A Practical Approach, Second Edition=Ronald D. Ho.pdf

PATHOGENESIS OF ABNORMAL DEVELOPMENT 79pathogenesis. Many developmental toxicants induce different defects in an organism based onfactors such as dose and timing of administration. In this case, the underlying pathogenesis maybe similar but the tissue affected and the degree to which it is affected changes, resulting in differentmalformations at term. Disruption defects, and in particular vascular disruption defects, are anotherexample of a group of defects that have a shared pathogenesis but have the potential to result invery different morphologic outcomes.Unlike malformations, disruption defects result from the destruction of existing tissues orstructures that may have previously developed normally. Vascular disruption defects refer to thoseinvolving the interruption or destruction of some part of the fetal vasculature. 9 The pathogenesisof vascular disruption is extremely important to developmental toxicology because it can causedysmorphology at nearly any stage of gestation, affect almost any tissue or structure, and occur asthe primary cause of dysmorphology or secondary to existing malformations. The latter situationcan be extremely difficult to resolve because the secondary disruption can obliterate evidence forthe primary malformation, thus hampering determination of the underlying cause of the congenitalanomaly.Vascular disruption defects usually occur as a consequence of localized or general fetal hypoxiaresulting from direct effects on the fetal vasculature or secondary to changes to the maternal uterineor placental vasculature. Vasoconstrictive drugs, such as cocaine, may alter both maternal and fetalhemodynamics. This results in decreased uterine and placental blood flow resulting from constrictionof the uterine arteries, and brings about increased fetal blood pressure and heart rate. 202Vasodilating agents may decrease uterine blood flow secondary to diversion of blood to peripheralvasculature and yet have no direct effect on fetal hemodynamics. 203 In humans, defects consistentwith a vascular disruption pathogenesis have been associated with exposure to cocaine, 204–206antihypotensives, 203 and the abortifacient misoprostol. 207–209 Defects associated with such mechanicaldisturbances as chorionic villus sampling (CVS), uterine trauma, twin–twin transfusion syndrome,and amnion disruption sequence may also result from vascular disruption. 9,210–212 In animals,defects attributable to vascular disruption have been induced with a variety of treatments. Theseinclude physical methods, such as uterine vascular clamping in the rat, 213–215 and cocaine and othervasoactive substances. 202–204,216,217Studies have shown that the fetal response to hypoxia follows the same pattern of eventsregardless of the agent or mechanism responsible. Early histopathological changes in affectedtissues reveal that fetal hypoxia leads to edema and an increase in vessel diameter, particularly indistal structures. Loss of fetal blood vessel wall integrity leads to vessel rupture, hemorrhage, andformation of subcutaneous blebs or blood-filled blisters. 204,214–217 Necrosis of affected tissues occurswithin 24 to 48 h, and subsequent resorption results in distortion or loss of already formed structures.It has recently been shown that mechanisms involved in the rupture of fetal vessels may sharesimilarities with mechanisms associated with ischemia-reperfusion injury in adult tissues andspecifically may involve the detrimental action of oxygen free radicals. 218–220Like other teratogenic events, the types of anomalies associated with vascular disruption dependon both the stage of gestation and severity of the insult. However, vascular disruptive events, unlikemost teratogens, have been shown to induce congenital defects to some degree during a broad rangeof developmental stages, including postorganogenesis. 9 Studies in humans who had been exposedto cocaine indicate that the fetus is sensitive to vascular disruptive defects throughout the secondand third trimesters, 205,206,221 although genitourinary tract malformations and more severe malformationsmay be induced during the first trimester. 222Of the types of defects ascribed to vascular disruption pathogenesis, limb defects, includingadactyly, transverse reduction defects, syndactyly, polydactyly, and club foot appear to be the mostcommon. 9,205,206,213–217 The type of defect depends largely on the blood vessel affected and theseverity of the ensuing hemorrhage. In animals and humans, the most distal parts of the skeletonare the most easily affected by fetal hypoxia; thus, abnormalities of the phalanges as well as facialabnormalities are the most frequent morphologic manifestations of fetal hypoxia. 9,216,223 Other© 2006 by Taylor & Francis Group, LLC