Benzo(a)pyrene exposure induced neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice

Abstract

Background: Exposure to benzo(a)pyrene (BaP) was associated with cognitive impairments and some Alzheimer's disease (AD)-like pathological changes. However, it is largely unknown whether BaP exposure participates in the disease progression of AD. Objectives: To investigate the effect of BaP exposure on AD progression and its underlying mechanisms. Methods: BaP or vehicle was administered to 4-month-old APPswe/PS1dE9 transgenic (APP/PS1) mice and wildtype (WT) mice for 2 months. Learning and memory ability and exploratory behaviors were evaluated 1 month after the initiation/termination of BaP exposure. AD-like pathological and biochemical alterations were examined 1 month after 2-month BaP exposure. Levels of soluble beta-amyloid (Aβ) oligomers and the number of Aβ plaques in the cortex and the hippocampus were quantified. Gene expression profiling was used to evaluate alternation of genes/pathways associated with AD onset and progression. Immunohistochemistry and Western blot were used to demonstrate neuronal loss and neuroinflammation in the cortex and the hippocampus. Treatment of primary neuron-glia cultures with aged Aβ (a mixture of monomers, oligomers, and fibrils) and/or BaP was used to investigate mechanisms by which BaP enhanced Aβ-induced neurodegeneration. Results: BaP exposure induced progressive decline in spatial learning/memory and exploratory behaviors in APP/PS1 mice and WT mice, and APP/PS1 mice showed severer behavioral deficits than WT mice. Moreover, BaP exposure promoted neuronal loss, Aβ burden and Aβ plaque formation in APP/PS1 mice, but not in WT mice. Gene expression profiling showed most robust alteration in genes and pathways related to inflammation and immunoregulatory process, Aβ secretion and degradation, and synaptic formation in WT and APP/PS1 mice after BaP exposure. Consistently, the cortex and the hippocampus of WT and APP/PS1 mice displayed activation of microglia and astroglia and upregulation of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP), and NADPH oxidase (three widely used neuroinflammatory markers) after BaP exposure. Furthermore, BaP exposure aggravated neurodegeneration induced by aged Aβ peptide in primary neuron-glia cultures through enhancing NADPH oxidase-derived oxidative stress.

Benzo[a]pyrene—Environmental Occurrence, Human Exposure, and Mechanisms of Toxicity

“…The exposure to B[ a ]P also resulted in a progressive decline in spatial learning/memory and exploratory behavior in APP/PS1 and WT mice [ 115 ]. The exposure to B[ a ]P also enhanced neurodegeneration induced by the aging Aβ peptide in primary cultures of glial neurons acting through enhancement of the oxidative stress derived from NADPH oxidase.…”

Key Disease Mechanisms Linked to Amyotrophic Lateral Sclerosis in Spinal Cord Motor Neurons

“…Similarly, exposure to benzo(a)pyrene in utero has been associated with alpha synuclein toxicity and microglial activation in mice (Xu et al, 2021 ). Further, benzo(a)pyrene exposure is associated with cognitive decline and exacerbation of Alzheimer’s disease pathology in mice (Liu et al, 2020 ). Exposure to electronic waste containing nickel and other metals is associated with an increased risk of neurodegeneration (Zhu et al, 2021 ).…”

Benzo(a)pyrene and cardiovascular diseases: An overview of pre-clinical studies focused on the underlying molecular mechanism

“…Therefore, continuous or high doses of BaP intake will inevitably cause errors during DNA replication leading to carcinogenic mutations ( 23 – 25 ). Besides, there is growing evidence that BaP has strong toxic effects on the nervous system ( 26 ), immune system ( 27 , 28 ), and reproductive system ( 29 ).…”