Combined Metabolic and Viral Insults in Pregnancy Disrupt Specific Placental Nutrient Transporter Systems in Mice

Maternal obesity and viral infection are each associated with adverse pregnancy outcomes, but how their co-exposure affects placental morphology and nutrient transporter expression across gestation remains unclear. We investigated placental morphometry, nutrient transporter expression, and fetoplacental growth in C57BL/6J mice fed a control (CON) or 62% high-fat (HF) diet for six weeks before and throughout pregnancy. Dams were injected with the viral mimic, poly(I:C) or vehicle (VEH) for 24h at gestational days (GD) 12.5, 15.5, and 18.5. Placentae were stained with haematoxylin and eosin to assess junctional (JZ) and labyrinth (LZ) zone morphology. Fatty acid (FAT/CD36, FATP1/4, FABPpm) and folate (FR-α, RFC1, PCFT, FR-β) transporter expression was assessed by immunohistochemistry and qPCR. Data were analysed by generalized linear mixed models (*p<0.05). HF diet reduced JZ and LZ area at GD12.5 while poly(I:C) increased interhaemal space, followed by compensatory expansion of JZ, LZ, and maternal blood spaces at GD18.5. At GD12.5, both stressors independently upregulated Fat/Cd36 mRNA and FR-α immunoreactivity (ir), indicating an early adaptive response to maintain fetal nutrient supply, whereas HF diet decreased ir-PCFT expression. By GD15.5, HF diet downregulated ir-FR-α but upregulated ir-PCFT, suggesting a shift in folate transport mechanisms over gestation. Viral infection selectively suppressed Rfc1 mRNA expression at GD18.5 and reduced placental and fetal weights across gestation. Maternal obesity and viral infection independently and synergistically disrupt placental morphology and nutrient transporter expression in a zone- and gestational age-specific manner. These findings suggest that combined effect of maternal overnutrition and infection have greater impact on placental function, compromising fetoplacental growth across pregnancy.