LAUSR

INTRODUCTION Despite a wealth of epidemiological evidence that cumulative parental lifetime stress experiences prior to conception are determinant of offspring developmental trajectories, there is a lack of insight on how these previous stress experiences are stored and communicated intergenerationally. Preconception experiences may impact offspring development through alterations in transcriptional regulation of the placenta, a major determinant of offspring growth and sex-specific developmental outcomes. We evaluated the lasting influence of maternal and paternal preconception stress (PCS) on the mid-gestation placenta and fetal brain, utilizing their transcriptomes as proximate readouts of intergenerational impact. METHODS To assess the combined vs. dominant influence of maternal and paternal preconception environment on sex-specific fetal development, we compared transcriptional outcomes using a breeding scheme of one stressed parent, both stressed parents, or no stressed parents as controls. RESULTS Interestingly, offspring sex affected the directionality of transcriptional changes in response to PCS, where male tissues showed a predominant downregulation, and female tissues showed an upregulation. There was also an intriguing effect of parental sex on placental programming where paternal PCS drove more effects in female placentas, while maternal PCS produced more transcriptional changes in male placentas. However, in the fetal brain, maternal PCS produced overall more changes in gene expression than paternal PCS, supporting the idea that the intrauterine environment may have a larger overall influence on the developing brain than it does on shaping the placenta. DISCUSSION Preconception experiences drive changes in the placental and the fetal brain transcriptome at a critical developmental timepoint. While not determinant, these altered transcriptional states may underlie sex-biased risk or resilience to stressful experiences later in life.