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We investigated the causes of EEb depletion by evaluating effects of DHA on EEbs in whole embryo culture (WEC). Rat embryos cultured starting on Day 9\u00a0pc were treated with 1 or 7\u00a0\u03bcM DHA for 24\u00a0hr starting after 19\u00a0hr of culture (\u223cDay 10\u00a0pc) and for 2 to 12\u00a0hr starting after 43\u00a0hr of culture (\u223cDay 11\u00a0pc). DHA effects indicating the depletion of EEbs were paling of the visceral yolk sac and reductions in visible blood cells, H&amp;E\u2010stained normal (Type II or III) EEbs, and dividing (BrdU\u2010stained) EEbs. DHA\u2010induced abnormal cell division was indicated by increases in symmetric and asymmetric binuclear cells. DHA\u2010induced apoptosis was indicated by increases in TUNEL\u2010 and Caspase\u20103\u2010positive cells and EEbs with fragmented nuclei. In addition, although the overall number of EEbs was decreasing, DHA caused increases in the numbers of circulating early\u2010stage (Type I or earlier) EEbs that could not be accounted for by cell division, suggesting the release of new, less sensitive erythroblasts from the yolk sac. In summary, treatment of Day 10 or 11\u00a0pc rat embryos with DHA in WEC resulted in defective and arrested cell division in EEbs followed by apoptosis, suggesting a mechanism for their depletion after artesunate treatment in vivo.<\/jats:p>","DOI":"10.1002\/bdrb.21088","type":"journal-article","created":{"date-parts":[[2014,1,3]],"date-time":"2014-01-03T18:57:07Z","timestamp":1388775427000},"page":"445-458","source":"Crossref","is-referenced-by-count":13,"title":["Dihydroartemisinin (DHA) Treatment Causes an Arrest of Cell Division and Apoptosis in Rat Embryonic Erythroblasts in Whole Embryo Culture"],"prefix":"10.1002","volume":"98","author":[{"given":"Lorraine M.","family":"Posobiec","sequence":"first","affiliation":[{"name":"Safety Assessment GlaxoSmithKline King of Prussia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert L.","family":"Clark","sequence":"additional","affiliation":[{"name":"Artemis Pharmaceutical Research Lansdale Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul B.","family":"Bushdid","sequence":"additional","affiliation":[{"name":"Safety Assessment GlaxoSmithKline King of Prussia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan B.","family":"Laffan","sequence":"additional","affiliation":[{"name":"Safety Assessment GlaxoSmithKline King of Prussia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai\u2010Fen","family":"Wang","sequence":"additional","affiliation":[{"name":"Safety Assessment GlaxoSmithKline King of Prussia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tacey E. 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