Comparative RNA-seq analysis of fetal and maternal guinea pig liver transcriptomes reveals widespread transcriptional divergence.
Background: Maternal Western diet (WD) consumption during pregnancy is linked to adverse gestational and offspring metabolic outcomes. Dimethyl fumarate (DMF), a Nrf2 activator with antioxidant and anti-inflammatory properties, is a proposed therapeutic candidate, but its safety and efficacy during pregnancy remain unexplored. This pilot study aimed to establish a guinea pig model of gestational WD consumption and evaluate the feasibility of DMF treatment on maternal, placental, and fetal outcomes. Methods: Pregnant guinea pigs consuming a modified WD were randomized to receive either DMF or vehicle beginning at gestational day 19. Maternal weight, urinalysis, blood glucose, and ketones were monitored weekly. Dams were sacrificed near-term and placental and fetal biometric measures were recorded. The placenta was evaluated for a panel of antioxidant and angiogenic candidate genes via RT-qPCR, and maternal and fetal livers were assessed for triglyceride content, histopathology, and transcriptomic changes via RNA-sequencing. Results: DMF did not alter maternal weight, blood glucose, urinalysis, nor fetal or placental gross outcomes. Hepatic triglyceride concentrations were unaffected in both dams and fetuses. WD consumption resulted in maternal hepatic glycogen accumulation and mild vacuolar hepatopathy without fibrosis, while fetal livers exhibited microvesicular hepatopathy and abundant extramedullary hematopoiesis without fibrosis, irrespective of treatment. Placental RT-qPCR revealed that exposure to DMF led to a decrease in transcription of Sod1 (p = 0.046) and a tendency to decrease transcription of Hmgcr (p = 0.071) and Nqo1 (p = 0.067) with no changes in other measured genes. RNA-sequencing identified 38 differentially expressed genes (DEG) in maternal livers suggesting some immune suppression and induction of P450 pathway. Fetal hepatic RNA-sequencing identified 51 DEG, distinctly different from maternal DEG, indicating an activation of interleukin 12 production. Distinct differences between fetal and maternal liver transcriptomic profiles were evident, with over 9,000 DEG (65% of annotated transcripts). Dimethyl fumarate conferred no measurable benefit on maternal or fetal hepatopathy and had a paradoxical effect in lowering placental Sod1 gene expression, but, importantly, no overt harm was appreciated. These findings establish the feasibility of a gestational guinea pig WD model and gestational DMF therapy and provide initial insights into maternal-fetal responses to DMF, most notably highlighting divergent hepatic programming between dams and offspring. Future research should assess whether DMF or related Nrf2 activators can be developed as pregnancy therapeutics, explore interactions between antioxidants and placental angiogenesis, and determine long-term offspring outcomes after exposure to WD and DMF during gestational development. Overall design: This study compares hepatic transcriptomes from fetal and maternal guinea pig (Cavia porcellus) liver to characterize developmental differences and to evaluate the effect of a maternal treatment. A total of 12 biological samples were included: liver tissue from 6 dams fed a Western diet (3 treated with dimethyl fumarate, 3 control) and liver tissue from 6 corresponding fetuses (fetuses of the 3 treated dams are classified as exposed; fetuses of the 3 control dams are unexposed). Thus the design includes two main factors: tissue (maternal vs fetal) and treatment (treated vs control). For the maternal vs fetal comparison, each group has n = 6 biological replicates.