Apoptotic cell death and cell proliferative activity in the rat fetal central nervous system from dams administered with ethylnitrosourea (ENU)

Ethylnitrosourea (ENU), a weii known DNA alkylating agent, induces anomalies in the central nervous system (CNS), craniofacial tissues and male reproductive organs, and the enhancement of apoptosis is found in these tissues immediately after the administration of ENU (Katayama et al., 2000a). In this study, pregnant rats were treated with 6Omgíkg of ENU at day 13 of gestation, and kinetics of apoptotic cells, mitotic cells and bromodeoxyuridine (BrdU)-positive cells in the fetal CNS were examined from 3 to 48 hours after the treatment (HAT). From 3 HAT, a significant increase in the number of apoptotic cells and a significant decrease in the number of mitotic cells were detected in the fetal CNS, and BrdU-positive cells significantly decreased in accordance with the increase in the number of apoptotic cells. The present results strongly suggest that both excess cell death by apoptosis and cell growth arrest indicated by decreased number of mitotic cells and BrdU-positive cells may have a close relation to the later occurrence of microencephaly following ENU-administration, and that ENU affects mainly S-phase cells and causes apoptosis

Apoptosis in the developing mouse embryos from T-2 toxin-inoculated dams

T-2 toxin (3mglkg b.w.) was orally inoculated to pregnant mice at 11 days of gestation to examine the effect of T-2 toxin on the developing embryos. At 24 hours after T-2 toxin-inoculation, moderate pyknosis or karyorrhexis was generally observed in some layers of the central nervous system, caudal sclerotomic segment, caudal region of the tongue to pharyngeal- to laryngeal-mesenchyma, trachea and facial mesenchyma. These pyknotic or karyorrhectic nuclei were strongly stained by the modified TUNEL method widely used for the in situ detection of apoptotic nuclei and also showed ultrastructural changes characteristic for apoptosis. This is the first report of mycotoxin-induced apoptosis in embryos

Ethylnitrosourea (ENU)-induced apoptosis in the rat fetal tissues

Ethylnitrosourea (ENU), a well known DNA alkylating agent, induces anomalies in the central nervous system (CNS), craniofacial tissues and male reproductive organs. In this study, pregnant rats were treated with 60 mg/kg ENU at day 13 of gestation, and their fetuses were examined from 1 to 48 hours after treatment (HAT) to find a clue for clarifying the mechanisms of the ENU fetotoxicity and teratogenicity. From 3 to 12 HAT, the moderate to marked increase in the number of pyknotic cells was detected in the fetal CNS, craniofacial mesenchymal tissues, gonads and so on. These pyknotic cells had nuclei positively stained by the TUNEL method, which is widely used for the detection of apoptotic nuclei, and they also showed electron microscopic characteristics identical to those of apoptotic cells. The present results strongly suggest that excess cell death by apoptosis in the fetal CNS, craniofacial tissues and gonads may have a close relation to the later occurrence of anomalies reported in these tissues following ENU-administration

Prolonged oval cell proliferation with Ito cell activation and extracellular matrix accumulation in galactosamine-induced acute hepatitis in mini rats

Histopathological and immunohistochemical studies were carried out on D-galactosamine (Ga1NAc)- induced acute hepatitis in rats of the JCl: Wistar TgN (ARGHGEN) 1 Nts strain (Mini rats), in which expression of the growth hormone gene is suppressed by an antisense transgene. Hepatitis characterized by hepatocellular acidophilic necrosis with inflammatory cell infiltration was most prominent at 2 days after GalNAc (1000mglkg)-injection, when proliferation of Ito cells and deposition of fibronectin and laminin were found along the sinusoidal linings. At 72 hours after GalNAc-injection, Ito cell proliferation with deposition of laminin and fibronectin became more prominent, and marked proliferation of small epithelial cells was observed in the periportal area. At 7 days after GalNAcinjection, quite a number of a-smooth muscle actinpositive Ito cells, surrounded by abundant fibronectin, laminin and type IV collagen, were still observed in close juxtaposition to rapidly proliferating small epithelial cells. The small epithelial cells were found to be positive for both a-fetoprotein and cytokeratin 7 and were therefore considered to be so-called oval cells. The results suggest that there may be some relation between oval cell proliferation, Ito cell activation and extracellular matrix accumulation in GalNAc-induced acute hepatitis in Mini rats

Apoptotic cell death and cell proliferative activity in the rat fetal central nervous system from dams administered with ethylnitrosourea (ENU)

Ethylnitrosourea (ENU), a weii known DNA alkylating agent, induces anomalies in the central nervous system (CNS), craniofacial tissues and male reproductive organs, and the enhancement of apoptosis is found in these tissues immediately after the administration of ENU (Katayama et al., 2000a). In this study, pregnant rats were treated with 6Omgíkg of ENU at day 13 of gestation, and kinetics of apoptotic cells, mitotic cells and bromodeoxyuridine (BrdU)-positive cells in the fetal CNS were examined from 3 to 48 hours after the treatment (HAT). From 3 HAT, a significant increase in the number of apoptotic cells and a significant decrease in the number of mitotic cells were detected in the fetal CNS, and BrdU-positive cells significantly decreased in accordance with the increase in the number of apoptotic cells. The present results strongly suggest that both excess cell death by apoptosis and cell growth arrest indicated by decreased number of mitotic cells and BrdU-positive cells may have a close relation to the later occurrence of microencephaly following ENU-administration, and that ENU affects mainly S-phase cells and causes apoptosis

Ethylnitrosourea ENU - induced apoptosis in the rat fetal tissues

Ethylnitrosourea (ENU), a well known DNA alkylating agent, induces anomalies in the central nervous system (CNS), craniofacial tissues and male reproductive organs. In this study, pregnant rats were treated with 60 mg/kg ENU at day 13 of gestation, and their fetuses were examined from 1 to 48 hours after treatment (HAT) to find a clue for clarifying the mechanisms of the ENU fetotoxicity and teratogenicity. From 3 to 12 HAT, the moderate to marked increase in the number of pyknotic cells was detected in the fetal CNS, craniofacial mesenchymal tissues, gonads and so on. These pyknotic cells had nuclei positively stained by the TUNEL method, which is widely used for the detection of apoptotic nuclei, and they also showed electron microscopic characteristics identical to those of apoptotic cells. The present results strongly suggest that excess cell death by apoptosis in the fetal CNS, craniofacial tissues and gonads may have a close relation to the later occurrence of anomalies reported in these tissues following ENU-administration