FA patients frequently exhibit heterogeneous and multisystemic congenital abnormalities. Patients from certain FA complementation groups are also at increased risk for embryonal tumors. These observations suggest defects in a key developmental biology pathway in FA and the existence of a FA-specific teratogen and embryonal mutagen. In recent RNA-seq studies, we have discovered dysregulation of retinoic acid biosynthesis and signaling in FA-D2 (FANCD2-/-) fetal fibroblasts. These findings are significant for two reasons, 1) retinoic acid signaling is critical for embryonic patterning, growth, and organogenesis and 2) retinaldehyde – an intermediate in retinoic acid biosynthesis – is a potent mutagen and teratogen. Our findings lead us to hypothesize that aberrant retinoic acid signaling and/or excess levels of the endogenous metabolite retinaldehyde may play a critical role in the pathogenesis of FA. We are currently testing this hypothesis using several approaches: 1) We are studying retinoic acid biosynthesis and signaling in transformed and non-transformed human and mouse FA cell types from several FA complementation groups. 2) We are also examining the functional implications of these findings: we are determining if FA patient cells exhibit increased sensitivity to retinoid cytotoxicity and genotoxicity. We are also currently examining if the differential expression of retinoic acid biosynthesis genes observed in FA fetal fibroblasts is a compensatory mechanism to mitigate the cytotoxic and genotoxic effects of endogenous retinoids. 3) We are also analyzing transcriptional regulatory targets of retinoic acid in FA. We are currently evaluating the differential expression of direct and indirect retinoic acid transcriptional targets in FA-D2 fetal fibroblasts, e.g., HOX, PAX, and SOX genes, using qPCR and immunoblotting. In summary, we have discovered a potentially important link between retinoic acid metabolism and FA. As retinoic acid metabolism is both nutritionally and therapeutically actionable, our studies could pave the way for improved dietary/prophylactic and therapeutic interventions for FA patients.