Prenatal hydroxychloroquine exposure-induced morphological and functional changes in multiple organs of fetal mice and its characteristics.

Hydroxychloroquine is clinically widely used in the treatment of various autoimmune diseases and is one of the drugs that can be used throughout pregnancy. However, studies have suggested that prenatal hydroxychloroquine exposure (PHE) may affect early development of offspring, but a systematic and comprehensive evaluation is still lacking. Based on clinical medication regimens, this study administered hydroxychloroquine at different doses (20, 40, 80 mg/kg·d) to pregnant mice via oral gavage throughout gestation, aiming to observe changes in pregnancy outcomes, blood phenotypes of mothers and fetuses, and morphological and functional development of multiple fetal organs, as well as to explore the potential mechanisms.Results showed that PHE increased resorbed fetuses, stillbirths, and IUGR, and altered multiple blood indicators with the changes being particularly significant in feteses. The multi-organ functions were changed, inhibiting long bone and kidney development, adrenal steroid synthesis, placental trophoblast syncytialization, and promoting alveolar surfactant and hepatic bile acid synthesis, with females more affected gender differences and dose-effect relationship. Morphology confirmed abnormalities in long bones, gonads, and lungs. Correlation analysis showed multi-organ functional changes in females positively correlated with autophagy and apoptosis. This study confirms PHE causes adverse outcomes and abnormal multi-organ development, possibly via inhibited autophagy and increased apoptosis. This study has deepened our understanding of the developmental toxicity of hydroxychloroquine and provided experimental evidence for long-term hazard assessment and early prevention.