Nickel dichloride

Neurotoxicity

Administrative data

Endpoint:

neurotoxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Nickel-induced neurodegeneration in the hippocampus, striatum and cortex; an ultrastructural insight, and the role of caspase-3 and α-synuclein

Author:

Ijomone OM, Olatunji SY, Owolabi JO, Naicker T, Aschner M

Year:

2018

Bibliographic source:

Journal of Trace Elements in Medicine and Biology 50:16-23

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: This study investigated nickel-induced neurodegeneration in rats treated with Nickel Chloride by examining ultrastructural changes in certain brain regions and investigating the role of caspase-3 and α-synuclein.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nickel chloride

EC Number:

253-399-0

EC Name:

Nickel chloride

Cas Number:

37211-05-5

Molecular formula:

NiCl2

IUPAC Name:

nickel(2+) dichloride

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source of test material:
Sigma, St Louis, MO, USA

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Central Animal Holding, Babcock University
- Age at study initiation: Adults
- Weight at study initiation: 180 ± 20 grams
- Housing: Not stated
- Diet: Ad libitum
- Water: Ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Not specified.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

Not stated but assumed daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

10 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

20 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Not specified.

Control animals:

yes, concurrent vehicle

Details on study design:

Not specified.

Examinations

Observations and clinical examinations performed and frequency:

None performed.

Neurobehavioural examinations performed and frequency:

None performed.

Other examinations:

Brain tissue prepared for electron microscopy with semi-quamtification of ultrastructural alterations in neurons in the hippocampus, striatum and cortex. Additional sections of various areas of brain tissue underwent immunohistochemical preparation and staining followed by digital image analysis for caspase-3 immunoreactivity and also for expression of the protein alpha-synuclein.

Statistics:

Digital image analysis results were analysed using one-way ANOVA followed by Turkey's multiple comparison tests with GraphPad Prism Version 7 statistical software.

Results and discussion

Results of examinations

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

effects observed, treatment-related

Description (incidence and severity):

Caspase-3 levels -
Caspase-3 immunoreactivity was increased in the CA3 (P = 0.0008) and DG (P = 0.0011) regions of the hippocampus and the striatum (P = 0.0002) of rats treated with 20 mg/kg.

α-synucelin expression -
Expression of α-synuclein was significantly increased in the cortex of rats treated with 20 mg/kg (P = 0.0009). No effects were observed in the hippocampus or striatum.

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

effects observed, treatment-related

Description (incidence and severity):

Hippocampus -
An increased incidence of "electron-dense" neurons were observed in rats treated with 20 mg/kg. "Electron-dense" nuclei exhibit a larger proportion of heterochromatin to euchachromatin, and can also be referred to as "dark neurons". These neurons also exhibited nuclei crenations, with increased cytoplasmic density. An increased incidence of mitochondrial abnormalities was also observed in the hippocampus of rats treated with 20 mg/kg.

Striatum -
An increased incidence of nuclei shrinking was observed in neurons of the striatum in rats treated with 10 and 20 mg/kg. An increased incidence of mitochondrial damage was also observed in the striatum of rats treated with 20 mg/kg.


Cortex -
An increased incidence of mitochondrial damage was observed in the cortex of rats treated with 10 and 20 mg/kg.

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Effect levels

Dose descriptor:

LOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

other: gene expression / protein activity

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

10 mg/kg bw/day (nominal)

System:

nervous system

Organ:

brain

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Applicant's summary and conclusion

Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.

ROBUST SUMMARY DEVELOPED BY AN INDEPENDENT REVIEWER.