b. Foci of Basophilic Change in the Adrenal Medulla ................ .41
c. Blood-filled Sinuse and Cysts .................................. .42
d. Miscellaneous Nonneoplastic Findings .......................... .42
2. Neoplastic Lesions ................................................. .42
a. Cortical Adenomas ........................................... .42
b. Cortical Carcinomas ......................................... .43
c. Pheochromocytomas of the Adrenal Medulla ..................... .46
3. Discussion .........................................................4 7
D. Pituitary Gland ...........................................................4 9
1. Nonneoplastic Lesions .............................................. .49
2. Neoplastic Lesions ................................................. .49
a. Tumors of the Anterior Pituitary Gland ......................... .49
b. Other Pituitary Tumors ........................................ 51
3. Discussion ......................................................... 53
E. Pancreas ................................................................ 53
1. Nonneoplastic Lesions ............................................... 53
a. Atrophy ..................................................... 53
2. Neoplastic Lesions .................................................. 54
a. Islet Cell Tumors ............................................. 54
b. Exocrine Cell Tumors ......................................... 56
3. Discussion ......................................................... 57
F. Liver .................................................................... 58
1. Nonneoplastic Lesions ............................................... 58
a. Foci and Areas of Cellular Alterations ............................ 58
b. Bilary Cysts .................................................. 59
c. Miscellaneous Nonneoplastic Lesions ............................6 6
2. Neoplastic Lesions ..................................................6 7
a. Neoplastic Nodules ............................................6 7
b. Hepatocellular Carcinoma .....................................6 8
c. Malignant Hemangioendothelioma ..............................6 8
3. Discussion ......................................................... 68
G. Alimentary Tract and Abdominal Cavity ..................................... 70
1. Nonneoplastic Lesions ............................................... 70
a. Gastric Ulcers ................................................ 70
b. Miscellaneous Nonneoplastic Lesions ............................ 71
2. Neoplastic Lesions .................................................. 72
a. Head, Neck, and Mouth ....................................... 72
b. Stomach ..................................................... 72
c. Intestine ..................................................... 73
d. Abdominal Cavity ............................................ 74
3. Discussion ......................................................... 7 4
H. Salivary Gland ........................................................... 75
1. Nonneoplastic Lesions ............................................... 75
2. Neoplastic Lesions .................................................. 75
3. Discussion ......................................................... 75
I. Cardiovascular System ..................................................... 75
1. Nonneoplastic Lesions ............................................... 75
a. Myocardial Degeneration and Fibrosis of the Ventricular Wall ....... 75
b. Cartilaginous and Osseous Metaplasia ............................ 79
c. Cartilaginous Focus at the Base of the Aorta ...................... 80
d. Heart Valves ................................................. 80
e. Endocardial Disease ........................................... 82
f. Lesions of the Atrium and Auricle ............................... 83
g. Periarteritis Nodosa ........................................... 86
h. Incidental Vascular Lesions ..................................... 87
2. Neoplastic Lesions .................................................. 88
a. Chemoreceptor (Aortic Body) Tumors ........................... 89
b. Blood Vessels ................................................ 91
3. Discussion ......................................................... 91
1. Respiratory System ........................................................ 94
1. Nonneoplastic Lesions ...............................................9 4
2. Neoplastic Lesions ..................................................9 5
3. Discussion .........................................................9 5
K. Urinary System ...........................................................9 7
1. Nonneoplastic Lesions ...............................................9 7
a. Hydronephrosis ..............................................9 7
b. Urolithiasis .................................................. 98
c. Chronic Progressive Glomerulonephropathy ......................9 9
d. Inflammatory Lesions ........................................ 100
e. Miscellaneous Lesions ........................................ 100
2. Neoplastic Lesions ................................................. 100
a. Kidney Tumors .............................................. 100
b. Ureter and Bladder Tumors ................................... 101
3. Discussion ........................................................ 107
L. Hematopoietic System .................................................... 110
1. Nonneoplastic Lesions ............................................. 110
a. Thymus .................................................... 110
b. Lymph Nodes ............................................... 111
c. Spleen ..................................................... 112
2. Neoplastic Lesions ................................................. 112
3. Discussion ........................................................ 113
M. Female Reproductive System .............................................. 117
1. Nonneoplastic Lesions ............................................. 117
a. Ovaries .................................................... 117
b. Oviduct, Uterus, Cervix, and Vagina ........................... 122
2. Neoplastic Lesions ................................................. 122
a. Ovary ...................................................... 122
b. Oviduct .................................................... 123
c. Uterine Horns ............................................... 123
