Toxicol Sci 2003 Jul 01;741:139-46. doi: 10.1093/toxsci/kfg098.

Comparing the effects of stage and duration of retinoic Acid exposure on amphibian limb development: chronic exposure results in mortality, not limb malformations.

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Recently, high frequencies of malformations have been reported in amphibians across the United States. It has been suggested that the malformations may be the result of xenobiotic disruption of retinoid signaling pathways during embryogenesis and tadpole development. Therefore, a series of experiments were undertaken to examine life-stage specific effects of continuous retinoid exposure on Xenopus laevis. Continuous all-trans retinoic acid (RA) concentrations were delivered using a column saturator and a flow-through diluter system. Stage 8 embryos were exposed to RA concentrations ranging from 0.013 to 2 microgram/l. At the onset of hindlimb bud emergence (NF stage 48), a subset of tadpoles was moved to clean water, and remaining organisms were exposed continuously through metamorphosis. In addition, early limb-bud-stage tadpoles were exposed for 1 week, 2 weeks, or until tail resorption was complete, to eight concentrations of RA in the range of 0.031-3 microgram/l. RA exposure resulted in a concentration-dependent increase in mortality and dysmorphogenesis in embryos at concentrations of 0.24 microgram/l and above. However, this early embryonic exposure did not result in hindlimb abnormalities in surviving tadpoles allowed to mature in clean water. RA did not induce limb malformations in any surviving tadpole exposed during larval stages. We are confident that the concentrations used were high enough, given that the highest concentration used resulted in 100% mortality within 2 weeks of initiating the exposure. This result suggests that other aspects of growth and development, which are not externally obvious, are more sensitive to retinoids than skeletal development. From these experiments and our previous work, we conclude that it is unlikely that retinoid mimics would produce the spectrum of limb malformations which recently have been observed in amphibians collected from the field.

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