Dietary Retinoic Acid Induces Hindlimb and Eye Deformities inXenopus laevis

Abstract

This study investigated the effects of dietary retinoic acid (RA) on frog hindlimb development. Xenopus laevis (African clawed frog) tadpoles were fed a diet supplemented with 0, 1, 10, or 100 microg of RA/g of food for 2 or 5 d at different stages of metamorphosis. Hindlimb deformities were induced in the group fed 100 microg of RA/g of diet for 5 d. Exposures beginning at mid-hindlimb bud development induced bilaterally bent tibiafibula (bony triangles), while exposures later in hindlimb development induced deformities of the feet, including fusion of the 1st and 2nd clawed digits and reduced length of the 4th and 5th digits (due to reduced, missing, or misplaced phalanges). There were also cases of extra phalanges in the 5th digit. The eye was another target of RA exposure. In one experiment, 58% of the tadpoles fed 10 microg of RA/g had a smaller or absent right eye. Additionally, 11% of the tadpoles fed 100 microg of RA/g of diet developed a smaller or absent left eye. Waterborne heavy metals (Zn or Cu) modified RA effects on the hindlimb and eye. Co-exposure to metals and RA resulted in cases of unilateral bony triangles and reduced rates of smaller eyes. There were also cases of extra hindlimb digits in Zn-exposed animals. Dietary RA exposure in tadpoles can cause some deformities that differ from waterborne RA exposures in previous studies. RA also induced deformities that resemble those in affected wild frog populations (bony triangles), although the patterns of other deformities and missing segments (phalanges and metatarsals) are not similar to those documented in the wild.

Cyanobacteria blooms produce teratogenic retinoic acids

“…Because RAs are generally thought of as vertebrate-specific hormones that signal via nuclear receptors cascades (25), the signal-transduction pathway and function of RAs in cyanobacteria and algae remain to be elucidated. Exposure to RA through both diet and/or directly from water can cause mortality and deformities in tadpoles of X. laevis (14,15). Extracts of cyanobacteria can cause developmental toxicity, including mortality, growth inhibition, and malformations in X. laevis, and these effects have been shown not to be caused by microcystins (46).…”

“…Exposure of embryos to exogenous RAs causes a spectrum of malformations, including defects of the neural tube and central nervous system; skeleton, palate, ear, and other craniofacial malformations; defects in the heart, thymus, and urogenital system; as well as missing or duplicate limbs and digits in offspring of humans, rodents, chickens, the African clawed frog (Xenopus laevis), and fish (3)(4)(5)(6)(7)(8)(9)(10). When frogs were exposed to RAs during metamorphosis, a suite of abnormalities, such as reductions and deletions of the hind limb, bony triangles, and eye deformities, could occur (11)(12)(13)(14)(15). These abnormalities observed in the laboratory are similar to those found in wild frogs (16,17).…”

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

“…However, both deficiency and excess of RAs and related retinoids during pregnancy cause abnormal morphological development (teratogenesis) of various organs and tissues, such as the eye, brain, heart, segment and limbs in the offspring (Collins and Mao, 1999;Zile, 2001). Teratogenesis by excess RAs has been observed in various vertebrates including fish (Herrmann, 1995;Haga et al, 2002), amphibians (Degitz et al, 2000(Degitz et al, , 2003Alsop et al, 2004) and mammals (Lee et al, 1995;Ritchie et al, 2003). It has also been reported that high dietary intake of vitamin A by pregnant women can cause birth defects (Rothman et al, 1995).…”

Determination and occurrence of retinoic acids and their 4‐oxo metabolites in Liaodong Bay, China, and its adjacent rivers

“…Although retinoids are essential for the life of all chordates, an excess of retinoids causes teratogenesis in humans and animals [8]. Exposure to a high amount of at-RA can induce various patterns of deformities in different organisms, such as deformities of the brain, central nervous system, and tail in zebrafish [9,10], deformities in the lower jaw, caudal fin, and vertebrae in the larvae of Japanese flounder [11], malformations of the skeleton and of the neural tube in mice [12], as well as hindlimb and eye deformities in Xenopus laevis [13]. With respect to 13c-RA, a large number of studies have demonstrated that it can act as a potent teratogen as at-RA [14].…”