Chloroquine embryotoxicity in the postimplantation rat conceptus in vitro.
The embryotoxicity of the antimalarial drug chloroquine (CQ) was evaluated in vitro using the rat whole embryo culture system. CQ was found to be embryotoxic and dysmorphogenic when added directly to the culture media containing gestational day (GD) 10 rat conceptuses. Twenty-six-hr exposure to CQ elicited dose-related decreases in embryonic crown-rump length, protein and DNA contents and increases in the incidence of morphologically abnormal embryos. At 30 microM CQ, embryonic protein content was decreased to 67% and DNA content to 58% of control while the incidence of morphological abnormalities rose to 100%. Abnormal axial rotation, micro-ophthalmia, and selective cephalic hypoplasia were the most common developmental abnormalities observed. Visceral yolk sac (VYS) vasculature and blood pigmentation were also decreased in a dose-dependent manner, as was VYS DNA content (80% of control at 30 microM). VYS protein content, however, showed an alternate pattern of response, decreasing to 87% of control at 10 microM CQ but increasing to 125% of control at 30 microM. Histologic evaluation revealed that the cytoplasm of the VYS endoderm epithelium was distended due to vacuolization produced by CQ exposure. In the embryo proper, CQ inhibited cranial neural tube development and altered the morphology of cranial neural crest cells. These observations document the in vitro embryotoxicity of CQ and suggest altered VYS histiotrophic nutrition as well as direct embryonic effects as possible mechanisms of CQ embryotoxicity.
Ambroso
J L
JL
Department of Environmental and Industrial Health, University of Michigan, Ann Arbor 48109.
Harris
C
C
D000015:Abnormalities, Multiple / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D002738:Chloroquine / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005865:Gestational Age; D066298:In Vitro Techniques; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015017:Yolk Sac / Q000098:blood supply / Q000187:drug effects
D011506:Proteins; D002738:Chloroquine; D004247:DNA