Prenatal exposure to TiO2 nanoparticles in mice causes behavioral deficits with relevance to autism spectrum disorder and beyond

Abstract

Environmental factors are involved in the etiology of autism spectrum disorder (ASD) and may contribute to the raise in its incidence rate. It is currently unknown whether the increasing use of nanoparticles such as titanium dioxide (TiO2 NPs) in consumer products and biomedical applications may play a role in these associations. While nano-sized TiO2 is generally regarded as safe and non-toxic, excessive exposure to TiO2 NPs may be associated with negative health consequences especially when occurring during sensitive developmental periods. To test if prenatal exposure to TiO2 NPs alters fetal development and behavioral functions relevant to ASD, C57Bl6/N dams were subjected to a single intravenous injection of a low (100 µg) or high (1000 µg) dose of TiO2 NPs or vehicle solution on gestation day 9. ASD-related behavioral functions were assessed in the offspring using paradigms that index murine versions of ASD symptoms. Maternal exposure to TiO2 NPs led to subtle and dose-dependent impairments in neonatal vocal communication and juvenile sociability, as well as a dose-dependent increase in prepulse inhibition of the acoustic startle reflex of both sexes. These behavioral alterations emerged in the absence of pregnancy complications. Prenatal exposure to TiO2 NPs did not cause overt fetal malformations or changes in pregnancy outcomes, nor did it affect postnatal growth of the offspring. Taken together, our study provides a first set of preliminary data suggesting that prenatal exposure to nano-sized TiO2 can induce behavioral deficits relevant to ASD and related neurodevelopmental disorders without inducing major changes in physiological development. If extended further, our preclinical findings may provide an incentive for epidemiological studies examining the role of prenatal TiO2 NPs exposure in the etiology of ASD and other neurodevelopmental disorders.

Translocation of (ultra)fine particles and nanoparticles across the placenta; a systematic review on the evidence of in vitro, ex vivo, and in vivo studies

“…The study also showed that the 4–8 nm TiO 2 NPs were not able to cross the placenta in an ex vivo perfusion model [ 34 ], whereas PS NPs up to 240 nm have been shown to reach the fetal circuit [ 43 ] in a similar perfusion study. In agreement, in pregnant mice, 5 nm TiO 2 did not cross the placenta [ 79 ], while PS NPs up to 500 nm could be observed in various organs of fetuses [ 27 ]. Moreover, Kloet et al observed a difference in translocation behavior of PS NPs with a similar size and surface charge but acquired from different manufactures [ 28 ].…”

“…On the other hand, radioactivity detected in fetuses was lower at later stages compared with earlier stages of gestation (0.2% at GD11 and 0.04% at GD18), which can be explained by the lack of a developed placenta during early gestation [ 87 ]. Seven animal studies did not find evidence of maternal-fetal transfer of engineered NPs [ 56 , 63 , 68 , 72 , 77 , 79 , 82 ].…”

“… [ 78 ] Wistar rats 12 TiO 2 NPs 10 a oral/ 0 or 100 mg/kg/ GD2–21 g ICP-MS / Ti accumulated in hippocampus of rat offspring after gestational TiO 2 NP exposure. [ 79 ] C57Bl/6 mice 15 TiO 2 NPs 5–6 b i.v./ 0, 0.1, or 1 mg/mouse/ GD9 d SF-ICP-MS / No significant accumulation of Ti in maternal plasma, placenta, fetal liver, and fetal brain for the 3 groups exposed to different concentrations of TiO 2 NPs. [ 80 ] CD-1 mice 12 TiO 2 NPs 25–70 a s.c./ 0 or 0.1 mg/mouse/ GD3, 7, 10, and 14 g / FE-SEM/EDX TiO 2 NP transfer from pregnant mice into the brain and testis of their offspring.…”

“…, values exceeding the empirically defined size and/or concentration limits. Nonetheless, other studies reported contradictory results and report the absence of NP placental transfer or fetal uptake of Au NPs [ 56 ], Cu NPs [ 68 ], Pt NPs [ 72 ], TiO 2 NPs [ 77 , 79 ], QDs [ 63 ], and ZnO NPs [ 82 ]. Yet, this may be due to inadequate size and concentration detection limits of the employed techniques, as discussed in the section “advantages and disadvantages of methods used to assess maternal-fetal NP translocation”.…”

“…Third, another factor with considerable influence on maternal-fetal NP transfer is particle dose as discussed in 9 included studies [ 24 , 45 , 48 , 62 , 66 , 76 , 79 , 81 , 86 ]. By increasing the dosage of i.v.…”