Embryotoxicity induced by alkylating agents: left-sided preponderance of paw malformations induced by acetoxymethyl-methylnitrosamine in mice

Abstract

The alkylating agent acetoxymethyl-methylnitrosamine (DMN-OAc) triggers preferential left-sided paw defects in mice following IP administration on either day 11 or 12 of pregnancy. Predominantly, ectrodactyly and hypoplasia of the left paws were found. In an organ culture system, using limb buds of 11-day-old mouse embryos, differentiation is severely impaired following addition of 2 microM DMN-OAc to the culture medium. Left and right limbs are equally affected. In contrast, when DMN-OAc is administered in vivo to the dams with subsequent culturing of the limb buds, growth and differentiation of the left limb buds is more affected when compared to the right. Furthermore, DNA alkylation experiments were performed: in vitro, following addition of (14C)-DMN-OAc (2.3 microM) to the culture medium, the DNA alkylation rate of the limb bud DNA is determined. In vivo, following IP administration of 10 mg/kg DMN-OAc to the dams on day 11 of pregnancy, the extent of DNA alkylation of whole-embryo DNA is similar. However, the DNA alkylation rate of separately pooled left and right limb buds exhibits a two-fold difference according to the different teratogenic susceptibility. The results obtained with both in vivo and in vitro systems are consistent with the thesis that a certain amount of DNA alkylation in the tissue of the embryos is the initial step of alkylating agent-induced teratogenicity.

Nitrosatable drug exposure during pregnancy and risk of stillbirth

“…An underlying mechanism whereby exposure to N‐nitroso compounds may cause stillbirth is not established, but some animal studies have indicated that nitrate, nitrite, and N‐nitroso compounds cross the placenta and affect the fetus in utero . It has been suggested that the teratogenic effect of N‐nitroso compounds is causing abnormal development through DNA alkylation …”

Challenges in the recruitment of adolescents and young adults to cancer clinical trials

“…Various N ‐nitroso compounds have been observed to be teratogenic in animal models and may cause abnormal development through DNA alkylation of target organs (Bochert et al, 1985). In mice, defects associated with exposure to N ‐nitroso compounds have included exencephaly, cleft palate, (Platzek et al, 1983), limb malformations (Bochert et al, 1985), hydrocephalus, spina bifida, gastroschisis, and skeletal anomalies (Diwan, 1974). In rats, maternal exposure to such compounds resulted in increased incidence of limb malformations, neural tube defects, microcephalus, and hydrocephalus (Koyama et al, 1970).…”

Teratological Research Using In Vitro Systems. II. Rodent Limb Bud Culture System

“…Acetoxymethyl-methylnitrosamine (DMN-OAc) triggers preferential left-sided paw defects in mice only after in vivo administration. A good correlation was found between the relative in vitro DNA alkylation rates with '4C-DMN-OAc ofseparately pooled right and left limbs from fetuses of DMN-OAc-treated mice and the asymmetric teratogenic response to this compound (79). In the case of a noncompound-related condition, genetically determined polydactyly in mouse embryos was found to be associated with increased in vitro DNA synthesis and cAMP-phosphodiesterase within the region of the limb bud peculiar to the prospective polydactylous region (80).…”