Physiologically Based Pharmacokinetic Modeling of Fetal and Neonatal Manganese Exposure in Humans: Describing Manganese Homeostasis during Development

Abstract

Concerns for potential vulnerability to manganese (Mn) neurotoxicity during fetal and neonatal development have been raised due to increased needs for Mn for normal growth, different sources of exposure to Mn, and pharmacokinetic differences between the young and adults. A physiologically based pharmacokinetic (PBPK) model for Mn during human gestation and lactation was developed to predict Mn in fetal and neonatal brain using a parallelogram approach based upon extrapolation across life stages in rats and cross-species extrapolation to humans. Based on the rodent modeling, key physiological processes controlling Mn kinetics during gestation and lactation were incorporated, including alterations in Mn uptake, excretion, tissue-specific distributions, and placental and lactational transfer of Mn. Parameters for Mn kinetics were estimated based on human Mn data for milk, placenta, and fetal/neonatal tissues, along with allometric scaling from the human adult model. The model was evaluated by comparison with published Mn levels in cord blood, milk, and infant blood. Maternal Mn homeostasis during pregnancy and lactation, placenta and milk Mn, and fetal/neonatal tissue Mn were simulated for normal dietary intake and with inhalation exposure to environmental Mn. Model predictions indicate similar or lower internal exposures to Mn in the brains of fetus/neonate compared with the adult at or above typical environmental air Mn concentrations. This PBPK approach can assess expected Mn tissue concentration during early life and compares contributions of different Mn sources, such as breast or cow milk, formula, food, drinking water, and inhalation, with tissue concentration.

Content and balance of trace elements in placenta on different stages of gestation

“…Відомо, що Mn відіграє важливу роль як кофактор для багатьох ферментативних реакцій. Він також бере участь у функ-ціонуванні антиоксидантних ферментів, таких як супе-роксиддисмутаза, та активує глікозилтрансферазу, яка має важливе значення для розвитку кісткової та сполучної тканини [8]. Деякі дослідження показують взаємозв'язок між рівнем марганцю у крові матері та масою тіла при народженні дитини [9].…”

Modeling Manganese Kinetics for Human Health Risk Assessment

“…This tissue description served as the basis for a series of Mn models subsequently covering different species and life stages. [36][37][38][39][40] These models, referred as ''second generation'' of Mn PMPK models in the review by Taylor and colleagues, 41 were developed in a stepwise fashion with increasing model complexity added sequentially to the basic description ( Figure 13.2). The basic model structure was developed and evaluated in the rat first because the available PK data are most extensive in this species.…”

“…Modified from Schroeter et al 37 Modeling Manganese Kinetics for Human Health Risk Assessment 339 on Mn kinetics during fetal and neonatal development. [38][39][40] The models were first developed in the rat in order to identify differences in Mn homeostatic controls between young animals and adults and then appropriately extrapolated to consider expected behavior in human neonates and children.…”

“…The rat models for gestation and lactational periods in rats successfully addressed these questions by capturing underlying biology and physiology of Mn homeostasis during pre-and postnatal development in a PBPK model, 38,39 which was then adapted for the basis of a human developmental model. 40 For fetal and neonatal development, ensuring sufficient Mn supply from the mother through placenta and milk is a critical aspect in Mn homeostasis. On the other hand, keeping tissue Mn stable in response to the large daily fluctuation of Mn intake from a diet rich in this element is more important for maintaining homeostasis in the adult.…”

“…[38][39][40] For inter-species extrapolation, it is necessary to account for differences in the timing of neurodevelopment. The time profiles of age-dependent changes in brain diffusion and binding parameters were appropriately included.…”