Mechanisms regulating toxicant disposition to the embryo during early pregnancy: an interspecies comparison.
The dose of toxicant reaching the embryo is a critical determinant of developmental toxicity, and is likely to be a key factor responsible for interspecies variability in response to many test agents. This review compares the mechanisms regulating disposition of toxicants from the maternal circulation to the embryo during organogenesis in humans and the two species used predominantly in regulatory developmental toxicity testing, rats and rabbits. These three species utilize fundamentally different strategies for maternal-embryonic exchange during early pregnancy. Early postimplantation rat embryos rely on the inverted visceral yolk sac placenta, which is in intimate contact with the uterine epithelium and is equipped with an extensive repertoire of transport mechanisms, such as pinocytosis, endocytosis, and specific transporter proteins. Also, the rat yolk sac completely surrounds the embryo, such that the fluid-filled exocoelom survives through most of the period of organogenesis, and can concentrate compounds such as certain weak acids due to pH differences between maternal blood and exocelomic fluid. The early postimplantation rabbit conceptus differs from the rat in that the yolk sac is not closely apposed to the uterus during early organogenesis and does not completely enclose the embryo until relatively later in development (approximately GD13). This suggests that the early rabbit yolk sac might be a relatively inefficient transporter, a conclusion supported by limited data with ethylene glycol and one of its predominant metabolites, glycolic acid, given to GD9 rabbits. In humans, maternal-embryo exchange is thought to occur via the chorioallantoic placenta, although it has recently been conjectured that a supplemental route of transfer could occur via absorption into the yolk sac. Knowledge of the mechanisms underlying species-specific embryonic disposition, factored together with other pharmacokinetic characteristics of the test compound and knowledge of critical periods of susceptibility, can be used on a case-by-case basis to make more accurate extrapolations of test animal data to the human.
Carney
Edward W
EW
Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674, USA. EWCarney@dow.com
Scialli
Anthony R
AR
Watson
Rebecca E
RE
DeSesso
John M
JM
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002220:Carbamazepine / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D010634:Phenobarbital / Q000378:metabolism; D010672:Phenytoin / Q000378:metabolism; D010920:Placenta / Q000378:metabolism* / Q000502:physiology; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D020156:Salicylic Acid / Q000378:metabolism; D013045:Species Specificity; D013723:Teratogens / Q000493:pharmacokinetics*; D018675:Toxicity Tests / Q000379:methods*; D014212:Tretinoin / Q000378:metabolism; D014635:Valproic Acid / Q000378:metabolism; D015017:Yolk Sac / Q000166:cytology* / Q000502:physiology
D013723:Teratogens; D002220:Carbamazepine; D014212:Tretinoin; D014635:Valproic Acid; D010672:Phenytoin; D020156:Salicylic Acid; D010634:Phenobarbital