Age- and dose-dependent transplacental carcinogenesis byN-nitrosoethylurea in Syrian golden hamsters

Abstract

Syrian golden hamsters have a very short period (15 days) of gestation. The implantation of the blastocyst occurs on day 5, embryogenesis proceeds very rapidly thereafter and neural tube closure is completed by day 9. In the present study the effects of two different doses of N-nitrosoethylurea (NEU) administered at various stages of gestation were quantitatively evaluated in Syrian golden hamsters. NEU at either 0.2 or 0.5 mmol/kg was administered transplacentally as a single i.p. injection to pregnant hamsters on gestation days 7, 8, 9, 10, 11, 12, 13, or 14. The incidence, latency period and multiplicity of tumors varied with the dose of NEU and the stage of development at the time of NEU administration. Although tumors of the peripheral nervous system predominated, a variety of other tumors, including melanomas and visceral tumors of epithelial and mesenchymal origin, were also observed in hamster offspring exposed transplacentally to NEU. Sensitivity to transplacental carcinogenesis was maximal during late gestation and very low before day 9.

Constitutive activation of the neuregulin‐1/ErbB receptor signaling pathway is essential for the proliferation of a neoplastic Schwann cell line

“…Rats (Druckrey et al, 1966;Jones et al, 1973), mice (Anderson et al, 1989;Buzard et al, 1999), and hamsters (Diwan et al, 1996) transplacentally exposed to the alkylating agent N-ethyl-N-nitrosourea (EtNU) frequently develop malignant Schwann cell neoplasms. These tumors, variously referred to as malignant peripheral nerve sheath tumors Conley et al, 1976) or malignant schwannomas (e.g., Nikitin et al, 1991b), frequently express an activated form of the erbB2 (c-neu) proto-oncogene (Bargmann et al, 1986a;Hudziak et al, 1987;Bargmann and Weinberg, 1988;Weiner et al, 1989;Di Marco et al, 1990;Nikitin et al, 1991a) thought to confer a proliferative advantage on immature Schwann cells (Nikitin et al, 1991a).…”

neu mutation in schwannomas induced transplacentally in Syrian golden hamsters by N -nitrosoethylurea: high incidence but low allelic representation

“…Cerebral gliomas and cutaneous melanomas were also seen, but less commonly. Transplacentally induced tumors of other than neuroectodermal origin were occasionally observed in additional organs, including kidney, liver, thyroid, pancreas, and skin, as detailed previously by Diwan et al (1996). PNT were as large as 6 cm in diameter and frequently contained a conglomerate of nodular masses.…”

Cell sensitivity to transplacental carcinogenesis by N-ethyl-N-nitrosourea is greatest in early post-implantation development

“…Ž For hamsters exposed transplacentally to ENU 23 . mgrkg , the average number of tumors per animal w x has been calculated from the data of Diwan et al 5 . These were mainly neurogenic tumors, plus occasional neoplasms of thyroid, pancreas, skin, kidney, and other sites.…”

“…In the mouse, transplacental ENU causes lung tumors with highest w x w x sensitivity on gestation day 16 4 . Diwan et al 5 reported that exposure of the developing Syrian hamster fetus to ENU induced mostly tumors of the peripheral nerves, again with highest incidence after treatment late in gestation. These data might seem to imply that cells in the embryo are resistant to the carcinogenic effects of ENU.…”