LETTERS
Letter to the Editor I would like to comment on the scholarly article by Matsunaga and Shiota on holoprosencephaly in human embryos published recently in this journal (Matsunaga and Shiota, '77). Their study detailed epidemiologic data on 150 embryos from Nishimura's valuable Human Embryo Center in Kyoto, Japan. They reviewed the human literature exhaustively, but the related, and I believe highly relevant, experimental literature produced by Keeler and Binns and co-workers (Keeler and Binns, '68; Keeler, '70) was not mentioned. This latter group of scientists have demonstrated that in the ewe and rabbit cyclopamine and other derivatives of a plant, Veratrum californicum, can produce cyclopia associated with defects of the brain which are almost identical to those of human cyclopia. This plant tends to grow a t high altitude and to be consumed when other more palatable foliage is less available. One could raise the question whether cyclopamine is teratogenic in humans, and also if it could be introduced into the diet of a pregnant woman through inges-
tion of either cows milk or some other animal product. Such an exposure would more than likely be seasonal, and Matsunaga and Shiota have noted a higher winter conception rate in their subjects. Another interesting point regarding these women would be their source of animal dietary products, and particularly whether these animals could have ingested Veratrum californicum. LITERATURE CITED Keeler, R . E., and W. Binns 1968 Teratogenic comparison of cyclopian effects of steroidal alkaloids from plant and structurally related compounds from other sources. Teratology. I: 5-10. Keeler, R. F. 1970 Teratogenic compounds of Veratrum californicum (Durand) IX Structure-activity relation. Teratology, 3: 169-174. Matsunaga, E.,and K. Shiota 1977 Holoprosencephaly in human embryos: Epidemiologic studies of 150 cases. Teratology, 16: 261-272.
THOMAS H. SHEPARD Central Laboratory for Human Embryology, School of Medicine, University of Washington, Seattle, Washington 981 95
A Reply to Doctor Shepard's Letter to the Editor While we were aware of the teratogenicity of certain alkaloids in Veratrum californicum (cyclopamine or 11-deoxojervine, jervine, and cycloposine or 3-glucosyl-11-deoxojervine) producing a cyclopian-type malformation in experimental animals (Keeler, '701, we believed this is not relevant to the occurrence of holoprosencephaly in humans, particularly in our sample. Several Veratrum species, not including V. californicum, are noted to grow in northern part of Japan (Makino, '621, far from the area from which our embryo sample was obtained. Of these, V. grandiflorum is known to contain 11-deoxojervine (Masamune et al., '64), and some others probably contain jervine. Although these plants may grow in range areas, neither epidemic nor occurrence of a cyclopian-type malformation among cows TERATOLOCY (1979) 19: 127-128.
or sheep has been reported in our country. The consumption of meat and milk (together with milk products) by Japanese has been increasing during the last 20 years. However, according to the national nutrition survey conducted by the Ministry of Health and Welfare ('781, their daily intakes per capita in 1976 were 64.4 g and 100.6 g respectively, still substantially lower than those in western Europe and North America. In our data, holoprosencephaly occurred largely a t random, but more cases appeared in winter (Matsunaga and Shiota, '77). This is in sharp contrast to the observed pattern of an epidemic in sheep; the malformation occurred in lambs from ewes t h a t were bred in August or early September while on certain alpine range areas where V. californicum grew (Binns et al., '63).We
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consider therefore t h a t t h e link between t h e high incidence of holoprosencephaly in our embryo sample and t h e teratogenic alkaloids in Veratrum species is a remote possibility. LITERATURE CITED Binns. W., L. F. James, J. L. Shupe and G. Everett 1963 A congenital cyclopian-type malformation in lambs induced by maternal ingestion of a range plant, Veratrurn californicum. Am. J. Vet. Res., 24: 1164-1175. Keeler. R. F. 1970 Teratogenic compounds in Veratrurn calrfornicurn (Durand) IX. Structure-activity relation. Teratology, 3: 169-174.