d. Cervix and Vagina ........................................... 125
3. Discussion ........................................................ 127
N. Male Reproductive System ................................................ 129
1. Nonneoplastic Lesions ............................................. 129
a. Testicle and Epididymis ...................................... 129
b. Accessory Sex Glands ........................................ 129
2. Neoplastic Lesions ................................................. 135
3. Discussion ........................................................ 137
0. Brain .................................................................. 139
I. Nonneoplastic Lesions ............................................. 139
a. Vacuolation (Vacuolar Encephalopathy) ........................ 139
b. Lipofuscin .................................................. 139
c. Basophilic PAS-positive Bodies ................................ 139
d. Melanosis .................................................. 139
e. Infarcts .................................................... 144
f. Hydrocephalus .............................................. 144
g. Multifocal Spongiform Encephalopathy ......................... 144
2. Neoplastic Lesions ................................................. 145
a. Granular Cell Tumors ........................................ 145
b. Glial Tumors ............................................... 148
c. Meningioma ................................................ 150
d. Pineal Gland ................................................ 150
3. Discussion ........................................................ 150
P. Spinal Cord and Nerve Roots .............................................. 153
I. Nonneoplastic Lesions ............................................. 153
2. Neoplastic Lesions ................................................. 158
3. Discussion ............................ ·. ........................... 158
Q. Musculoskeletal System .................................................. 159
I. Nonneoplastic Lesions ............................................. 159
2. Neoplastic Lesions ................................................. 159
3. Discussion ........................................................ 160
R. Skin and Subcutaneous Tissues (Excluding Mammary Tissue) .................. 161
I. Nonneoplastic Lesions ............................................. 161
2. Neoplastic Lesions ................................................. 161
3. Discussion ........................................................ 163
S. Mammary Gland ........................................................ 163
I. Nonneoplastic Lesions ............................................. 163
2. Neoplastic Lesions ................................................. 163
3. Discussion .................· ....................................... 167
III. General Discussion ............................................................ 167
Chapter 5
Evaluation of the Age-associated Risk for Multiple Tumors and Tumor Metastases in Aging Rats 169
I. Introduction .................................................................. 169
II. Age-associated risk for Multiple Neoplastic Lesions ................................. 169
III. Age-associated Risk for Malignant Neoplasms to Metastasize ......................... 169
IV. Discussion .................................................................... 170
Chapter 6
Comparisons of the Incidence of Lesions in Rats that Died Spontaneously to Those Killed at Differ-
ent Ages ............................................................................ 177
I. Introduction .................................................................. 177
II. Comparisons of the Percentage of Selected Lesions in Dead Rats vs. Percentage in the Popu-
lation at Risk as Determined by Life Table Calculations .............................. 177
A. Medullary Thyroid Carcinomas ............................................ 177
B. Pituitary Tumors ........................................................ 178
C. Urothelial Tumors ....................................................... 178
D. Nonneoplastic Lesions ................................................... 178
III. Comparisons of the Percentage of Selected Lesions in Rats Killed vs. Those that Died Spon-
taneously ..................................................................... 178
A. Pituitary Tumors ........................................................ 182
B. Medullary Thyroid Carcinomas ............................................ 185
C. Ureter Carcinoma ....................................................... 186
D. Biliary Cysts ............................................................ 187
E. Liver Foci, Areas, and Nodules ............................................ 188
F. Mammary Tumors ....................................................... 188
IV. Discussion .................................................................... 188
Chapter 7
Spontaneously Occurring Posterior Paralysis: Further Studies to Determine the Age of Onset and
Progression ofthe Syndrome .......................................................... 191
I. Introduction .................................................................. 191
II. Semiserial Sections of Spinal Cords ............................................... 191
III. Mineral Deposits in the Vertebral Canal of Male (WAG x BN)F, Rats .................. 191
IV. Serial Killings of Clinically Normal Male and Female (WAG x BN)F, Rats .............. 193
V. Discussion .................................................................... 196
Part IV: General Discussion
Chapter 8
The F, Hybrid: Comparison with the Parent Strains ....................................... 201
Chapter 9
Summary of Potential Models for Aging and Carcinogenesis Research Using BN/Bi, W AG/Rij, and
(WAG x BN)F, Rats ................................................................. 203
Chapter 10
Importance of Life Span Longevity and Pathology Data from Rats .......................... 205
Chapter 11
The Onset of Age-associated Lesions and Aging in Rats .................................... 207
Summary ........................................................................... 211
References .......................................................................... 213
Index .............................................................................. 221