Premium
Embryopathic effects of thalidomide and its hydrolysis products in rabbit embryo culture: evidence for a prostaglandin H synthase (PHS)‐dependent, reactive oxygen species (ROS)‐mediated mechanism
Author(s) -
Lee Crystal J. J.,
Gonçalves Luisa L.,
Wells Peter G.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-178814
Subject(s) - reactive oxygen species , in vivo , chemistry , embryo , prostaglandin , biochemistry , limb bud , microbiology and biotechnology , biology , genetics
Thalidomide (TD) causes birth defects in humans and rabbits via several potential mechanisms, including bioactivation by embryonic prostaglandin H synthase (PHS) enzymes to a reactive intermediate that enhances reactive oxygen species (ROS) formation. We show herein that TD in rabbit embryo culture produces relevant embryopathies, including decreases in head/brain development by 28% and limb bud growth by 71% ( P <0.05). Two TD hydrolysis products, 2‐phthalimidoglutaramic acid (PGMA) and 2‐phthalimidoglutaric acid (PGA), were similarly embryopathic, attenuating otic vesicle (ear) and limb bud formation by up to 36 and 77%, respectively ( P <0.05). TD, PGMA, and PGA all increased embryonic DNA oxidation measured as 8‐oxoguanine (8‐oxoG) by up to 2‐fold ( P <0.05). Co‐ or pretreatment with the PHS inhibitors eicosatetraynoic acid (ETYA) or acetylsalicylic acid (ASA), or the free‐radical spin trap phenylbutylnitrone (PBN), completely blocked embryonic 8‐oxoG formation and/or embryopathies initiated by TD, PGMA, and PGA. This is the first demonstration of limb bud embryopathies initiated by TD, as well as its hydrolysis products, in a mammalian embryo culture model of a species susceptible to TD in vivo , indicating that all likely contribute to TD teratogenicity in vivo , in part through PHS‐dependent, ROS‐mediated mechanisms.—Lee, C. J. J., Gonçalves, L. L., Wells, P. G. Embryopathic effects of thalidomide and its hydrolysis products in rabbit embryo culture: evidence for a prostaglandin H synthase (PHS)‐dependent, reactive oxygen species (ROS)‐mediated mechanism. FASEB J. 25, 2468–2483 (2011). www.fasebj.org