Inhibition of the transforming growth factor-β/SMAD cascade mitigates the anti-neurogenic effects of the carbamate pesticide carbofuran

Abstract

The widely used carbamate pesticide carbofuran causes neurophysiological and neurobehavioral deficits in rodents and humans and therefore poses serious health hazards around the world. Previously, we reported that gestational carbofuran exposure has detrimental effects on hippocampal neurogenesis, the generation of new neurons from neural stem cells (NSC), in offspring. However, the underlying cellular and molecular mechanisms for carbofuran-impaired neurogenesis remain unknown. Herein, we observed that chronic carbofuran exposure from gestational day 7 to postnatal day 21 altered expression of genes and transcription factors and levels of proteins involved in neurogenesis and the TGF-β pathway ( TGF-β; SMAD-2, -3, and -7; and SMURF-2) in the rat hippocampus. We found that carbofuran increases TGF-β signaling ( increased phosphorylated SMAD-2/3 and reduced SMAD-7 expression) in the hippocampus, which reduced NSC proliferation because of increased p21 levels and reduced cyclin D1 levels. Moreover, the carbofuran-altered TGF-β signaling impaired neuronal differentiation (BrdU/DCX and BrdU/NeuN cells) and increased apoptosis and neurodegeneration in the hippocampus. Blockade of the TGF-β pathway with the specific inhibitor SB431542 and via SMAD-3 siRNA prevented carbofuran-mediated inhibition of neurogenesis in both hippocampal NSC cultures and the hippocampus, suggesting the specific involvement of this pathway. Of note, both and studies indicated that TGF-β pathway attenuation reverses carbofuran's inhibitory effects on neurogenesis and associated learning and memory deficits. These results suggest that carbofuran inhibits NSC proliferation and neuronal differentiation by altering TGF-β signaling. Therefore, we conclude that TGF-β may represent a potential therapeutic target against carbofuran-mediated neurotoxicity and neurogenesis disruption.

Carbofuran accelerates the cellular senescence and declines the life span of spns1 mutant zebrafish

“…These senescence and ageing effects of carbofuran in spns1 −/− mutant fish might be mediated by carbofuran-induced ROS generation ( Figure 6), because elevated ROS level is a key factor of ageing-related pathologies such as neurodegenerative diseases, endocrine abnormalities and reproductive impairments. 25,29 The loss of the spns1 gene in the mutant zebrafish induces genotoxic stress, which was revealed by yolk opaqueness, senescence and shortened life span. 14,34 Carbofuran-induced ROS generation made additional stress in spns1 mutant fish and exacerbated these phenotypes of the age-associated reduction of DNA methylation was manifested.…”

BMSC-CM prevents over-differentiation of NSCs to astrocytes by upregulating Smad 6 expression

“…The inhibition of TGF-β in the early phase led to over-activation of in ammation-associated signaling, resulting in the apoptosis of neurons around the injury lesion. Second, TGF-β has the ability to promote gliosis in the CNS [65]. The early inhibition of TGF-β might lead to a dysfunction in the scar formation process, which would then attenuate the effect on the limitation of in ammation.…”

Small airway remodeling in diabetic and smoking chronic obstructive pulmonary disease patients

“…Ten days before the rats were sacrificed, the SB431542 group was intraperitoneally injected with 2.5 mg/kg SB431542 dissolved in 5% dimethyl AGING sulfoxide, and the buffer group was intraperitoneally injected with 5% dimethyl sulfoxide only [36][37][38]. The injections were performed every 48 hours for a total of five times.…”