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Transcriptome analysis reveals differences in developmental neurotoxicity mechanism of methyl-, ethyl-, and propyl- parabens in zebrafish embryos

ABSTRACT: Limited studies on comparison of developmental (neuro)toxicity of parabens have been conducted and unharmonized concentrations between phenotypic observations and transcriptomic analysis hamper understanding of their differential molecular mechanism. Developmental toxicity testing was conducted with commonly used methyl- (MtP), ethyl- (EtP) and propyl-paraben (PrP) in zebrafish embryos. Based on benchmark dose 5% (BMD5), embryonic mortality based-point of departure (M-PoD) values of three parabens were determined and changes in locomotor behavior were evaluated at concentrations of 0, M-PoD/50, M-PoD/10, and M-PoD in which transcriptomic analysis was conducted to explore the underlying neurotoxicity mechanism. Higher long-chained parabens were more toxic than short-chained parabens, as determined by M-PoD values of 154.1, 72.6, and 24.2 µM for MtP, EtP, and PrP, respectively. While exposure to EtP resulted in hyperactivity, no behavior effect was observed by MtP and PrP. Transcriptomics analysis revealed that abnormal behaviors in EtP-exposed group are associated with the distinctly enriched pathways in signal, transport, calcium ion binding, and metal-binding. In contrast, exposure to MtP and PrP mainly disrupted the membrane and transmembrane, which are closely linked to abnormal embryonic development rather than neurobehavior changes. According to the changes in expression of signature mRNAs, tentative transcriptomic-based PoD (T-PoD) values for each paraben were determined as MtP (2.68 µM), EtP (3.85 µM), and PrP (1.4 µM).

ORGANISM(S): Danio rerio

PROVIDER: GSE239773 | GEO | 2023/08/07

REPOSITORIES: GEO

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Project description:In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) and Gerstmann-Sträussler-Scheinker (GSS) disease, two genetically determined Prion protein (PrP) amyloidoses characterized by the deposition of PrP amyloid (APrP) in the vessel walls and in the cerebral parenchyma, respectively. A nonsense and a missense mutation in the PRNP gene lead to a premature termination of translation at codon position 160 (Q160Ter) of PrP in PrP-CAA, or to the substitution of an amino acid at residue 198 (F198S) of PrP in GSS. These two diseases have different clinical and pathologic phenotypes; however, in both diseases, neuropathologic analyses have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA and GSS are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA, Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA and GSS brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA and GSS are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

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Transcriptome analysis reveals differences in developmental neurotoxicity mechanism of methyl-, ethyl-, and propyl- parabens in zebrafish embryos

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