Regulation of S-adenosyl methionine synthesis in the mouse embryo.
In early embryos, methylation is involved in "gamete imprinting" and inactivation of artificially introduced foreign genes. We studied the biosynthesis of the universal methylation cofactor: S-Adenosyl methionine (SAM). In the mouse, SAM conversion from methionine is limited by saturation of the methionine endogenous pool. SAM is present at a practically unchanged level from the unfertilized oocyte to early morula. SAM synthesis is increased at the time of compaction. In blastocysts, although methionine uptake is increased, the conversion rate from methionine is lowered. We observed no differences between C57 Black and Swiss albino random bred strains. In few experiments with human unfertilized oocytes and spared embryos, we observed higher methionine incorporation, and higher conversion to SAM. Next, the effect of two methylation inhibitors was tested, on early mouse embryonic development, at the one-cell and the two-cell stage. We found that ethionine is very toxic, even at the lowest tested concentration of 25 microM. Homocysteine is more potent at the one-cell stage than at the 2-cell stage, and it only partially blocks blastocyst formation from the 2-cell stage even at a concentration of 500 microM. It clearly acts as a methylation inhibitor; it lowers the SAM pool and the methylation index, SAH/SAM ratio (SAH: S-Adenosyl Homocysteine). We also found that homocysteine is an unexpected competitor for methionine influx and efflux.
Menezo
Y
Y
INRA INSA, LA 23 203-20, Villeurbanne, France.
Khatchadourian
C
C
Gharib
A
A
Hamidi
J
J
Greenland
T
T
Sarda
N
N
D000818:Animals; D001667:Binding, Competitive; D001755:Blastocyst / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D005001:Ethionine / Q000494:pharmacology; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D008715:Methionine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008815:Mice, Inbred Strains; D009028:Morula / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000096:biosynthesis*
D006710:Homocysteine; D012436:S-Adenosylmethionine; D008715:Methionine; D005001:Ethionine