Effect of Titanium Dioxide Nanoparticles on the Stereological Parameters of the Dentate Gyrus and the Morphology of Granular Hippocampal Neurons in Mice

Rahnama, Sharare; Hassanpour, Azam; Yadegari, Maryam; Anvari, Morteza; Hosseini-sharifabad, Mohammad

doi:10.4067/s0717-95022020000601623

Cited by 2 publications

(4 citation statements)

References 15 publications

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“…In mice, the Panel noted that the reduced volume of the polymorph layer of the hippocampal dentate gyrus and reduced density and number of dentate gyrus granular neurons reported by Rahnama et al. (2020) with TiO 2 NPs (21 nm), is consistent with the behavioural effects reported by Zhang et al. (2020) also with TiO 2 NPs (21 nm), i.e.…”

Section: Assessmentsupporting

confidence: 83%

“…The most sensitive endpoint observed in adult mice was reduced volume of the hippocampus, and the polymorph layer of the dentate gyrus, and reduced density and total number of dentate gyrus granular cells at all doses tested (in males dosed for 35 days) (Rahnama et al., 2020; scoring 4 for NSC). The mice in this study (n = 20/group) were dosed by gavage with TiO 2 NPs (21 nm) at 0, 2.5, 5 or 10 mg/kg bw per day.…”

Section: Assessmentmentioning

confidence: 99%

“…The Panel noted that the most sensitive endpoint in adult mice was reduced volume of hippocampus and dentate gyrus granular layer, and density and number of dentate gyrus granular cells observed with TiO 2 NPs (21 nm) at 2.5 mg/kg bw per day, the lowest dose tested, in males dosed for 35 days (Rahnama et al., 2020).…”

Section: Assessmentmentioning

confidence: 99%

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Safety assessment of titanium dioxide (E171) as a food additive

Flavourings¹,

Younes²,

Aquilina³

et al. 2021

EFS2

131

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The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E 171) based on new relevant scientific evidence considered by the Panel to be reliable, including data obtained with TiO 2 nanoparticles ( NP s) and data from an extended one‐generation reproductive toxicity ( EOGRT ) study. Less than 50% of constituent particles by number in E 171 have a minimum external dimension < 100 nm. In addition, the Panel noted that constituent particles < 30 nm amounted to less than 1% of particles by number. The Panel therefore considered that studies with TiO 2 NP s < 30 nm were of limited relevance to the safety assessment of E 171. The Panel concluded that although gastrointestinal absorption of TiO 2 particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E 171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO 2 NP s (> 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the EOGRT study. However, observations of potential immunotoxicity and inflammation with E 171 and potential neurotoxicity with TiO 2 NP s, together with the potential induction of aberrant crypt foci with E 171, may indicate adverse effects. With respect to genotoxicity, the Panel concluded that TiO 2 particles have the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico‐chemical properties of TiO 2 particles and the outcome of either in vitro or in vivo genotoxicity assays. A concern for genotoxicity of TiO 2 particles that may be present in E 171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO 2 particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut‐off value for TiO 2 particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO 2 NP s. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel concluded that E 171 can no longer be considered as safe when used as a food additive.

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Section: Assessmentsupporting

confidence: 83%

Section: Assessmentmentioning

confidence: 99%

See 1 more Smart Citation

Safety assessment of titanium dioxide (E171) as a food additive

Flavourings¹,

Younes²,

Aquilina³

et al. 2021

EFS2

131

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show abstract

“…Keywords: Nanoparticles, PrP C receptor, Signaling, TNFα receptors, Aβ peptides, Neuroinflammation, Nanoneurotoxicity, Alzheimer's disease structure involved in memory processes and affected early and severely in AD [27]. In the hippocampus, different forms of TiO 2 -NPs were shown to exert some adverse effects such as oxidative stress, mitochondrial dysfunction, gliosis, and to provoke neuronal lesions [1,[28][29][30]. Exploiting reconstructed neuronal networks, TiO 2 -NPs were also reported to severely impair the electrical activity of neurons [31].…”

Section: Introductionmentioning

confidence: 99%

Titanium dioxide and carbon black nanoparticles disrupt neuronal homeostasis via excessive activation of cellular prion protein signaling

et al. 2022

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Background Epidemiological emerging evidence shows that human exposure to some nanosized materials present in the environment would contribute to the onset and/or progression of Alzheimer’s disease (AD). The cellular and molecular mechanisms whereby nanoparticles would exert some adverse effects towards neurons and take part in AD pathology are nevertheless unknown. Results Here, we provide the prime evidence that titanium dioxide (TiO2) and carbon black (CB) nanoparticles (NPs) bind the cellular form of the prion protein (PrPC), a plasma membrane protein well known for its implication in prion diseases and prion-like diseases, such as AD. The interaction between TiO2- or CB-NPs and PrPC at the surface of neuronal cells grown in culture corrupts PrPC signaling function. This triggers PrPC-dependent activation of NADPH oxidase and subsequent production of reactive oxygen species (ROS) that alters redox equilibrium. Through PrPC interaction, NPs also promote the activation of 3-phosphoinositide-dependent kinase 1 (PDK1), which in turn provokes the internalization of the neuroprotective TACE α-secretase. This diverts TACE cleavage activity away from (i) TNFα receptors (TNFR), whose accumulation at the plasma membrane augments the vulnerability of NP-exposed neuronal cells to TNFα -associated inflammation, and (ii) the amyloid precursor protein APP, leading to overproduction of neurotoxic amyloid Aβ40/42 peptides. The silencing of PrPC or the pharmacological inhibition of PDK1 protects neuronal cells from TiO2- and CB-NPs effects regarding ROS production, TNFα hypersensitivity, and Aβ rise. Finally, we show that dysregulation of the PrPC-PDK1-TACE pathway likely occurs in the brain of mice injected with TiO2-NPs by the intra-cerebro-ventricular route as we monitor a rise of TNFR at the cell surface of several groups of neurons located in distinct brain areas. Conclusion Our in vitro and in vivo study thus posits for the first time normal cellular prion protein PrPC as being a neuronal receptor of TiO2- and CB-NPs and identifies PrPC-coupled signaling pathways by which those nanoparticles alter redox equilibrium, augment the intrinsic sensitivity of neurons to neuroinflammation, and provoke a rise of Aβ peptides. By identifying signaling cascades dysregulated by TiO2- and CB-NPs in neurons, our data shed light on how human exposure to some NPs might be related to AD.

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Effect of Titanium Dioxide Nanoparticles on the Stereological Parameters of the Dentate Gyrus and the Morphology of Granular Hippocampal Neurons in Mice

Cited by 2 publications

References 15 publications

Safety assessment of titanium dioxide (E171) as a food additive

Safety assessment of titanium dioxide (E171) as a food additive

Titanium dioxide and carbon black nanoparticles disrupt neuronal homeostasis via excessive activation of cellular prion protein signaling

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