Makino, T. 1962 Makino's New Illustrated Flora of Japan. Hokuryukan, Tokyo. pp. 830-831. Masamune. T., Y. Mori, M. Takasugi and A. Murai 1964 A new alkaloid from Veratrum species, 11-deoxojervine. Tetrahedron Letters, No. 16: 913-917. Matsunaga, E., and K. Shiota 1977 Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology, 16: 261-272. Ministry of Health and Welfare, Japan 1978 National nutrition survey in 1976. Kosei-no-shihyo, 25(3): 37-47. E. MATSUNACA AND K. SHIOTA Departrnenf o f Human Genetics, National Znstitute of Genetics, Mishima, Shizuoka-ken 411, Japan
Letter to the Editor I would like to comment on the scholarly article by Matsunaga and Shiota on holoprosencephaly in human embryos published recently in this journal (Matsunaga and Shiota, '77). Their study detailed epidemiologic data on 150 embryos from Nishimura's valuable Human Embryo Center in Kyoto, Japan. They reviewed the human literature exhaustively, but the related, and I believe highly relevant, experimental literature produced by Keeler and Binns and co-workers (Keeler and Binns, '68; Keeler, '70) was not mentioned. This latter group of scientists have demonstrated that in the ewe and rabbit cyclopamine and other derivatives of a plant, Veratrum californicum, can produce cyclopia associated with defects of the brain which are almost identical to those of human cyclopia. This plant tends to grow a t high altitude and to be consumed when other more palatable foliage is less available. One could raise the question whether cyclopamine is teratogenic in humans, and also if it could be introduced into the diet of a pregnant woman through inges-
tion of either cows milk or some other animal product. Such an exposure would more than likely be seasonal, and Matsunaga and Shiota have noted a higher winter conception rate in their subjects. Another interesting point regarding these women would be their source of animal dietary products, and particularly whether these animals could have ingested Veratrum californicum. LITERATURE CITED Keeler, R . E., and W. Binns 1968 Teratogenic comparison of cyclopian effects of steroidal alkaloids from plant and structurally related compounds from other sources. Teratology. I: 5-10. Keeler, R. F. 1970 Teratogenic compounds of Veratrum californicum (Durand) IX Structure-activity relation. Teratology, 3: 169-174. Matsunaga, E.,and K. Shiota 1977 Holoprosencephaly in human embryos: Epidemiologic studies of 150 cases. Teratology, 16: 261-272.
THOMAS H. SHEPARD Central Laboratory for Human Embryology, School of Medicine, University of Washington, Seattle, Washington 981 95
A Reply to Doctor Shepard's Letter to the Editor While we were aware of the teratogenicity of certain alkaloids in Veratrum californicum (cyclopamine or 11-deoxojervine, jervine, and cycloposine or 3-glucosyl-11-deoxojervine) producing a cyclopian-type malformation in experimental animals (Keeler, '701, we believed this is not relevant to the occurrence of holoprosencephaly in humans, particularly in our sample. Several Veratrum species, not including V. californicum, are noted to grow in northern part of Japan (Makino, '621, far from the area from which our embryo sample was obtained. Of these, V. grandiflorum is known to contain 11-deoxojervine (Masamune et al., '64), and some others probably contain jervine. Although these plants may grow in range areas, neither epidemic nor occurrence of a cyclopian-type malformation among cows TERATOLOCY (1979) 19: 127-128.
or sheep has been reported in our country. The consumption of meat and milk (together with milk products) by Japanese has been increasing during the last 20 years. However, according to the national nutrition survey conducted by the Ministry of Health and Welfare ('781, their daily intakes per capita in 1976 were 64.4 g and 100.6 g respectively, still substantially lower than those in western Europe and North America. In our data, holoprosencephaly occurred largely a t random, but more cases appeared in winter (Matsunaga and Shiota, '77). This is in sharp contrast to the observed pattern of an epidemic in sheep; the malformation occurred in lambs from ewes t h a t were bred in August or early September while on certain alpine range areas where V. californicum grew (Binns et al., '63).We
127
128
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consider therefore t h a t t h e link between t h e high incidence of holoprosencephaly in our embryo sample and t h e teratogenic alkaloids in Veratrum species is a remote possibility. LITERATURE CITED Binns. W., L. F. James, J. L. Shupe and G. Everett 1963 A congenital cyclopian-type malformation in lambs induced by maternal ingestion of a range plant, Veratrurn californicum. Am. J. Vet. Res., 24: 1164-1175. Keeler. R. F. 1970 Teratogenic compounds in Veratrurn calrfornicurn (Durand) IX. Structure-activity relation. Teratology, 3: 169-174.
Makino, T. 1962 Makino's New Illustrated Flora of Japan. Hokuryukan, Tokyo. pp. 830-831. Masamune. T., Y. Mori, M. Takasugi and A. Murai 1964 A new alkaloid from Veratrum species, 11-deoxojervine. Tetrahedron Letters, No. 16: 913-917. Matsunaga, E., and K. Shiota 1977 Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology, 16: 261-272. Ministry of Health and Welfare, Japan 1978 National nutrition survey in 1976. Kosei-no-shihyo, 25(3): 37-47. E. MATSUNACA AND K. SHIOTA Departrnenf o f Human Genetics, National Znstitute of Genetics, Mishima, Shizuoka-ken 411, Japan
