A Novel Mouse Model to Examine the Double-Burden of Ambient Heat and Micronutrient Insufficiency on Fetal Growth

OBJECTIVES: Undernutrition and malnutrition in women of childbearing age are associated with increased risk of fetal growth restriction and poor infant development. Climate change, specifically the rise in ambient temperature, is thought to exacerbate the effects of malnutrition. However, few mechanistic models exist to examine the interactions between maternal nutritional status and ambient temperature on fetal growth. METHODS: Female C57BL6/J mice (8 wk old, n = 6–8/group) were given ad libitum access to either AIN-93G (CON) or a modified AIN-93 diets containing 70% mineral, micronutrient, and vitamin mix (70MMV) for 4 weeks. The 70MMV diet is not designed to cause nutritional deficiency, but rather a lower nutritional plane. Plug positive females were housed at either 22⁰C or 33⁰C in an environmental chamber for the duration of pregnancy, while remaining on their respective diets. Body weights and food intake were assessed weekly. Placenta tissue as well as fetal, placental, and liver weights were collected at dpc 17.5. ER stress related gene targets in the placenta were assessed by RT-qPCR. RESULTS: Body weight gains over pregnancy were significantly reduced in animals fed 70MMV compared to CON diet. There was no change in liver to body weight ratios across groups, however there was a slight reduction in liver to body ratio in the 33⁰C compared to 22⁰C group on CON diet. Placental weights were significantly reduced in 33⁰C group, with a more severe reduction in the 70MMV + 33⁰C group. Notably, fetal weights of dams exposed to both 33⁰C and 70 MMV diet showed significant reductions in fetal weights. Two-way ANOVA for fetal weights showed a significant diet and temperature interaction. Pairwise comparisons showed no difference between temperatures on CON diet, but significantly lower fetal weights in the 70MMV + 33⁰C relative to 70MMV + 22⁰C. CONCLUSIONS: Our results point to an interaction between modest heat and micronutrient insufficiency in the pathogenesis of fetal growth restriction, highlighting the emerging nexus of maternal nutrition and heat stress typically seen in resource-restrained settings. FUNDING SOURCES: CU-Department of Pediatrics and Anschutz Health and Wellness Center.