Oral Administration of TiO Nanoparticles During Early Life Impacts Cardiac and Neurobehavioral Performance and Metabolite Profile in an Age- and Sex-related Manner

Background: Nanoparticles (NPs) are increasingly incorporated in everyday products. To investigate the effects of early life exposure to orally ingested TiO NP, male and female Sprague-Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight TiO NP (diameter: 21 ± 5 nm) or vehicle control (water) by gavage at three different pre-weaning ages: postnatal day (PND) 2-5, PND 7-10, or PND 17-20. Cardiac assessment and basic neurobehavioral tests (locomotor activity, rotarod, and acoustic startle) were conducted on PND 20. Pups were sacrificed at PND 21. Select tissues were collected, weighed, processed for neurotransmitter and metabolomics analyses.

Results: Heart rate was found to be significantly decreased in female pups when dosed between PND 7-10 and PND 17-20. Females dosed between PND 2-5 showed decrease acoustic startle response and when dosed between PND 7-10 showed decreased performance in the rotarod test and increased locomotor activity. Male pups dosed between PND 17-20 showed decreased locomotor activity. The concentrations of neurotransmitters and related metabolites in brain tissue and the metabolomic profile of plasma were impacted by TiO NP administration for all dose groups. Metabolomic pathways perturbed by TiO NP administration included pathways involved in amino acid and lipid metabolism.

Conclusion: Oral administration of TiO NP to rat pups impacted basic cardiac and neurobehavioral performance, neurotransmitters and related metabolites concentrations in brain tissue, and the biochemical profiles of plasma. The findings suggested that female pups were more likely to experience adverse outcome following early life exposure to oral TiO NP than male pups. Collectively the data from this exploratory study suggest oral administration of TiO NP cause adverse biological effects in an age- and sex-related manner, emphasizing the need to understand the short- and long-term effects of early life exposure to TiO NP.