Developmental and behavioral adverse effects of early-life trace-element oversupplementation assessed using the...

Total parenteral nutrition (TPN) for preterm infants includes essential trace elements (TEs)-manganese (Mn), zinc (Zn), copper (Cu), chromium (Cr), and selenium (Se)-that are critical for early development and later health. However, supplemented levels have at times exceeded regulatory recommendations and have been linked to adverse effects on the brain, prompting discontinuation of several TPN products. These concerns warrant systematic evaluation of the effects of developmental TEs exposure on growth and neurobehavior, particularly in light of increasing concern over early-life disruption of stress-regulatory and neurodevelopmental pathways. Using the zebrafish embryo model, we investigated how individual and combined developmental exposures to Mn, Zn, Cu, Cr, and Se-spanning 25-fold below to 25-fold above recommendations-affect development and stress response behaviors. Embryos were enzymatically dechorionated and exposed from 6 to 120 h post-fertilization. Individual TEs exposures induced concentration-dependent increases in mortality and developmental defects, while their mixture caused less pronounced yet significant effects. All TE exposures significantly reduced larval length, and higher concentrations altered acute stress-response behaviors. Collectively, our findings highlight adverse effects on larval development and stress-related neurobehaviors in response to clinical recommended levels and elevated multiples thereof, highlighting the importance of evaluating developmental sensitivity to clinically relevant TE exposure ranges and element-element interactions.