Dose- and stage-dependent toxic effects of prenatal prednisone exposure on fetal articular cartilage development

Abstract

Prednisone is frequently used to treat rheumatoid diseases in pregnant women because of its high degree of safety. Whether prenatal prednisone exposure (PPE) negatively impacts fetal articular cartilage development is unclear. In this study, we simulated a clinical prednisone treatment regimen to examine the effects of different timings and doses of PPE on cartilage development in female and male fetal mice. Prednisone doses (0.25, 0.5, and 1 mg/kg/d) was administered to Kunming mice at different gestational stages (0–9 gestational days, GD0–9), mid-late gestation (GD10–18), or during the entire gestation (GD0–18) by oral gavage. The amount of matrix aggrecan (ACAN) and collagen type II a1(COL2a1), and expression of transforming growth factor β1 (TGFβ1) signaling pathway also demonstrated that the chondrocyte count and ACAN and COL2a1 expression reduced in fetal mice with early and mid-late PPE, with the reduction being more significant in the mice with early PPE than that in those with PPE at other stages. Prenatal exposure to different prednisone doses prevented the reduction of TGFβ signaling pathway-related genes [TGFβR1, SMAD family member 3 (Smad3), SRY-box9 (SOX9)] as well as ACAN and COL2a1 mRNA expression levels in fetal mouse cartilage, with the most significant decrease after 1 mg/kg·d PPE. In conclusion, PPE can inhibit/restrain fetal cartilage development, with the greatest effect at higher clinical dose (1 mg/kg·d) and early stage of pregnancy (GD0–9), and the mechanism may be related to TGFβ signaling pathway inhibition. The result of this study provide a theoretical and experimental foundation for the rational clinical use of prednisone.