Autism‐like behavior of murine offspring induced by prenatal exposure to progestin is associated with gastrointestinal dysfunction due to claudin‐1 suppression

Autism spectrum disorders (ASD) are associated with the contribution of many prenatal risk factors; in particular, the sex hormone progestin and vitamin D receptor (VDR) are associated with gastrointestinal (GI) symptoms in ASD development, although the related mechanism remains unclear. We investigated the possible role and mechanism of progestin 17‐hydroxyprogesterone caproate (17‐OHPC) exposure‐induced GI dysfunction and autism‐like behaviours (ALB) in mouse offspring. An intestine‐specific VDR‐deficient mouse model was established for prenatal treatment, while transplantation of haematopoietic stem cells (HSCT) with related gene manipulation was used for postnatal treatment for 17‐OHPC exposure‐induced GI dysfunction and ALB in mouse offspring. The in vivo mouse experiments found that VDR deficiency mimics prenatal 17‐OHPC exposure‐mediated GI dysfunction, but has no effect on 17‐OHPC‐mediated autism‐like behaviours (ALB) in mouse offspring. Furthermore, prenatal 17‐OHPC exposure induces CLDN1 suppression in intestine epithelial cells, and transplantation of HSCT with CLDN1 expression ameliorates prenatal 17‐OHPC exposure‐mediated GI dysfunction, but has no effect on 17‐OHPC‐mediated ALB in offspring. In conclusion, prenatal 17‐OHPC exposure triggers GI dysfunction in autism‐like mouse offspring via CLDN1 suppression, providing a possible explanation for the involvement of CLDN1 and VDR in prenatal 17‐OHPC exposure‐mediated GI dysfunction with ASD. Prenatal exposure of progestin 17‐OHPC induces epigenetic changes, triggering autism‐like behaviours and gastrointestinal (GI) dysfunction in mouse offspring. Prenatal treatment by intestine‐specific VDR deficiency with CLDN1 suppression mimics 17‐OHPC exposure‐mediated GI dysfunction, while postnatal treatment of transplantation of haematopoietic stem cells with CLDN1 expression ameliorates 17‐OHPC‐mediated GI dysfunction, indicating that 17‐OHPC‐mediated epigenetic changes and CLDN1 suppression contributes to GI dysfunction in mouse offspring.