Maternal high-fat diet disrupts placental spliceosome pathways independent of obesity phenotype: time-series transcriptome analysis during mid-to-late gestation in rats

Maternal obesity is known to adversely affect fetal development, with placental transcriptional dysregulation being one of the key mechanisms. However, the effect of a maternal high-fat diet (HFD) on dynamic placental gene expression, particularly in the context of obesity propensity, remains poorly understood. This study aimed to investigate the impact of a maternal HFD on time-dependent placental transcriptome alterations, with a focus on identifying key dysregulated pathways during mid-to-late gestation in rats. Female Sprague-Dawley rats were fed either a HFD or control chow (CC) diet before and during pregnancy. HFD-treated rats were categorized into obese-prone (OP) and obese-resistant (OR) groups based on pre-pregnancy weight. Maternal and fetal characteristics, as well as fetal outcomes, were recorded at gestational days (GD) 14.5, 17.5, and 19.5. Plasma cytokine levels were also measured. RNA sequencing (RNA-seq) was used to compare the transcriptomes of the three groups at GD 14.5, GD 17.5, and GD 19.5. At GD 14.5, OP and OR groups showed significantly lower fetal body weight, placental weight, and efficiency compared to the CC group, with these measures increasing significantly by GD 17.5. Concurrently, RNA-seq time-series analysis revealed a significant dysregulation of the spliceosome pathway in the OR group and the parathyroid hormone synthesis pathway in the OP group during mid-to-late gestation. Specifically, 19 out of 229 annotated spliceosome genes were differentially expressed in the OR group. These transcriptomic findings were robustly validated by qPCR, which confirmed the upregulation of Sf3a1 and Sart1 in both the OR and OP groups at GD 14.5, while Sf3a2, Sf3b4, and Rbm22 were specifically elevated in the OP group. Maternal HFD disrupts placental transcriptome dynamics during mid-to-late gestation, particularly affecting spliceosome pathways, regardless of maternal obesity phenotype, contributing to placental dysfunction and adverse fetal outcomes. The observed time-dependent divergences highlight the need for phenotype- and gestational stage-specific interventions to mitigate developmental risks associated with maternal HFD.