DIFFERING POLYAMINE RESPONSES DURING TERATOGENESIS WITH DIPHENYLHYDANTOIN AND FOLIC ACID ANTAGONIST

Abstract

Polyamine content is correlated with nucleic acid synthesis in rapidly growing tissue and may serve as an indicator of damage by toxins, including teratogens. This report concerns the alterations in embryonic polyamine content after exposure to teratogens. Primagravid Swiss albino mice were injected intraperitoneally on day 9 with diphenylhydantoin (DPH), 88 mg/kg body weight; embryos were recovered on day 11. Pregnant Long-Evans rats were intubated on day 10 and a modified diet was supplemented with 9-methyl pteroylglutamic acid (9-methyl PGA) on days 10-13. Spermidine, spermine and putrescine were quantitated on a Durrum D-500 amino acid analyzer, and are reported as nmoles/mg of embryonic protein. Rat embryos from pregnancies treated with 9-methyl PGA had unaltered polyamines. Mouse embryos whose mothers were exposed to DPH had significant reductions in spermidine and spermine, but putrescine levels remained comparable. Growth during polyamine accumulation is attributed to their stimulation of dihydrofolate reductase, the enzyme antagonized by 9-methyl PGA. Since polyamines were unchanged during this antagonism, they may play no direct role in the reactivation of this enzyme system.

Following DPH treatment embryonic DNA was lowered proportionally more than protein content, suggesting a block in DNA synthesis.

Folate deficiency has been suggested as the mechanism of DPH teratogenesis. However, the differing polyamine responses to the 9-methyl PGA and DPH teratogenic regimens indicate different mechanisms may exist.

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