Hydroxyurea (HU)-induced apoptosis in the mouse fetal lung.
In this study, the cytotoxicologic effects of HU on the fetal lung were assessed by exposing pregnant mice to HU on day 13 of gestation. The number of TUNEL-positive cells, i.e., apoptotic cells, in the fetal lung began to increase at 3 h after treatment (h), peaked at 6 h, and decreased thereafter, and the sequence of the number of cleaved caspase 3-positive cells corresponded to that of TUNEL-positive cells. Such positive reactivity for TUNEL and cleaved caspase 3 was mainly seen in pulmonary mesenchymal cells. Prior to the induction of apoptosis, the number of p53-positive cells in the fetal lung prominently increased at 1 and 3 h, and decreased thereafter. Among p53 transcriptional target genes (p21, fas, bax, apaf1, cyclin G, mdm2, and gad 45) examined, the expression levels of p21, bax, and cyclin G mRNAs were significantly elevated. In addition, the expression of fas mRNA tended to show higher levels compared with controls until 24 h. In addition, the results of flow cytometric analysis suggested that cell cycle arrest might be induced in S phase at 3 h. The present results suggest that HU-induced apoptosis in the mouse fetal lung may be closely related with the induction of p53.
Woo
Gye-Hyeong
GH
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.
Bak
Eun-Jung
EJ
Nakayama
Hiroyuki
H
Doi
Kunio
K
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D005260:Female; D005333:Fetus; D005434:Flow Cytometry; D006918:Hydroxyurea / Q000633:toxicity*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D006918:Hydroxyurea