Neurotoxicity effects of atrazine-induced SH-SY5Y human dopaminergic neuroblastoma cells via microglial activation

Abstract

Atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) is a broad-spectrum herbicide with a wide range of applications worldwide. However, ATR is neurotoxic; it reduces dopamine levels in the substantia nigra and corpus striatum in the midbrain, affects the absorption of synaptic vesicles and synaptic bodies, and interferes with dopamine storage and uptake in synaptic vesicles, leading to neurodegenerative disorders. Microglia are resident immunocompetent and phagocytic cells that regulate and participate in the microenvironment in the central nervous system. They demonstrate macrophage characteristics after activation by releasing inflammatory cytokines and neurotoxic substances to increase the inflammatory response, and are thus involved in neurodegeneration. The aim of this study was to investigate the neurotoxic effects of ATR-activated microglia-mediated neuronal damage in terms of human dopaminergic neuroblastoma SH-SY5Y cell death. ATR was administered to BV-2 microglial cells at 12.5, 25, and 50 μM for 1, 6, 12, 24 and 48 h, respectively. ATR increased activated-microglia-induced overexpression of reactive oxygen species, inducible nitric oxide synthase, nitric oxide, gp91(phox), p47(phox), and the inflammatory cytokines tumor necrosis factor α and interleukin-1β, thus reducing SH-SY5Y cell viability. These results suggest that activated microglia may play a critical role in inflammation-mediated dopaminergic neuronal death, and provide the basis for further studies on the mechanisms of ATR-induced dopaminergic system toxicity.

Isoflavones Induce BEX2-Dependent Autophagy to Prevent ATR-Induced Neurotoxicity in SH-SY5Y Cells

“…In previous reports, we demonstrated that ATR reduces cell viability in a time- and dose-dependent manner and found that the median lethal dose (LD 50 ) of ATR was 250 µM after a 24 h exposure [27]. Therefore, we used ATR at 250 µM for further experiments.…”

“…Furthermore, ATR can significantly change the levels of catecholamine neurotransmitters, especially norepinephrine (NE) and DA. In addition to the effects of ATR on DA in the nervous system, studies have shown that ATR induces apoptosis and reactive oxygen species (ROS) levels in SH-SY5Y cells [26, 27]. Other results show that ATR induces apoptosis in PC12 cells by altering the expression of p53, caspase-3 and caspase-9 [28].…”

Chemical Pesticides and Human Health: The Urgent Need for a New Concept in Agriculture

“…Moreover, it was found that there is a possible statistical relationship between triazine herbicides and breast cancer incidence ( 104 ). Atrazine is the most known of the triazines, and it is a very widely used herbicide that has been associated with oxidative stress ( 103 ), cytotoxicity ( 105 , 106 ), and dopaminergic effects ( 107 , 108 ). Furthermore, the exposure of experimental animals to atrazine has been associated with reproductive toxicity ( 109 ) and delays in sexual maturation ( 110 ).…”

Atrazine exposure elicits copy number alterations in the zebrafish genome

“…Histidine decarboxylase is the only enzyme that converts histidine to histamine, which is an important bioamine that contributes to inflammation, allergies, and neurotransmission (Ku et al, 2014). Although not investigated as predominately as the neuroendocrine dysfunction caused by atrazine, the inflammatory and immune responses are currently under investigation (Ma et al, 2015; Thompson et al, 2015; Zhao et al, 2013). As hdc expression is predominantly altered in adult male brain tissue, these data could provide support for further studies investigating the immune responses later-in-life following an embryonic atrazine exposure.…”