Teratogenic and macromolecular synthesis inhibitory effects of trimethylamine on mouse embryos in culture.
Trimethylamine (TMA) is an aliphatic amine, and its blood levels can increase after ingestion of certain foods, such as fish, and during disease states, such as chronic renal failure. We recently reported that TMA can inhibit fetal development in vivo and in vitro in mice. The present studies were done to find out if the inhibitory effects of TMA on embryonic development are caused by a decrease in macromolecular synthesis, using mouse embryo cultures as the experimental model. At a submaximally toxic concentration (0.75mM), TMA inhibited the growth of embryos to approximately 70% of control and caused neural-tube defects in 73% of embryos. By 42 h of culture, DNA, RNA, and protein content of TMA-treated embryos were approximately 50% of the control values. Embryotoxic effects of TMA were not caused by changes in pH and osmolarity of the culture media. The inhibitory effects of TMA on embryonic growth were time dependent and apparent at 2-4 h of culture. The inhibition of growth was accompanied by a decrease in the incorporation of tritium-labeled thymidine, uridine, and leucine into DNA, RNA, and proteins, respectively. Thiols (L- and D-cysteine, glutathione) and the antioxidant L-ascorbic acid did not cause significant antagonism of embryotoxic effects of TMA. It is concluded that TMA exerts teratogenic effects on mouse embryos in culture and inhibits their growth by reducing macromolecular synthesis; these effects may not involve glutathione depletion or generation of free radicals.
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Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
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D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D046508:Culture Techniques; D004247:DNA / Q000096:biosynthesis*; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D006863:Hydrogen-Ion Concentration; D007930:Leucine / Q000378:metabolism; D046911:Macromolecular Substances; D008744:Methylamines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D008954:Models, Biological; D009994:Osmolar Concentration; D011247:Pregnancy; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis*; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D014529:Uridine / Q000378:metabolism
D046911:Macromolecular Substances; D008744:Methylamines; D013438:Sulfhydryl Compounds; D014316:Tritium; D012313:RNA; D004247:DNA; D007930:Leucine; C023336:trimethylamine; D001205:Ascorbic Acid; D013936:Thymidine; D014529:Uridine