Cyclopian-Type Malformation in Lambs

Binns, Wayne; James, Lynn F.; Shupe, J. L.; Thacker, E. J.

doi:10.1080/00039896.1962.10663251

Cited by 84 publications

(58 citation statements)

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“…Veratrum californicum when eaten by pregnant ewes produces abortion and birth defects (Binns et al 1960). We tested a solution of the dry leaves in water, 1 gm per 100cc, and found it to be as effective in breaking onion chromosomes as 25r/day of gamma rays.…”

Section: Discussionmentioning

confidence: 99%

Possible Mutagenic Hazards of Some Food Additives, Beverages and Insecticides

Sax¹,

Sax²

1968

The Japanese journal of genetics

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It has long been known that radiomimetic chemical agents which produce chromosome aberrations in plant and animal cells may also produce mutations.The early discovery by Kihlman and Levan (1949) that caffeine induces aberrations in plant chromosomes and the more recent report by Ostertag (1966) that caffeine breaks human chromosomes has led to further tests of the radiomimetic effect of beverages, food additives and home insecticides. Agents which break plant chromosomes may not break animal chromosomes, but the correlation is high (Kihlman 1966). The onion root tip technique provides a rapid method for making preliminary tests of suspected radiomimetic agents. MATERIALS AND METHODSThe agents to be tested were made up in concentrations which permit essentially normal growth of the onion root tips. Ten cc of the solution was poured over 5 layers of paper toweling in a petri dish and about 100 onion seeds were sown on the moist paper. When the roots were 0.5-1.0 cm long, usually in 3 days, they were fixed in alcohol-acetic acid for 24 hours and then transferred to alcohol until the aceto-carmine smears were made. The chromosome aberrations, which were scored at anaphase, consisted of acentric fragments and dicentric bridges.There was considerable variations in aberration frequency, but the analysis of 10 root tips, each with an average of more than 100 anaphases, for each test, gave reasonably consistent results. RESULTSThe fantastic increase in the use of artificial sweeteners in beverages and food products in recent years, and the controversy regarding their use, led us to test the radiomimetic effects of "Sucaryl", which contains 8 % of sodium cyclamate and 0.8 % of saccharin; and saccharin tablets which contain 1/4 grain of saccharin.At the concentrations recommended, 6 drops of sucaryl per 6 oz. cup or 1 saccharin tablet per cup, the aberration frequency did not exceed that of the controls. At relatively high concentrations both agents were radiomimetic.For comparative purposes tests of moderate concentrations of sugar and salt were included. Higher concentrations of sugar greatly retared growth of the root tips. The results are shown in Table 1.

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Section: Discussionmentioning

confidence: 99%

Possible Mutagenic Hazards of Some Food Additives, Beverages and Insecticides

Sax¹,

Sax²

1968

The Japanese journal of genetics

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“…Plants of the genus Veratrum have a long history of use in the folk remedies of many cultures (Namba 1993;Levetin and McMahon 1996), and the jervine family of alkaloids (Fried and Klingsberg 1953), which constitute a majority of Veratrum secondary metabolites, have been used for the treatment of hypertension and cardiac disease. The association of Veratrum californicum with an epidemic of sheep congenital deformities during the 1950s (Binns et al 1962) raised the possibility that jervine alkaloids are also potent teratogens. Extensive investigations by the U.S. Department of Agriculture subsequently confirmed that jervine and cyclopamine (11-deoxojervine) given during gestation can directly induce cephalic defects in lambs, including cyclopia in the most severe cases (Keeler and Binns 1965).…”

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confidence: 99%

Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened

Chen¹,

Taipale²,

Cooper³

et al. 2002

Genes Dev.

