Embryotoxicity induced by alkylating agents: 6. DNA adduct formation induced by methylnitrosourea in mouse embryos

Abstract

Formation of DNA adducts in 11-day-old mouse embryos was studied by measuring the initial alkylation rates of the methylated purine bases 7-methylguanine, O6-methylguanine, and 3-methyladenine. In the first part of the studies the adduct rates were measured in the teratogenic dose range (ED10-ED90, 2.7-5.6 mg/kg). These results were compared with similar data obtained from studies with ethylmethanesulfonate and acetoxymethyl-methylnitrosamine. For the three investigated substances a correlation was found between the initial adduct rate of O6-alkylguanine in the DNA of the embryos and the teratogenic potency. In the second part of the study the rate of adduct formation was measured in the sub-teratogenic dose range. These data will be used for molecular dosimetry in a risk assessment of low doses.

Embryotoxicity induced by alkylating agents: 7. Low dose prenatal‐toxic risk estimation based on NOAEL risk factor approach, dose‐response relationships, and DNA adducts using methylnitrosourea as a model compound

“…In the case of slope = 5 , the extrapolated incidences from "safe doses" obtained by dividing through all risk factors used (10,30,100) were smaller than 1 x 10". This means that in the case of steep dose-response functions (slope of 2 5 from probit analysis), even with the lowest risk factor 10, a dose value is assessed which would be assigned to a risk of <1 X lo4 when extrapolating the risk using probit analysis.…”

“…DNA alkylation rates of the purine bases 7-methylguanine, 06-methylguanine, and 3-methyladenine in the embryos were determined using a method previously described [ 10,14,15]. This method includes the following steps: (1) The dams were treated i.p.…”

DNA alkylation studies of combined treatment with methylnitrosourea and ethylmethanesulfonate in mice

“…to the dams on day 11 of pregnancy. The methodology for the determination of alkylated DNA bases has been described previously [5,6].…”

“…Previously, in large-scale studies on dose-response relationships, the teratogenic potency of the alkylating agents ethylmethanesulfonate (EMS) [1], acetoxymethyl-methylnitrosamine (DMN-OAc) [2], and methylnitrosourea (MNU) [3] was assessed by our group. Additionally, the for-mation of methylated and ethylated DNA adducts in 11-day-old embryos was determined by investigating these agents: DMN-OAc [4], MNU [5], and EMS [6]. Against this background, the low-dose prenatal toxic risk was estimated using various approaches including molecular dosimetry [7,8].…”

Effects of O6-benzylguanine on growth and differentiation of P19 embryonic carcinoma cells treated with alkylating agents

“…However, a specific target for developmental toxicity has not yet been identified. Whereas a strong correlation has been established between alkylation at the O 6 position of guanine and carcinogenicity [7][8][9][10][11], studies by Bochert et al [12] are the only ones which show a correlation between adduct levels at the O 6 position of guanine and teratogenic potency. Studies recently completed in our lab [13] support the idea that adducts at the O 6 position of guanine may have particular relevance for developmental toxicity of some alkylating agents.…”