Ethylnitrosourea induces apoptosis and growth arrest in the trophoblastic cells of rat placenta.
Ethylnitrosourea (ENU), a well known alkylating agent, induces congenital anomalies in fetuses when it is administered to pregnant animals. In previous studies, we reported that ENU induced apoptosis and growth arrest in fetal tissues and organs immediately after its administration to pregnant rats. In the present study, we investigated the histopathological changes of the placenta after ENU administration to pregnant rats on Day 13 of gestation (GD13) to obtain a clue for clarifying the role of the placenta in the process of fetal developmental disability induced by genotoxic stress. Apoptotic cells increased and DNA-replicating cells decreased in the trophoblastic cells in the placental labyrinth zone of the ENU-treated group by 3 h after treatment. The number of apoptotic cells peaked at 6 h after treatment and returned to control levels at 48 h after treatment. The number of DNA-replicating cells reached minimum levels at 6 h after treatment and returned to control levels at 48 h after treatment. By immunohistochemistry, p53-positive signals were observed in trophoblastic cells in the labyrinth zone of the ENU-treated group from 3 to 6 h after treatment. Significant decreases in fetal and placental weights were observed in the ENU-treated group at 2 days (GD15) and 8 days (GD21) after treatment. A reduction in the thickness of the labyrinth zone was histopathologically significant in the ENU-treated group. These results indicate that ENU induces apoptosis and growth arrest not only in fetal tissues, but also in trophoblastic cells in the rat placental labyrinth zone, and these placental changes may have roles in the induction of fetotoxicity and teratogenicity of ENU. Moreover, a possible involvement of p53 in the induction of apoptosis and growth arrest is suggested.
Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. aa07188@mail.ecc.u-tokyo.ac.jp
Kei-ichi
K
Katayama
Masaki
M
Ueno
Hirotake
H
Takai
Noriko
N
Ejiri
Koji
K
Uetsuka
Hiroyuki
H
Nakayama
Kunio
K
Doi
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites; D017209:Apoptosis / Q000187:drug effects*; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000166:cytology* / Q000187:drug effects; D010929:Placentation; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D013723:Teratogens / Q000494:pharmacology*; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000477:Alkylating Agents; D000963:Antimetabolites; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; D001973:Bromodeoxyuridine; D005038:Ethylnitrosourea