Original Article

Cholesterol deficit but not accumulation of aberrant sterols is the major cause of the teratogenic activity in the Smith-Lemli-Opitz syndrome animal model

Correspondence to: Claude Wolf

Low cholesterol and high 7-dehydrocholesterol (7DHC) levels are associated with a blockade of 7-reductase in the Smith-Lemli-Opitz syndrome (SLOS) and in the animals treated with the inhibitor AY9944. The impact of the cholesterol deficit and of the accumulation of 7DHC on the embryo were investigated in AY9944-treated pregnant rats receiving an enriched cholesterol or 7DHC diet. Sterol profiling was performed under the various nutritional conditions. AY9944 caused a severe decrease in the maternal and embryo cholesterol. The deficit in the embryo was sustained by the embryonic uptake of the inhibitor. A cholesterol-rich diet was efficient in restoring the maternal and embryonic cholesterol and phenotype but a 7DHC-rich diet did not modify the sterol status compared with dams treated with only AY9944. The offspring phenotype remained deleterious whether or not the dams received 7DHC-rich diet. Over 80% of the 7DHC was absorbed, as was cholesterol, which was not quantitatively influenced by AY9944. When cholesterol and 7DHC were simultaneously administered, a competition for intestinal absorption enhanced the lowering cholesterol effect of AY9944.

Whether or not the dams received a 7DHC dietary supplement, the offspring's phenotype became normal when the diet was supplemented with cholesterol. Under conditions in which the ratio of cholesterol/7DHC is substantially varied, the normal development of embryos can be achieved as long as the cholesterol is sufficient. The phenotype is reversed in vivo by cholesterol which contrasts with the irreversible effects manifested in vitro by oxidized 7DHC by-products.—Gaoua, W., C. Wolf, F. Chevy, F. Ilien, and C. Roux. Cholesterol deficit but not accumulation of aberrant sterols is the major cause of the teratogenic activity in the Smith-Lemli-Opiz syndrome animal model. J. Lipid Res. 2000. 41: 637;–646.

Supplementary key words: cholesterol synthesis inhibitor AY9944, embryo, dietary supplementation of the dam

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Fernandez, M. Martin, D. Gomez-Coronado, and M. A. Lasuncion Effects of distal cholesterol biosynthesis inhibitors on cell proliferation and cell cycle progression J. Lipid Res., May 1, 2005; 46(5): 920 - 929. [Abstract] [Full Text] [PDF]

				M. Fukami, R. Horikawa, T. Nagai, T. Tanaka, Y. Naiki, N. Sato, T. Okuyama, H. Nakai, S. Soneda, K. Tachibana, et al. Cytochrome P450 Oxidoreductase Gene Mutations and Antley-Bixler Syndrome with Abnormal Genitalia and/or Impaired Steroidogenesis: Molecular and Clinical Studies in 10 Patients J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 414 - 426. [Abstract] [Full Text] [PDF]

				I. Serbanescu, M. A. Ryan, R. Shukla, M. A. Cortez, O. C. Snead III, and S. C. Cunnane Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols J. Lipid Res., November 1, 2004; 45(11): 2038 - 2043. [Abstract] [Full Text] [PDF]

				P. A. Krakowiak, C. A. Wassif, L. Kratz, D. Cozma, M. Kovarova, G. Harris, A. Grinberg, Y. Yang, A. G.W. Hunter, M. Tsokos, et al. Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency Hum. Mol. Genet., July 1, 2003; 12(13): 1631 - 1641. [Abstract] [Full Text] [PDF]

				F. Gofflot, C. Hars, F. Illien, F. Chevy, C. Wolf, J. J. Picard, and C. Roux Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling Hum. Mol. Genet., May 15, 2003; 12(10): 1187 - 1198. [Abstract] [Full Text] [PDF]

				A. S. Pappu, R. D. Steiner, S. L. Connor, D. P. Flavell, D. S. Lin, L. Hatcher, D. R. Illingworth, and W. E. Connor Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion J. Lipid Res., October 1, 2002; 43(10): 1661 - 1669. [Abstract] [Full Text] [PDF]

				B. Lindenthal, T. A. Aldaghlas, J. K. Kelleher, S. M. Henkel, R. Tolba, G. Haidl, and K. von Bergmann Neutral sterols of rat epididymis: high concentrations of dehydrocholesterols in rat caput epididymidis J. Lipid Res., July 1, 2001; 42(7): 1089 - 1095. [Abstract] [Full Text] [PDF]

				J. A. McConihay, P. S. Horn, and L. A. Woollett Effect of maternal hypercholesterolemia on fetal sterol metabolism in the Golden Syrian hamster J. Lipid Res., July 1, 2001; 42(7): 1111 - 1119. [Abstract] [Full Text] [PDF]