High oxygen environment during pregnancy rescues sickle cell anemia mice from prenatal death.
Several mouse models of sickle cell disease have been developed for the study of the pathophysiology of sickle cell disease and the investigation of drug and gene therapies. In previous years, we produced a sickle cell anemia mouse model in which the endogenous mouse alpha- and beta-globin genes were knocked out and replaced by the human alpha- and beta(s)-globin transgenes. The beta(s)-globin gene was contained in a 240 kb YAC that preserved the entire native genomic context of the beta-globin locus. These mice have hemolytic anemia, reticulocytosis and irreversible sickle cells in the peripheral blood, as well as other pathological features of sickle cell disease. However, in the embryo, the gamma-globin, like the mouse embryonic globin, declined quickly, and was replaced by beta(s)-globin expression from 12 days of gestation. The low level of fetal hemoglobin expression in utero led to intrauterine sickling and fetal death so that very few live-born sickle cell anemia mice could be obtained. To rescue these mice from intrauterine death, we investigated the effect of placing the pregnant mothers in a high O(2) environment. From the tenth day of gestation onwards, we placed the mothers into a chamber containing 50% O(2) and kept them with the newborn pups in it for another 10 days after birth. The frequency of sickle cell anemia mice we obtained was increased from less than 2% to 35%. The survived sickle cell anemia mice develop congestion, atrophy, and infarcts in multiple organs similar to those found in patients with sickle cell disease. We conclude that a high oxygen environment can be used to obtain more sickle cell anemia mice in those models that have a high perinatal mortality. The higher yield of these mice has facilitated physiological and therapeutic studies of sickle cell anemia.
Ye
Lin
L
Department of Medicine, Cardiovascular Research Institute, Institute for Human Genetics, University of California, San Francisco, CA 94143-0793, USA.
Chang
Judy C
JC
Lu
Ronghua
R
Kan
Yuet Wai
YW
D000755:Anemia, Sickle Cell / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004913:Erythrocytes, Abnormal / Q000378:metabolism; D005260:Female; D005914:Globins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010100:Oxygen; D011247:Pregnancy; D015996:Survival Rate
D005914:Globins; D010100:Oxygen