Maternal exposure to titanium dioxide nanoparticles disrupts ultrasonic vocalization development in mouse offspring

Early neurodevelopment is a critical period during which environmental exposures can have lasting effects on brain function and behavior. One key indicator of early neurodevelopmental integrity in rodents is the production of neonatal ultrasonic vocalizations (USVs), which are essential for maternal-offspring communication. Given the widespread use of titanium dioxide nanoparticles (TiO2NPs) in food and consumer products, there is growing concern that perinatal exposure to these particles may interfere with normal neurodevelopment. However, the effects of TiO2NPs exposure on USV production remain poorly investigated.

In the present study, pregnant mice were orally exposed to TiO2NPs (200 µg/g) from conception to weaning, and their offspring underwent a maternal separation test to assess USVs between postnatal day P2 and P13. TiO2NP-exposed pups exhibited a significant reduction in the number of USVs at P6-7, accompanied by a delayed peak vocalization period. This reduction was primarily attributable to shorter vocalization series rather than fewer isolated calls. Additionally, acoustic analysis revealed that pups emitted two types of USVs, simple and complex, both of which were significantly reduced in number at P6-7 in the exposed group. Fast Fourier transform (FFT)-based analysis showed that complex USVs had a lower mean frequency, while both call types exhibited increased variability in mean frequency. Furthermore, TiO2NP-exposed pups displayed alterations in USV syntax, including a lower proportion of simple USVs and disrupted developmental maturation of call structure. Electrophysiological recordings revealed that the intermediate reticular oscillator (iRO), a key brainstem center involved in vocalization control, exhibited reduced excitability and an increased activity variability in exposed pups, suggesting that nanoparticle exposure compromises vocal motor regulation at the neural level. Lastly, playback experiments demonstrated that USVs from TiO2NP-exposed pups failed to elicit appropriate maternal attraction, indicating impaired communicative effectiveness.

Perinatal exposure to TiO2NPs disrupts the normal development of USVs, impairing both vocalization patterns and neural excitability of the iRO. These changes may contribute to altered maternal-offspring interactions and highlight the potential neurodevelopmental risks of early-life TiO2NPs exposure. Given the widespread presence of TiO2NPs in consumer products, further research is necessary to assess their long-term consequences on neural circuits underlying communication and social behavior.