[CANCER RESEARCH 28, 2323-2326,
November 1968]
Effects of Teratogenic Agents in Range Plants
Wayne Binns, Lynn F. James, Richard F. Keeler, and Lew Dell Balls
Agricultural Research Service, USDA, Animal Disease and Parasite Research Division, Poisonous Plant Research Laboratory, Logan, Utah 84321
SUMMARY
A cyclopian-type malformation in lambs has been produced
by maternal ingestion of Veratrum califomicum. Arthrogryposis, torticollis, scoliosis, and cleft palate in calves resulted from
the maternal ingestion of two toxic species of lupine. Con
tracted tendons of the forelimbs and hypermobility of the
hock and stifle joints were noted in lambs from ewes that had
eaten locoweeds.
Two teratogenic steroidal alkaloids have been specifically
identified in V. califomicum An apparent relationship be
tween locoism and lathyrism has been hypothesized on the
basis of the botanical and chemical relationship of plants and
the similarity of congenital deformities.
INTRODUCTION
Numerous poisonous plants are present on the western
livestock range areas of the United States. They were not
considered to be possible causative agents for congenital
anomalies in calves and lambs until 1963. At that time, it was
reported (1-3) that the maternal ingestion of Veratrum
califomicum by pregnant ewes on a specific day of gestation
induced a cyclopian-type malformation in lambs. The terato
genic compound in V. califomicum that induces the cyclopi
an-type deformity in lambs was subsequently isolated (6).
Other poisonous range plants also have been extensively
studied by research scientists of the Agricultural Research
Service, USDA, Animal Disease and Parasite Research Division,
Poisonous Plant Research Laboratory, Logan, Utah. A com
mon congenital deformity, identified as "crooked calf disease"
characterized by arthrogryposis and/or torticollis, scoliosis,
and occasionally cleft palate (13, 14) has been known to be
caused by maternal ingestion of Lupinus sericeus and L.
caudatus. Locoweeds, Astragalus lentiginosus, A. pubentissimus, and Oxytropis sericeus have been shown to contain
teratogenic agents that produce congenital anomalies in calves
and lambs by maternal ingestion (4, 5).
MATERIALS AND METHODS
In the V. califomicum work, from i to 1 ton of individual
species of possibly causative poisonous plants were collected
from range areas where specific types of congenital deformities
had been endemic. The plants were taken to the Poisonous
Plant Research Laboratory, Logan, Utah, air dried, ground,
and stored in plastic bags at 5°C. As is done in all our
investigations,
the species of animals in which the deformity
commonly occurred was used for bioassays of the suspected
plants. Each plant was mixed with water and fed daily to the
animals at a subclinical toxic level via stomach tube. This
feeding was continued for a specific period during gestation. In
addition, experimental animals are fed alfalfa hay and mineral
supplements free choice.
RESULTS
A congenital cyclopian-type malformation in lambs was
found to be caused by maternal ingestion of V. califomicum
(Fig. 1) with the time of insult being on the 14th day of
gestation (1—3). The deformities ranged from anophthalmia,
cyclopia, and/or cebocephalus, to a slight shortening of the
nasal bones (Fig. 2). Prolonged gestation is commonly associ
ated with the more severe deformities. The gestation period
has been prolonged to as much as 87 days beyond the normal
gestation time of 147 to 152 days. If these prolonged gesta
tions are interrupted by caesarian section or by a sacrificing of
the ewe, the lambs are obtained alive, but die immediately
from suffocation due to a bony partition in the nasopharyngeal region obstructing the passage of air.
Maternal feeding of Lupinus sericeus or L. caudatus from the
40th to the 70th day of gestation produced "crooked calf
disease" which is common in all western states and Alaska (13,
14). This period of insult caused a marked arthrogryposis of
the front legs (Figs. 3, 4). The deformities of torticollis,
scoliosis, and cleft palate are apparently associated with other
insult periods.
Locoweeds have been studied for many years by numerous
research scientists, but the USDA workers were the first to
report that maternal ingestion of locoweeds produced congeni
tal deformities in lambs. The deformities have ranged from a
slight and temporary to a marked and permanent flexing of
the carpal or pastern joints and/or anterior flexure with
hypermobility of the hock joint (5).
The teratogenic agents in V. califomicum have been identi
fied (4, 6, 11, 12) as steroidal alkaloids. One, cyclopamine (8,
10), was found to be responsible for cyclopian-type deformi
ties. Another alkaloid of similar structure (10), veratramine,
induced leg deformities ranging from a slight lateral or medial
bowing of the front legs to marked flexure of the carpal joint
and/or hypermobility of the hock and stifle joints. In some
cases, complete lack of muscular control was produced (7, 9).
