Preimplantation embryo exposure to ketone bodies exerts sex-specific effects on mouse fetal and placental transcriptomes

Abstract

Research question: Does in vitro exposure of preimplantation mouse embryos to the ketone bodies β-hydroxybutyrate (βOHB) and acetoacetate (AcAc) impact post-transfer fetal and placental gene expression?

Design: Blastocysts cultured in vitro with or without 2 mmol/l βOHB alone ('βOHB') or combined with 0.8 mmol/l AcAc ('Keto') underwent embryo transfer. Transcriptional profiles of sexed placenta, liver and brain at gestational day 14.5 were examined via RNA sequencing and DAVID functional analysis.

Results: A sexually dimorphic response to in vitro ketone exposure was observed. Both βOHB and Keto exposure down-regulated genes related to oxidative phosphorylation specifically in female liver. βOHB down-regulated female placental steroid biosynthetic processes, while Keto treatment up-regulated genes relevant to blood vessel formation and cell migration in male placenta. Brain transcriptomes were minimally affected. X-linked genes and chromatin modifiers were identified as differentially expressed in both liver and placenta, alluding to a sex-specific regulatory mechanism.

Conclusions: Transient preimplantation ketone exposure perturbs sex-specific fetal liver and placental gene expression, demonstrating a developmental programming effect that warrants future investigation of the postnatal metabolic health of male and female offspring.

Keywords: Acetoacetate; Developmental origins of health and disease; Ketogenic diet; Nutrients; Periconception; β-hydroxybutyrate.