Pathogenesis of caudal dysgenesis/sirenomelia induced by Ochratoxin A in chick embryos

Abstract

Caudal dysgenesis/sirenomelia is a malformation complex for which the pathogenesis is controversial. This report describes the particular vulnerability of specific caudal structures to Ochratoxin A (OA), a fungal toxin, as the basis for caudal dysgenesis in an avian model. The experimental procedure involved injection of 1 microgram of OA into the air sac of eggs that had been incubated for 48 hours prior to treatment (i.e., embryos that had reached Hamburger and Hamilton stage 9-10 (6-10 somite pairs) [Hamburger and Hamilton (1951) Dev. Dyn. 195:231-272] by the time of treatment). Six to twelve hours following OA injection, excessive cell death, as shown by vital staining and routine histology, was evident in selected cell populations, including cells of the caudal-most mesoderm (the mesoderm that apparently forms the external genitalia and median infraumbilical region), the tail bud, and the neural tube caudal to the wing buds (corresponding to the level of the presomitic mesoderm). The notochord was not severely affected, although there were degenerative changes in the presomitic mesoderm. Except for positional abnormalities, development of the lateral plate mesoderm from which the leg buds are derived appeared relatively normal in most of the treated embryos. Six days post-treatment, varying degrees of caudal dysgenesis, presenting in severely affected specimens as sirenomelia, were observed in approximately 30% of the surviving treated embryos. The potential basis for the differential vulnerability of the affected cell populations and, therefore, the cellular basis for the genesis of caudal dysgenesis/sirenomelia in this model are discussed.

Partial urorectal septum malformation sequence: A report of 25 cases

“…One current hypothesis is that mesodermal de®ciencies are responsible for these defects. Sulik and associates have shown that several different teratogens, ochratoxin A (a fungal toxin) in chick embryos and etretinate (a retinoic acid derivative) in mouse embryos, selectively damage mesoderm and lead to conditions similar to the full and partial URSM sequences in the chick and the mouse embryos [Alles and Sulik, 1993;Mesrobian et al, 1994;Wei and Sulik, 1996]. The spectrum of abnormalities in the affected mouse embryo appears to be related to the timing of exposure, with earlier exposures resulting in more severe effects.…”

“…We believe that the majority of urorectal septal defects are due to either new dominant mutations or possible teratogen exposure. Teratogen exposure has not been shown in any of our patients, but given the abnormalities seen in mice and chicks when exposed to a retinoic acid derivative and a fungal toxin, respectively, this has to be considered as a possibility in humans [Alles and Sulik, 1993;Mesrobian et al, 1994;Wei and Sulik, 1996].…”

Sirenomelia inBmp7andTsgcompound mutant mice:requirement for Bmp signaling in the development of ventral posterior mesoderm

“…In the mouse, other work has implicated low Bmp signaling both in decreased cell proliferation and/or increased apoptosis (Solloway and Robertson, 1999;Fujiwara and Hogan, 2001). Although sirenomelia has variable phenotypic traits and multiple causes (Wei and Sulik, 1996;Padmanabhan, 1998), its occurrence is always associated with defects in posterior primitive streak. The sirenomelia phenotype observed here is consistent with a defective differentiation of the posterior and ventral mesoderm caused by decreased Bmp signaling.…”

Sirenomelia without Vitelline Artery Steal

“…Excessive primary cell death in the caudal mesoderm and hindgut endoderm 5,6 seems to be one such factor. Axial mesodermal dysplasia and midline developmental field defects have also been suggested as plausible mechanisms, especially in patients with cephalic and caudal defects.…”