Maternal Undernutrition Exacerbates Effects of Ambient Heat during Pregnancy in Mice

Meghan L Ruebel; Stephanie P Gilley; Purevsuren Jambal; Jasmine Dado-Fox; Deaunabah N Yazza; Niyati Nakra; Charis Ulson; Lei Sian; Sreenitya Kode; Quentin D Read; Laxmi Yeruva; Jamie LE Westcott; Paul S MacLean; Nancy F Krebs; Kartik Shankar

doi:10.1016/j.tjnut.2025.05.021

Maternal Undernutrition Exacerbates Effects of Ambient Heat during Pregnancy in Mice

J Nutr. 2025 May 27:S0022-3166(25)00303-7. doi: 10.1016/j.tjnut.2025.05.021. Online ahead of print.

Authors

Affiliations

¹ Microbiome and Metabolism Research Unit, USDA-ARS, Southeast Area, Little Rock, AR, United States; Arkansas Children's Nutrition Center, Little Rock, AR, United States. Electronic address: meghan.ruebel@usda.gov.
² Department of Pediatrics, Section of Nutrition, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
³ Microbiome and Metabolism Research Unit, USDA-ARS, Southeast Area, Little Rock, AR, United States; Arkansas Children's Nutrition Center, Little Rock, AR, United States.
⁴ USDA-ARS, North Carolina State University, Raleigh, NC, United States.
⁵ Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
⁶ USDA-ARS, Responsive Agricultural Food Systems Research Unit, College Station, TX, United States. Electronic address: kartik.shankar@usda.gov.

PMID: 40441381
DOI: 10.1016/j.tjnut.2025.05.021

Abstract

Background: Undernutrition in females of childbearing age increases 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.

Objectives: This study aims to 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 wk. 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 days post coitum 17.5. Placenta tissue was used for RNA-seq and snRNA-seq, protein, and histological analyses. Two-way and 3-way analyses of variance and linear mixed models to account for litter effects were used.

Results: Placental weights were significantly lower in MMV.33C group compared with CON.22C (P < 0.01) with a greater reduction in females compared with 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 differentially expressed genes (DEGs)] compared with females (331 DEGs). In males, gene expression related to vascularization, nutrient transport, and stress-related responses (i.e., Endoplasmic Reticulum (ER) stress and inflammation) was impacted in the combination group, whereas 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.

Keywords: fetus; heat stress; placenta; pregnancy; undernutrition.