1,371

1,070

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The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct binding of cyclopamine to the heptahelical bundle of Smoothened (Smo). Cyclopamine also can reverse the retention of partially misfolded Smo in the endoplasmic reticulum, presumably through binding-mediated effects on protein conformation. These observations reveal the mechanism of cyclopamine's teratogenic and antitumor activities and further suggest a role for small molecules in the physiological regulation of Smo. Plants of the genus Veratrum have a long history of use in the folk remedies of many cultures (Namba 1993;Levetin and McMahon 1996), and the jervine family of alkaloids (Fried and Klingsberg 1953), which constitute a majority of Veratrum secondary metabolites, have been used for the treatment of hypertension and cardiac disease. The association of Veratrum californicum with an epidemic of sheep congenital deformities during the 1950s (Binns et al. 1962) raised the possibility that jervine alkaloids are also potent teratogens. Extensive investigations by the U.S. Department of Agriculture subsequently confirmed that jervine and cyclopamine (11-deoxojervine) given during gestation can directly induce cephalic defects in lambs, including cyclopia in the most severe cases (Keeler and Binns 1965).It is now known that the teratogenic effects of jervine and cyclopamine are due to their specific inhibition of vertebrate cellular responses to the Hedgehog (Hh) family of secreted growth factors (Cooper et al. 1998;Incardona et al. 1998), as first suggested by similarities between the Vertarum-induced developmental malformations and holoprosencephaly-like abnormalities associated with loss of Sonic hedgehog (Shh) function (Chiang et al. 1996;Roessler et al. 1996). In accordance with this general mechanism, cyclopamine also has shown some promise in the treatment of medulloblastoma tumors caused by inappropriate Hh pathway activation (Berman et al. 2002). How cyclopamine specifically inhibits Hh pathway activation is unclear, but it appears to interfere with the initial events of vertebrate Hh signal reception, which involve the multipass transmembrane (TM) proteins Patched (Ptch) and Smoothened (Smo;Ingham and McMahon 2001). During normal Hh signaling, Hh proteins bind to Ptch (Marigo et al. 1996;Stone et al. 1996;Fuse et al. 1999), thereby alleviating Ptch-mediated suppression of Smo, a distant relative of G-protein-coupled receptors (GCPRs). Smo activation then triggers a series of intracellular events, culminating in the activation of Gli-dependent transcription (Alexandre et al. 1996;Aza-Blanc et al. 1997).Cyclopamine appears to interfere with these signaling events by influencing Smo function, as it antagonizes Hh pathway activity in a Ptch-independent manner and exhibits attenuated potency toward an oncogenic, const...

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“…Ewes 23 and 9 bore lambs which were dead or moribund when delivered by Caesarian section only 3 and 7 days after term. Furthermore, Binns, Anderson & Sullivan (1960) (Symenoidis, 1948;McClure, 1961;Emmens & Finn, 1962) (Pose & Fielitz, 1961) and the same applies also to the guinea-pig (M. X. Zarrow, personal communication; B. M. Schofield, unpublished data). The ewes seem to fall into the same category.…”

Section: Introductionmentioning

confidence: 92%

Progesterone and the Accomplishment of Parturition in the Sheep

Bengtsson¹,

Schofield²

1963

Reproduction

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Summary. A flock of thirty ewes was observed through two pregnancies to determine whether parturition could be delayed by the systemic administration of gestagens. In the first season, the four treated groups received daily injections of 2-5 and 10 mg, 6a-methyl-17a-hydroxyprogesterone acetate (6-map) and 10 and 40 mg progesterone for 14 days starting 1 week before the expected date of delivery. The time and course of delivery appeared to be unaffected. The following season the dose levels were increased to 25 and 40 mg 6-map, and 80 and 160 mg progesterone. A high proportion of pregnancies was affected by this treatment. Some sheep delivered to schedule but most of the others had to be subjected to Caesarian section. The mortality of lambs delivered at term was higher than in the control group and in all the cases of delayed parturition the lambs died in utero. The foetal death was not considered to be due to post-maturity. The results are discussed and it is concluded tentatively that placental progesterone in the ewe is not replaceable by systemic progesterone.

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Cyclopian-Type Malformation in Lambs

Cited by 84 publications

References 0 publications

Possible Mutagenic Hazards of Some Food Additives, Beverages and Insecticides

Possible Mutagenic Hazards of Some Food Additives, Beverages and Insecticides

Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened

Progesterone and the Accomplishment of Parturition in the Sheep

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