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Subchronic perfluorooctanesulfonate (PFOS) exposure induces elevated mutant frequency in an in vivo ? transgenic medaka mutation assay.

ABSTRACT: Perfluorooctanesulfonate (PFOS) has been widely detected in the environment, wildlife and humans, but few studies have ever examined its mutagenic effect in vivo. In the present study, we use a transgenic fish model, the ? transgenic medaka, to evaluate the potential mutagenicity of PFOS in vivo following a subchronic exposure of 30 days. The mutant frequency of cII target gene was 3.46?×?10^-5 in liver tissue from control fish, which increased by 1.4-fold to 4.86?×?10^-5 in fish exposed to 6.7??g/L PFOS, 1.55-fold to 5.36?×?10^-5 in fish exposed to 27.6??g/L PFOS, and 2.02-fold to 6.99?×?10^-5 in fish exposed to 87.6??g/L PFOS. This dose-dependent increase of mutant frequency was also accompanied with mutational spectrum changes associated with PFOS exposure. In particular, PFOS-induced mutation was characterized by +1 frameshift mutations, which increased from 0% in control fish to 13.2% in fish exposed to 27.6??g/L PFOS and 14.6% in fish exposed to 87.6??g/L PFOS. Our findings provide the first evidence of PFOS's mutagenicity in an aquatic model system. Given the fact that most conventional mutagenic assays were negative for PFOS, we propose that PFOS-induced mutation in liver tissue of ? transgenic medaka may be mediated through compromised liver function.

SUBMITTER: Chen Y

PROVIDER: S-EPMC5144067 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Subchronic perfluorooctanesulfonate (PFOS) exposure induces elevated mutant frequency in an in vivo λ transgenic medaka mutation assay.

Chen Yuanhong Y Hu Wei W Huang Changjiang C Hua Shushan S Wei Qihao Q Bai Chenglian C Chen Jiangfei J Norris Michelle B MB Winn Richard R Yang Dongren D Dong Qiaoxiang Q

Scientific reports 20161208

Perfluorooctanesulfonate (PFOS) has been widely detected in the environment, wildlife and humans, but few studies have ever examined its mutagenic effect in vivo. In the present study, we use a transgenic fish model, the λ transgenic medaka, to evaluate the potential mutagenicity of PFOS in vivo following a subchronic exposure of 30 days. The mutant frequency of cII target gene was 3.46 × 10<sup>-5</sup> in liver tissue from control fish, which increased by 1.4-fold to 4.86 × 10<sup>-5</sup> in ...[more]

PMID: 27929129

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Project description:Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Researchers have identified 44 mutations in the TARDBP gene that encode TDP-43 as causative for cases of sporadic and familial ALS http://www.molgen.ua.ac.be/FTDMutations/. Certain mutant forms of TDP-43, such as M337V, are associated with increased low molecular weight (LMW) fragments compared to wild-type (WT) TDP-43 and cause neuronal apoptosis and developmental delay in chick embryos. Such findings support a direct link between altered TDP-43 function and neurodegeneration.To explore the pathogenic properties of the M337V mutation, we generated and characterized two mouse lines expressing human TDP-43 (hTDP-43(M337V)) carrying this mutation. hTDP-43(M337V) was expressed primarily in the nuclei of neurons in the brain and spinal cord, and intranuclear and cytoplasmic phosphorylated TDP-43 aggregates were frequently detected. The levels of TDP-43 LMW products of ~25 kDa and ~35 kDa species were also increased in the transgenic mice. Moreover, overexpression of hTDP-43(M337V) dramatically down regulated the levels of mouse TDP-43 (mTDP-43) protein and RNA, indicating TDP-43 levels are tightly controlled in mammalian systems. TDP-43M337V mice displayed reactive gliosis, widespread ubiquitination, chromatolysis, gait abnormalities, and early lethality. Abnormal cytoplasmic mitochondrial aggregates and abnormal phosphorylated tau were also detected in the mice.Our novel TDP-43M337V mouse model indicates that overexpression of hTDP-43(M337V) alone is toxic in vivo. Because overexpression of hTDP-43 in wild-type TDP-43 and TDP-43M337V mouse models produces similar phenotypes, the mechanisms causing pathogenesis in the mutant model remain unknown. However, our results suggest that overexpression of the hTDP-43(M337V) can cause neuronal dysfunction due to its effect on a number of cell organelles and proteins, such as mitochondria and TDP-43, that are critical for neuronal activity. The mutant model will serve as a valuable tool in the development of future studies designed to uncover pathways associated with TDP-43 neurotoxicity and the precise roles TDP-43 RNA targets play in neurodegeneration.

Dataset Information

Subchronic perfluorooctanesulfonate (PFOS) exposure induces elevated mutant frequency in an in vivo ? transgenic medaka mutation assay.

Publications

Subchronic perfluorooctanesulfonate (PFOS) exposure induces elevated mutant frequency in an in vivo λ transgenic medaka mutation assay.

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