Abstract
Vitamin A deficiency is still a public health concern affecting millions of pregnant women and children. Retinoic acid, the active form of vitamin A, is critical for proper mammalian embryonic development. Embryos can generate retinoic acid from maternal circulating β-carotene upon oxidation of retinaldehyde produced via the symmetric cleavage enzyme β-carotene 15,15′-oxygenase (BCO1). Another cleavage enzyme, β-carotene 9′,10′-oxygenase (BCO2), asymmetrically cleaves β-carotene in adult tissues to prevent its mitochondrial toxicity, generating β-apo-10′-carotenal, which can be converted to retinoids (vitamin A and its metabolites) by BCO1. However, the role of BCO2 during mammalian embryogenesis is unknown. We found that mice lacking BCO2 on a vitamin A deficiency-susceptible genetic background (Rbp4−/−) generated severely malformed vitamin A-deficient embryos. Maternal β-carotene supplementation impaired fertility and did not restore normal embryonic development in the Bco2−/−Rbp4−/− mice, despite the expression of BCO1. These data demonstrate that BCO2 prevents β-carotene toxicity during embryogenesis under severe vitamin A deficiency. In contrast, β-apo-10′-carotenal dose-dependently restored normal embryonic development in Bco2−/−Rbp4−/− but not Bco1−/−Bco2−/−Rbp4−/− mice, suggesting that β-apo-10′-carotenal facilitates embryogenesis as a substrate for BCO1-catalyzed retinoid formation. These findings provide a proof of principle for the important role of BCO2 in embryonic development and invite consideration of β-apo-10′-carotenal as a nutritional supplement to sustain normal embryonic development in vitamin A-deprived pregnant women.
Highlights
Mammalian embryonic development requires vitamin A for normal cell fate specification, patterning and differentiation[1]
Bco2−/−Rbp4−/− mice were viable and fertile when maintained on a vitamin A-sufficient (VAS) chow diet
When Bco2−/−Rbp4−/− dams were fed a purified vitamin A-deficient (VAD) diet during pregnancy, their vitamin A status became more tenuous (Table 1), and their embryonic retinol levels were further reduced compared to the Rbp4−/− (Fig. 1A) and to wild-type (WT) embryos from WT dams under the same dietary conditions (Supplementary Fig. S1)
Summary
Mammalian embryonic development requires vitamin A for normal cell fate specification, patterning and differentiation[1] These activities are attributed predominantly to retinoic acid, the vitamin A metabolite that binds the nuclear retinoic acid receptors to regulate the transcription of hundreds of genes that are critical for normal embryogenesis[2,3]. Asymmetric β-carotene cleavage by the mitochondrial enzyme β,β-carotene 9′,10′-oxygenase (BCO2) generates β-ionone and β-apo-10′-carotenal[13] The latter can be cleaved by BCO1, yielding retinaldehyde and its downstream derivatives, retinol and retinoic acid[10,14]. We demonstrate that BCO2 is critical for preventing β-carotene toxicity during embryogenesis under severe vitamin A deficiency, and that β-apo-10′-carotenal can restore normal development in a mouse model of severe vitamin A deficiency. These findings provide key insights into the unsolved problem of gestational vitamin A deficiency
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