Sex-specific alterations in placental mitochondria, oxidative damage and apoptosis in mice of advanced maternal age

Although advanced maternal age (AMA) increases the risk of fetal growth restriction (FGR) and stillbirth, the mechanisms leading to the placental dysfunction observed in AMA are unknown. Mitochondrial function declines and oxidative stress increases with age. Furthermore, FGR, of which placental dysfunction is a major cause, is associated with alterations in respiratory function of placental mitochondria. Therefore, this study aimed to examine placental mitochondrial function, oxidative stress, and apoptosis in AMA mice using respirometry and immunohistochemistry. Relative to young mice (12-16 weeks), AMA mice (36-42 weeks) demonstrated reduced weight in both female and male fetuses, but placental alterations occurred in a sex-specific manner. In AMA, lipid peroxidation and apoptosis were increased in the placental junctional zone (Jz) and labyrinth zone (Lz) of male but not female fetuses. Placental mitochondrial content was significantly increased in the Lz and Jz of male fetuses and the Lz of female fetuses in AMA. When normalised to sample mitochondrial content, complex I + II-linked respiration, electron transfer capacity, and complex IV activity were significantly reduced in the Jz of male fetuses and Lz of female fetuses in AMA. However, when normalised to protein content, no differences were observed in placentas of female fetuses; in the Lz of male fetuses, complex I-linked respiration was increased and complex IV activity was reduced. Collectively, these findings suggest that the observed increase in mitochondrial content could be an adaptation by the placenta to maintain appropriate bioenergetic capacity and that oxidative damage may contribute to placental dysfunction in male fetuses in AMA pregnancies.