Intergenerational Transmission of Metabolic Changes in Oocytes From Aged Mice

The increase in maternal age of pregnancies is a global phenomenon that may have wide-ranging implications for the future health of the next generations. We have previously shown that oocytes from females at advanced maternal age (AMA F0) accumulate intracytoplasmic lipid droplets (LDs), and that oxidative changes to lipids in oocytes from AMA F0 mice are maintained in preimplantation embryos. Here we explore whether oxidative changes are transmitted to the foetus, and what effects this has on neonatal and adult organ development, and the transgenerational inheritance of these changes. First, we show increased antioxidants in lipid-rich organs (liver and brain) of AMA-derived prenatal mice (AMA F1), indirectly showing increased oxidative stress. Then, we provide evidence of metabolic reprogramming in adult offspring of AMA and the accumulation of lipids in AMA-derived third generation (AMA F3) mouse oocytes. In particular, we demonstrate the accumulation of retinoids and other mediators of oxidative phosphorylation (OXPHOS) in AMA F0 and AMA F3 oocytes. Altogether, an altered oxidative metabolism of AMA F0 oocytes may constitute a base of oxidative changes in the organs of offspring and of their transgenerational inheritance to AMA F3 oocytes. Our findings indicate a remodelling of lipid homeostasis in oocytes of female mice derived from AMA great-grandmothers and highlight the need to take a closer look at the inheritance of metabolic changes from mothers of advanced age into their offspring.