Exposure to maternal obesity in utero is associated with marked developmental effects in offspring that may not be evident until adulthood. Mechanisms regulating the programming effects of maternal obesity on fetal development have been reported, but little is known about how maternal obesity affects the earliest periods of embryonic development. This work explored how obesity influences endometrial gene expression during the peri-implantation period using a sheep model. Ewes were assigned randomly to diets that produced an obese state or maintained a lean state. After 4 mo, obese and lean ewes were bred and then euthanized at day 14 post-breeding. The uterus was excised, conceptuses were flushed, and endometrial tissue was collected. Isolated RNA from endometrial tissues (n = 6 ewes/treatment) were sequenced using an Illumina-based platform. Reads were mapped to the Ovis aries genome (Oar_4.0). Differential gene expression was determined, and results were filtered (false discovery rate ≤ 0.05 and ≥2-fold change, ≥0.2 reads/kilobase/million reads). Differentially expressed genes (DEGs) were identified (n = 699), with 171 downregulated and 498 upregulated in obese vs. lean endometrium, respectively. The most pronounced gene ontology categories identified were cellular process, metabolic process, and biological regulation. Enrichments were detected within the DEGs for genes involved with immune system processes, negative regulation of apoptosis, cell growth, and cell adhesion. A literature search revealed that 125 DEGs were associated with either the trophoblast lineage or the placenta. Genes within this grouping were involved with wingless/integrated signaling, angiogenesis, and integrin signaling. In summary, these data indicate that the peri-implantation endometrium is responsive to maternal obesity. Transcript profile analyses suggest that the endometrial immune response, adhesion, and angiogenesis may be especially susceptible to obesity. Thus, alterations in uterine transcript profiles during early embryogenesis may be a mechanism responsible for developmental programming following maternal obesity exposure in utero.
Keywords: endometrium; ovine; pregnancy; transcriptomics.
Mammals derived from obese mothers can exhibit a host of health issues after birth and into adulthood. It remained unclear how early these adverse effects of maternal obesity could influence pregnancies. This work describes how obesity changes uterine gene expression early in pregnancy in ewes. Uterine tissue was harvested, and RNA was isolated and sequenced. A total of 699 differentially expressed genes were identified. These genes were associated with various cellular and reproductive processes, including placental development and function, cellular metabolic processes, immune system processes, cell death, cell growth, and cell adhesion. These data are supportive of the idea that the peri-implantation endometrium is susceptible to maternal obesity. Changes in the local immune system, uterine function, and early placental development seem to be especially prone to modifications based on the body condition of the mother. Thus, changes in uterine gene expression and uterine biology occurring early in gestation could be one mechanism for developmental programming.
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