A possible relationship between locoism and lathyrism (4,
11, 12) was hypothesized from the botanical relationship of
the plants, congenital deformities induced, and the chemical
characteristics. Preliminary assay of locoweed extracts suggests
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2323
Wayne Binns, Lynn F. James, Richard F. Keeler, and Lew Dell Balls
the presence of lathyrogens, aminoacetonitrile,
•y-diaminobutyricacid in locoweeds.
and
a,
DISCUSSION
The experimental feeding of poisonous plants and purified
teratogenic agents induced deformities identical to the respec
tive congenital anomalies observed under range conditions.
Many poisonous and nonpoisonous plants may contain teratogens only at specific stages of growth or when exposed to
adverse environmental conditions.
7.
8.
9.
REFERENCES
1. Binns, W., Thacker, E. J., James, L. F., and Huffman, W. T. A.
Congenital Cyclopian-Type Malformation in Lambs. J. Am. Vet.
Med. Assoc., 46: 180-183, 1959.
2. Binns, W., James, L. F., Shupe, J. L., and Everett, George. A
Congenital Cyclopian-Type Malformation in Lambs Induced by
Maternal Ingestion of a Range Plant, Veratrum californicum. Am.
J. Vet. Res., 24: 1164-1175, 1963.
3. Binns, W., Shupe, J. L., Keeler, R. F., and James, L. F. Chronologic
Evaluation of Teratogenicity in Sheep Fed Veratrum californicum.
Am. Vet. Med. Assoc., 147: 839-842,1965.
4. James, L. F., and Binns, W. Blood Changes Associated with
Locoweed Poisoning. Am. J. Vet. Res., 28: 1107-1110,1967.
5. James, L. F., Shupe, J. L., Binns, W., and Keeler, R. F. Abortive
and Teratogenic Effects of Locoweed on Sheep and Cattle. Am. J.
Vet. Res., 28: 1379-1388,1967.
6. Keeler, R. F. Teratogenic Compounds of Veratrum californicum
2324
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14.
(Durand). IV. First Isolation of Veratramine and Alkaloid Q and a
Reliable Method for Isolation of Cyclopamine. Phytochemistry, 7:
303-306,1968.
Keeler, R. F., Binns, W. Chemical Compounds of Veratrum
californicum Related to Congenital Ovine Cyclopian Malforma
tions: Extraction of Active Material (29178). Proc. Soc. Exptl.
Biol. Med., 116: 123-127,1964.
Keeler, R. F., and Binns, W. Teratogenic Compounds of Veratrum
californicum (Durand). II. Production of Ovine Fetal Cyclopia by
Fractions and Alkaloid Preparations. Can. J. Biochem., Physical,
44: 829-838, 1966.
Keeler, R. F., and Binns, W. Possible Teratogenic Effects of
Veratramine (31639). Proc. Soc. Exptl. Biol. Med., 123: 921-923,
1966.
Keeler, R. F., and Binns, W. Teratogenic Compounds of Veratrum
californicum (Durand). I. Preparation and Characterization of
Fractions and Alkaloids for Biologic Testing. Can. J. Biochem.,
Physiol., 44: 819-828, 1966.
Keeler, R. F., and Binns, W. Teratogenic Compounds of Veratrum
californicum (Durand). III. Malformations of the VeratramineInduced Type from Ingestion of Plant or Roots (32474). Proc.
Soc. Exptl. Biol. Med., 726: 452-454, 1967.
Keeler, R. F., James, L. F., Binns, W., and Shupe, J. L. An
Apparent Relationship Between Locoism and Lathyrism. Can. J.
Comp. Med. Vet. Sci., 31: 334-341, 1967.
Shupe, J. L., James, L. F., and Binns, W. Observations on Crooked
Calf Disease. Am. Vet. Med. Assoc., 151: 191-197,1967.
Shupe, J. L., James, L. F., Binns, W., and Keeler, R. F. Lupine, a
Cause of Crooked Calf Disease. Am. Vet. Med. Assoc., 757:
198-203, 1967.
CANCER
RESEARCH
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Teratogenic Agents in Range Plants
A
Fig. 1. Veratrum californicum in flowering stage.
Fig. 2. Cyclopian malformed lamb induced by maternal ingestion of Veratrum californicum.
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2325
Wayne Binns, Lynn F. James, Richard F. Keeler, and Lew Dell Balls
Fig. 3. Lupinas sericeus.
Fig. 4. Crooked calf disease induced by maternal ingestion of Lupinus sericeus.
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CANCER RESEARCH
VOL. 28
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Effects of Teratogenic Agents in Range Plants
Wayne Binns, Lynn F. James, Richard F. Keeler, et al.
Cancer Res 1968;28:2323-2326.
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