Hydrazine Genotoxicity in the Neonatal Rat

Abstract

The neonatal rat, because of its relatively rapid rate of liver DNA replication without chemical or surgical induction, was used to assess the genotoxicity of the carcinogen hydrazine. Hydrazine is a more potent acute toxicant in the neonate than in the adult rat. Administration of hydrazine sc (1.5-50 mg/kg body wt) to newborn rats during the period of rapid liver DNA synthesis, 72-96 hr after birth, resulted in the formation of 7-methylguanine and O 6-methylguanine in hepatic DNA; O 6-methylguanine was seen only in animals given near-lethal doses of the carcinogen. Methylguanines were detectable in liver DNA only when the dose of hydrazine was necrogenic, but lethal doses of hydrazine to neonates produced more methylguanines in liver DNA than in adult rats given equal doses. Southern analyses were performed on liver DNA from neonates treated with 25 or 50 mg hydrazine/kg, doses which were necrogenic to the liver. The results indicated that one or more MspI restriction sites (5′-C↓CGG-3′) were lost or blocked in liver DNA from hydrazine-treated animals and that these sites were located at or near the genes for γ-glutamyl transpeptidase and cytochrome P450 IIB1. Restriction sites near albumin, H- ras, and cytochrome P450 IIE1 genes cut by MspI, HpaII, or HhaI did not appear to be affected by hydrazine treatment. The results suggest that hydrazine-induced damage is not random in the DNA molecule. The neonate shows less DNA adduct formation at low doses of hydrazine, but higher levels at high doses.