2,5-Hexanedione increases the percentage of proliferative Sox2 + cells in rat hippocampus

Abstract

n-Hexane is an organic solvent widely used in industry. 2,5-Hexanedione (2,5-HD), the major neurotoxic metabolite of n-hexane, decreases the levels of neurofilaments (NFs) in neurons. Neurogenesis occurs throughout life, and the hippocampal dentate gyrus is one of two major brain areas showing neurogenesis in adulthood. In the current study, rats were intraperitoneally injected with normal saline solution or 2,5-HD five times per week for five continuous weeks. 2,5-HD was administered to the low-dose and high-dose groups at 200 and 400 mg/kg/day, respectively. Then, immunoreactive cells were counted in the hippocampal granule cell layer (GCL) and subgranular zone (SGZ). Ki67⁺ cells significantly decreased in the high-dose group, while the percentage of proliferative Sox2⁺ cells significantly increased, consistent with high hippocampal Sox2 expression. Additionally, western blotting showed that exposure to high doses of 2,5-HD led to decreased NF-L in both the cortex and hippocampus, whereas low doses led to a significant reduction in the cortex only. In conclusion, 2,5-HD increases the percentage of proliferating neural stem and progenitor (Sox2⁺) cells in the SGZ/GCL.

Keywords

2,5-Hexanedione hippocampus Sox2 neurofilament Ki67

Get full access to this article

View all access options for this article.

References

Amador-Arjona

Cimadamore

Huang

. (2015) SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. Proceedings of the National Academy of Sciences of the United States of America 112(15): E1936–E1945.

Bowers

Jessberger

(2016) Linking adult hippocampal neurogenesis with human physiology and disease. Developmental Dymanics 245(7): 702–709.

Carney

Dardis

Cullen

. (2002) Early spatial memory deficit induced by 2,5-hexanedione in the rat. Toxicology Letters 128(1–3): 107–115.

Chen

Lin

Zhang

. (2004) A clinical and prognostic analysis of poisonous peripheral neuropathy caused by N-hexane. Journal of Apoplexy and Nervous Diseases 21(1): 57–58.

Cheng

Wang

. (2012) Exposure to 2,5-hexanedione can induce neural malformations in chick embryos. Neurotoxicology 33(5): 1239–1247.

Favaro

Valotta

Ferri

. (2009) Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nature Neuroscience 12(10): 1248–1256.

Graham

Khudyakov

Ellis

. (2003) SOX2 functions to maintain neural progenitor identity. Neuron 39(5): 749–765.

Huang

(2008) Polyneuropathy induced by n-hexane intoxication in Taiwan. Acta Neurologica Taiwanica 17(1): 3–10.

Iosif

Ekdahl

Ahlenius

. (2006) Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. The Journal of Neuroscience 26(38): 9703–9712.

10.

Jin

Piao

Dong

. (2014) Effects of mesenchymal stem cells transplantation on neurophysiological of peripheral neuropathy rats induced by n-Hexane. Journal of Dalian Medical University 36(4): 110–114.

11.

Kim

Park

. (2009) Neurotoxic effect of 2,5-hexanedione on neural progenitor cells and hippocampal neurogenesis. Toxicology 260(1-3): 97–103.

12.

Koo

Russo

Ferguson

. (2010) Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proceedings of the National Academy of Sciences of the United States of America 107(6): 2669–2674.

13.

Liu

Piao

Sun

. (2012) Arsenic-induced inhibition of hippocampal neurogenesis and its reversibility. Neurotoxicology 33(5): 1033–1039.

14.

LoPachin

Reid

(2005) 2,5-Hexanedione-induced changes in the neurofilament subunit pools of rat peripheral nerve. Neurotoxicology 26(2): 229–240.

15.

LoPachin

Reid

. (2004) 2,5-Hexanedione-induced changes in the monomeric neurofilament protein content of rat spinal cord fractions. Toxicology and Applied Pharmacology 198(1): 61–73.

16.

Ming

Song

(2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70(4): 687–702.

17.

Shipp

(2007) Structure and function of the cerebral cortex. Current Biology 17(12): R443–R449.

18.

Song

Zhang

. (2008) The reversibility of neurofilaments decline induced by 2,5-hexanedione in rat nerve tissues. Biochemical Pharmacology 75(3): 737–744.

19.

Song

Zhang

. (2007) Time-dependent alteration of cytoskeletal proteins in cerebral cortex of rat during 2,5-hexanedione-induced neuropathy. Neurochemical Research 32(8): 1407–1414.

20.

Suh

Consiglio

Ray

. (2007) In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2⁺ neural stem cells in the adult hippocampus. Cell Stem Cell 1(5): 515–528.

21.

Wang

(2006) Analysis on the occupational diseases reported in China, 2002. China Occupational Medicine 33(1): 46–47.

22.

Lin

(2009) Grey relation analysis of incidence of occupational diseases in Longgang District, Shenzhen in 1995-2008 by gray relation. China Tropical Medicine 9(8): 1585–1586.

23.

Zhang

Han

Zhao

. (2005) 2,5-Hexanedione induced reduction in protein content and mRNA expression of neurofilament in rat cerebral cortex. Environmental Toxicology and Pharmacology 20(1): 92–98.

24.

Zhao

Deng

Gage

(2008) Mechanisms and functional implications of adult neurogenesis. Cell 132(4): 645–660.

25.

Zhu

Couillard-Despres

Julien

(1997) Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Experimental Neurology 148(1): 299–316.