Amniotic fluid activates the nrf2/keap1 pathway to repair an epidermal barrier defect in utero

The loss of loricrin, a major component of the cornified envelope, results in a delay of epidermal barrier formation. Therefore, the living layers of the epidermis are aberrantly exposed to late-stage amniotic fluid, which may serve as the signal to upregulate genes that functionally compensate for the loss of loricrin. Consistent with this hypothesis, metabolomic studies revealed marked changes in amniotic fluid between E14.5 and E16.5 days postcoitum. In addition, we discovered that the Nrf2/Keap1 pathway detects these compositional changes and directly upregulates the expression of genes involved in the compensatory response, thus ensuring postnatal survival. In support of this finding, we demonstrate that genetically blocking the Nrf2 pathway abolishes the compensatory response and that preemptively activating Nrf2 pharmacologically rescues the delay in barrier formation in utero. Our findings reveal that the functions of Nrf2 and the composition of amniotic fluid have coevolved to ensure the formation of a functional barrier.