Mathematical modeling of calcium homeostasis in female rats: An analysis of sex differences and maternal adaptations.

Calcium plays a vital role in various biological processes, including muscle contractions, blood clotting, skeletal mineralization, and cell signaling. While extracellular calcium makes up less than 1% of total body calcium, it is tightly regulated since too high or too low extracellular calcium concentration can have dangerous effects on the body. Mathematical modeling is a well-suited approach to investigate the complex physiological processes involved in calcium regulation. While mathematical models have been developed to study calcium homeostasis in male rats, none have been used to investigate known sex differences in hormone levels nor the unique physiological states of pregnancy and lactation. Calcitriol, the active form of vitamin D, plays a key role in intestinal calcium absorption, renal calcium reabsorption, and bone remodeling. It has been shown that, when compared to age-matched male rats, females have significantly lower calcitriol levels. In this study we first seek to investigate the impact of this difference as well as other known sex differences on calcium homeostasis using mathematical modeling. Female bodies differ from male bodies in that during their lifetime they may undergo massive adaptations during pregnancy and lactation. Indeed, maternal adaptations impact calcium regulation in all mammals. In pregnant rodents, intestinal absorption of calcium is massively increased in the mother's body to meet the needs of the developing fetus. In a lactating rodent, much of the calcium needs of milk are met by bone resorption, intestinal absorption, and renal calcium reabsorption. Given these observations, the goal of this project is to develop multi-scale whole-body models of calcium homeostasis that represents (1) how sex differences impact calcium homeostasis in female vs. male rats and (2) how a female body adapts to support the excess demands brought on by pregnancy and lactation. We used these models to quantify the impact of individual sex differences as well as maternal adaptations during pregnancy and lactation. Additionally, we conducted "what if" simulations to test whether sex differences in calcium regulation may enable females to better undergo maternal adaptations required in pregnancy and lactation than males.