RESUMO
The teratogenic action of distal inhibitors of cholesterol synthesis has been known for some time. The induced malformations are of a particular type: they include holoprosencephalies. Recently these observations have solicited increased interest due to: 1/ the discovery in 1993 of a similar form of inhibition of cholesterol synthesis which is responsible for a human malformation syndrome, Smith-Lemli-Opitz; 2/ the demonstration of the involvement of the Sonic Hedgehog gene in normal development of prosencephalon and the description of the mode of action of the protein Shh: autoprocessing followed by "cholesterolisation".
Assuntos
Colesterol/farmacologia , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Animais , Anticolesterolemiantes/farmacologia , Colesterol/sangue , Colesterol/genética , Desenvolvimento Embrionário e Fetal/genética , Genes , Holoprosencefalia/induzido quimicamente , Holoprosencefalia/etiologia , Holoprosencefalia/genética , Técnicas In Vitro , Camundongos , Ratos , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano/farmacologiaRESUMO
The development and evolution of PKU can be prevented by prescribing an appropriate diet at an early age. A systematic neonatal screening has been set up in most countries. However, young women suffering from PKU give birth to very severely malformed children (PKU embryopathy: microcephaly, mental retardation, hypotrophy, cardiopathy) unless they again take up the specific diet, until the PHE level has lowered down to normal, before the beginning of gestation. The treatment has to be continued at least during the first months of gestation. This management is very unpleasant and sometimes not easily accepted. The mechanism of this embryopathy is still unknown. It is possible that (1) the excess of PHE or the presence of abnormal metabolites, or (2) serotonin deficiency (which is a feature of PKU) could be responsible for the maldevelopment of the embryo. Some authors consider that serontonin has a morphogenetic role in normal embryogenesis. Previously we described an experimental animal model using in vitro culture of rat embryos in human PKU sera. Mouse embryos have been subsequently used, since they show a greater sensitivity. Malformations, consisting essentially of neural tube defects, were present in almost 100% of the embryos cultured in serum from PKU patients. Using this animal model, we tested the hypothesis of serotonin deficiency. For this purpose, mouse embryos were cultured in human serum depleted of serotonin. Under these conditions, 100% of the embryos showed oculo-neural malformations characteristic of the experimental embryopathy. These results indicate the importance of serotonin deficiency in the occurrence of PKU embryopathy.
