Maternal undernutrition exacerbates effects of ambient heat during pregnancy in mice

Authors: Ruebel, Meghan; GILLEY, STEPHANIE - University Of Colorado; JAMBAL, PUREVSUREN - University Of Colorado; Dado-Fox, Jasmine; YAZZA, DEAUNABAH - University Of Colorado; NAKRA, NIYATI - University Of Colorado; ULSON, CHARIS - University Of Colorado; SIAN, LEI - University Of Colorado; KODE, SREENITYA - Nova Southeastern University; Read, Quentin; Yeruva, Venkat; WESTCOTT, JAMIE - University Of Colorado; MACLEAN, PAUL - University Of Colorado; KREBS, NANCY - University Of Colorado; Shankar, Kartik

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/20/2025
Publication Date: 5/27/2025
Citation: Ruebel, M., Gilley, S.P., Jambal, P., Dado-Fox, J.M., Yazza, D.N., Nakra, N., Ulson, C., Sian, L., Kode, S., Read, Q.D., Yeruva, V., Westcott, J.L., Maclean, P.S., Krebs, N.F., Shankar, K. 2025. Maternal undernutrition exacerbates effects of ambient heat during pregnancy in mice. Journal of Nutrition. https://doi.org/10.1016/j.tjnut.2025.05.021.
DOI: https://doi.org/10.1016/j.tjnut.2025.05.021

Interpretive Summary: There is emerging evidence that rising outdoor temperatures can be harmful to both mother and infant health. We also know that poor dietary intake (decreased intake of micronutrients) of the mother in addition to heat stress can lead to reduced growth of the baby. In this study, researchers from MMRU and the University of Colorado designed an animal model to look at the interaction of modest heat and reduced micronutrient intake during pregnancy to determine changes in placental and fetal development. Investigators found reduced growth of the placenta and fetus when exposed to the combination of heat and poor nutrition. The dams (moms) exposed to heat and or heat plus poor nutrition showed alterations to placenta gene expression (the organ that provides nutrients and oxygen to the baby during pregnancy) related nutrient transport, growth of blood vessels, and stress-related responses (i.e. inflammation and ER stress). Combined these results point to an interaction between modest heat and micronutrient depletion on placental dysfunction and the development of fetal growth restriction, highlighting the emerging link of maternal nutrition and heat stress typically seen in resource-restrained settings.

Technical Abstract: Background: Undernutrition in women of childbearing age increases the risk of fetal growth restriction and poor infant development. A rise in ambient temperature is thought to exacerbate the effects of undernutrition. However, few mechanistic studies exist to examine the interactions between maternal nutritional status and ambient temperature on fetal growth. Objective: Develop a novel animal model of marginal undernutrition and modest heat stress during pregnancy to understand interactive effects on fetal growth in mice. Methods: Female C57BL6/J mice (8 wk old, n = 6-8/group) were fed either AIN-93G (CON) or a modified AIN-93M diet containing 70% mineral, micronutrient, and vitamin mix (MMV) for 4 weeks. After breeding, females were housed at either 22°C or 33°C for the duration of pregnancy maintained on their respective diets. Fetal and placental weights were collected at dpc 17.5. Placenta tissue was used for RNA-seq and snRNA-seq, protein, and histological analyses. Two-way and three-way ANOVAs and linear mixed models to account for litter effects were used. Results: Placental weights were significantly lower in MMV.33C group compared to CON.22C (p<0.01) with greater reduction in females compared to males. Serum K, Fe, and Se levels were reduced by temperature (p<0.05). The combination of temperature and diet led to more changes in placental gene expression in males (610 DEGs) compared to females (331 DEGs). In males, gene expression related to vascularization, nutrient transport, and stress-related responses (i.e. ER stress and inflammation) were impacted in the combination group, while in females similar biological functions were affected by high temperature. Conclusions: Collectively, our results point to an interaction between modest heat and marginal micronutrient and protein depletion on placental dysfunction and the pathogenesis of fetal growth restriction, highlighting the emerging nexus of maternal undernutrition and heat stress typically seen in resource-restrained settings.