Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 99, Issue 20, Pages 13055-13060Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.162468499
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- NCI NIH HHS [P50 CA090270, CA8297601, CA9081001, CA90270] Funding Source: Medline
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Approximately 3% of children in developed countries are born with nongenetic birth defects. However, the nature and mechanisms of teratogenesis are poorly understood. We investigated mechanisms of teratogen-mediated blockade of maternofetal transport by screening a combinatorial library for peptides that bind nonendothelial placental vasculature in pregnant mice. Here, we identified a peptide motif, TPKTSVT, that homes to the yolk sac, induces placental necrosis, and disrupts embryo development. We show that TPKTSVT promotes transcytosis of phage into the embryo and blocks the transplacental transport of immunoglobulins. Based on these data, we propose a model in which TPKTSVT targets a placental Fc receptor. Absence of TPKTSVT placental homing in mice lacking beta(2)-Microglobulin (beta(2)M) suggests FcRn/beta(2)M as a target for the TPKTSVT, which is unexpected, given the normal development of FcRn/beta(2)m-deficient progeny. High-throughput screening for embryotoxins that target placental receptors could be developed to systematically identify and avoid exposure to teratogenic drugs.
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