Teratogenicity induced by targeting a placental immunoglobulin transporter.
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.
Kolonin
Mikhail G
MG
The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Pasqualini
Renata
R
Arap
Wadih
W
D020816:Amino Acid Motifs; D000818:Animals; D001692:Biological Transport; D005260:Female; D007074:Immunoglobulin G / Q000378:metabolism; D007136:Immunoglobulins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry; D010920:Placenta / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013723:Teratogens / Q000032:analysis*; D013997:Time Factors
D007074:Immunoglobulin G; D007136:Immunoglobulins; D019151:Peptide Library; D010455:Peptides; D011993:Recombinant Fusion Proteins; D013723:Teratogens