Annotated Bibliography
Ouellet,
M. et al. (1997). Hindlimb deformities (ectromelia, ectrodactyly) in free-living
anurans from agricultural habitats. J. Wildlife Diseases 33: 95-105.
This is the first report of data
from the Canadian Wildlife Service field surveys that began in 1992. In
this paper the authors report finding frogs with missing limb parts. Since
that time they have found the other malformations that have been observed
elsewhere, including extra limbs and limb parts. Their data indicate a
correlation with agricultural activity, and have established the baseline
frequency of malformations in pristine environments to be much less than
1%. The typical frequency of malformations in affected sites is 10% or
greater.
There are
three general hypotheses currently proposed to account for the observed
amphibian malformations:
(1) Trauma/mechanical:
Bryant, S.V., French, V. and Bryant, P.J. (1981).
Distal regeneration and symmetry. Science 212:993-1002.
This paper presents the theoretical basis for the formation
of supernumerary limb structures as a consequence of tissue rearrangements
that stimulate growth and pattern formation.
Sessions, S.K. and Ruth, S.B. (1990). Explanation
for naturally occurring supernumerary limbs in amphibians. J. exp. Zool.
254:38-47.
This paper is where the parasite hypothesis was first
presented. To date is the only publication presenting data in support
of this idea. Beads implanted as mimics of parasite cysts induced some
limbs with extra toes, providing indirect evidence that parasites could
cause one type of malformation (extra distal skeletal elements).
(2) UV-Irradiation:
Blaustein, A.R., et al. (1997). Ambient UV-B radiation
causes deformities in amphibian embryos. Proc. Natl. Acad. Sci. USA 94:13735-13737.
This paper demonstrates that UV-B can induce malformations
at early stages of development. The relationship between these malformations,
and those observed in metamorphic frogs is unclear. Unpublished observations
from the EPA lab in Duluth, MN, indicate that UV can induce truncated limbs
in metamorphic frogs; however, these truncations differ significantly from
many of those on animals from the field. The relevance of UV as a causal
agent in metamorphic frogs in the environment has yet to be determined.
(3) Chemical Agents:
There are thousands of peer-reviewed publications demonstrating
the ability of chemical agents to induce limb malformations. Research in
this area is included in the field of toxicology (Developmental Toxicology),
and has given rise to the scientific discipline of teratology. It is noteworthy
that there is one category of chemical agents, the retinoids, that are
known to induce all of the observed limb malformations in deformed frogs.
Bryant, S.V. and Gardiner, D.M. (1992). Retinoic acid,
local cell-cell interactions, and pattern formation in vertebrate limbs.
Devel. Biol. 152: 1-25.
There are hundreds of publications on the effects of retinoids
on limb development and regeneration. This paper is a comprehensive review
of that literature through the early 90's.
Rutledge, J.D., et al. (1994). Limb and lower-body
duplications induced by retinoic acid in mice. Proc. Natl. Acad. Sci. 91:
5436-5440.
Niederreither, K., et al. (1996). Morphological
and molecular characterization of retinoic acid-induced limb duplications
in mice. Devel. Biol. 176:185-198.
Both of these papers report the same, dramatic and disturbing
finding that retinoic acid induces the formation of extra hindlimbs in
mouse embryos. Retinoic acid is fed to the pregnant mother, the mice are
born with this malformation that is identical to the extra hindlimb malformation
that is observed in some of the frogs from the wild.
Cell, Vol. 83, December 15, 1995.
The molecular mechanisms of retinoid activity has been
well studied, and there are hundreds of publications. The information is
well reviewed in a series of articles published in this issue of Cell.
La Clair, J.J., Bantle, J.A. and Dumont, J. (1998).
Photoproducts and metabolites of a common insect growth regulator produce
developmental deformities in Xenopus. Environ. Sci. Technol. 32: 1453-1461.
One suspect pesticide that has been mentioned repeatedly
in the media is methoprene, which is a juvenile hormone mimic. Although
there is no evidence that its use is related to the metamorphic frog malformations,
a break down product (methoprene acid) will bind to and activate a retinoid
receptor. In this paper, the authors report that derivatives of methoprene
can induce early stage developmental abnormalities in Xenopus (FETAX assay).
It is unclear at this point how, or if, these results pertain to the types
of frog malformations observed in frogs from the wild.
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