Cardiovascular alterations in rabbit embryos in situ after a teratogenic dose of hydroxyurea: an in vivo microscopic study

The early cardiovascular (CV) responses of New Zealand white rabbit embryos in situ subsequent to maternal SC injection with hydroxyurea (HU) were analyzed by in vivo microscopic methods. Laparotomies were performed on gestational day 12, and the gravid uteri were exteriorized. The embryos were exposed by careful incisions of the uterine wall and reflection of the extraembryonic membranes. Temperature, water, and electrolyte homeostasis were maintained throughout all procedures. Maternal injection with HU at a teratogenic level (750 mg HU/kg) caused alterations in the embryonic CV system as early as 2 minutes post-treatment. Typically, within 4 minutes the embryonic craniofacial region responded with dilations of the anterior cardinal vein (ACV) and its tributaries. The ensuing pathological events included petechial hemorrhages and hematomas in the forebrain, postocular region, mandibular and nasal processes, and apparent collapse of the vasculature in the forelimb bud. Many embryos exhibited pericardial hemorrhage within 9 minutes. The most severely affected embryos displayed cardiac tamponade and stasis of blood flow through the cardiac chambers. In contrast, control embryos, which received either no drug treatment of SC injection of saline at various osmolarities and pH's, demonstrated none of the CV changes reported above, even after 120 minutes. Low doses of HU (500 mg/kg) produced only ACV dilations in some embryos by 30 minutes. Histologic analysis of HU embryos confirmed the in vivo microscopic observations. The drastic CV derangements exhibited by many embryos may be one of the causes for the high resorption rates associated with the treatment. Furthermore, since teratogenic doses of HU produce immediate hemorrhages and hematomas in the embryos in the same craniofacial areas which are later deformed in the term fetus, it is possible that the teratogenic action of this drug may be related to the initial vascular embryopathies.