Abstract

BackgroundNanoparticles (NPs) are increasingly incorporated in everyday products. To investigate the effects of early life exposure to orally ingested TiO2 NP, male and female Sprague–Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight TiO2 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.ResultsHeart 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 TiO2 NP administration for all dose groups. Metabolomic pathways perturbed by TiO2 NP administration included pathways involved in amino acid and lipid metabolism.ConclusionOral administration of TiO2 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 TiO2 NP than male pups. Collectively the data from this exploratory study suggest oral administration of TiO2 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 TiO2 NP.

Highlights

  • Nanoparticles (NPs) are increasingly incorporated in everyday products

  • Dosing solution characterization and stability The ­Titanium dioxide (TiO2) NP provided by the National Institute of Environmental Health Sciences (NIEHS)-Nanotechnology Health Implications Research (NHIR) Consortium was characterized by transmission electron microscopy (TEM), which showed a diameter of 21.5 ± 5.0 nm of the pristine NPs (Fig. 1A, B)

  • The ­TiO2 NP dosing solution was formulated at 2 mg/mL in deionized water and characterized by dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) showing a diameter of 477 ± 23 nm and 114 ± 76 nm, respectively (Fig. 1C)

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Summary

Introduction

To investigate the effects of early life exposure to orally ingested ­TiO2 NP, male and female Sprague–Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight ­TiO2 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. There is a significant knowledge gap in understanding the biological impact of early life exposure to nanoparticles (NPs). While orally administered ­TiO2 NP has been studied in adult animal models [18,19,20,21,22], little is known about the biological impact of T­ iO2 NP and potential toxicity in developing animals at different pre-weaning ages and developmental stages

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