Maternal Micronutrient Insufficiency Exacerbates Growth Restriction with Ambient Heat on Placental and Fetal Development during Pregnancy

Malnutrition in women of childbearing age is associated with an 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 studies exist to examine the interactions between maternal nutrition and ambient temperature on fetal growth. Here we develop a novel animal model of marginal micronutrient insufficiency and modest heat stress during pregnancy to understand interactive effects on fetal growth in mice. 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. After breeding females were housed at either 22⁰C or 33⁰C in an environmental chamber for the duration of pregnancy while remaining on their respective diets. Mice fed 70MMV diet had significantly reduced body weight gains during pregnancy in comparison to CON diet fed group. Serum K, Fe, Zn, and Se levels showed reduced levels either by diet or temperature. A novel interaction between modest heat and micronutrient insufficiency was identified and led to an altered placenta transcriptome and fetal growth restriction in this model. Sexually dimorphic differences were observed in placental and fetal tissues in the temperature groups. In males, placenta gene expression related to vascularization, nutrient transport, and stress-related responses (i.e. ER stress and inflammation) were impacted in the combination group exposed to 70MMV diet and elevated temperature, while in females the same biological functions were affected only in the CON-33C group. Collectively, our results point to an interaction between modest heat and micronutrient insufficiency on placental dysfunction and the pathogenesis of fetal growth restriction, highlighting the emerging nexus of maternal nutrition and heat stress typically seen in resource-restrained settings.