Mitochondrial dysfunction due to in vitro exposure to atrazine and its metabolite in striatum

Abstract

Atrazine (2‐chloro‐4‐ethylamino‐6‐isopropylamino‐s‐triazine) has been described as a potential toxic for dopaminergic metabolism both in vivo and in vitro. Its main metabolite diamino‐chloro triazine (DACT) has been shown to achieve higher levels in brain tissue than atrazine. The aim of this study was to evaluate the in vitro effects of atrazine and DACT on striatal mitochondrial function, active oxygen species generation, and nitric oxide (NO) content. Incubation of mitochondria with atrazine (10 µM) was not able to modify oxygen consumption. However, a 50% increase in malate‐glutamate state 4 respiratory rates was observed after DACT treatment (100 µM) without changes in respiratory state 3. Atrazine was able to inhibit complex I–III activity by 30% and DACT induced a tendency to decrease by 17% in the striatum. Regarding reactive oxygen species (ROS), DACT increased H2O2 production by 43%. Also, superoxide anion levels were higher (14%) after atrazine exposure than in control mitochondria. Incubation of striatal mitochondria with atrazine and DACT induced membrane depolarization by 15% and 19%, respectively. Also, atrazine increased NO content by 10% but no significant changes were observed after exposure of mitochondria to DACT. Glutathione peroxidase activity was inhibited (56%) by DACT and atrazine inhibited superoxide dismutase activity by 60%. Also, cardiolipin oxidation (15%) was observed after atrazine treatment. Summing up, the obtained results suggest that in vitro atrazine and DACT induce ROS production affecting striatal mitochondrial function. The atrazine effects would be attributed to a direct effect on the mitochondrial respiratory chain and superoxide dismutase activity while DACT appears to disturb glutathione‐related enzyme system.

Developmental regulation of cellular metabolism is required for intestinal elongation and rotation

“…The results described above suggest that, as previously observed ( Lim et al, 2009 ; Karadayian et al, 2023 ), ATR may inhibit electron transport via Complex I of the mitochondrial ETC. To determine whether specifically inhibiting Complex I by another means elicits the same phenotypes as ATR, we exposed embryos to rotenone, a well-characterized Complex I inhibitor known to dysregulate mitochondrial metabolism and compensatorily upregulate glycolysis ( Karlsson et al, 2016 ; Hou et al, 2018 ; Gonzalez-Hunt et al, 2021 ).…”

“…5E ). The specific depletion of succinate in the presence of ATR is therefore consistent with ATR-exposed mitochondria bypassing Complex I, the ETC component known to be inhibited by ATR in other contexts ( Lim et al, 2009 ; Karadayian et al, 2023 ). We also noted a significant decrease in malonic acid, a well-known competitive inhibitor of Complex II, in the presence of ATR ( Fig.…”

“…Importantly, structural and functional similarities between photosynthetic and mitochondrial ETC componentry suggest that ATR could also inhibit mitochondrial electron transport, thus crippling oxidative phosphorylation (OXPHOS) in animal cells. Indeed, in adult animals and animal cell culture, exposure to ATR has been shown to cause oxidative stress and metabolic dysfunction consistent with its inhibition of mitochondrial ETC Complex I ( Lim et al, 2009 ; Zaya et al, 2011 ; Jin et al, 2014 ; Semren et al, 2018 ; Yin et al, 2020 ; Jiang et al, 2021 ; Karadayian et al, 2023 ). Unfortunately, whether or how ATR affects cellular metabolic states in the developing embryo, and the potential consequences of metabolic perturbations for vertebrate gut morphogenesis, are largely unknown.…”

Association of Diabetes Outcome and Atrazine Exposure Among Pennsylvania Counties, 2011-2019

“…Mechanistic studies revealed that chronic exposure to atrazine decreased the basal metabolic rate, increased body weight, and caused insulin resistance in rats independent of their diet and exercise levels. This is mainly due to atrazine-triggered damage to mitochondrial function in both human and animal cells [48][49][50][51]. This disruption leads to decreased oxygen consumption and suppressed insulin-mediated phosphorylation of Akt, potentially contributing to oxidative stress and impaired glucose metabolism [48].…”

Lycopene Protects against Atrazine-Induced Kidney STING-Dependent PANoptosis through Stabilizing mtDNA via Interaction with Sam50/PHB1

“…10,11 In addition, ATR not only reduces the expression of Na + and K + -ATPase, 12 activates the nuclear xenobiotic receptors (NXRs) reaction, 13 disrupts the homeostasis of cytochrome P450 enzyme system (cyp450), activates the Nrf2 pathway, causes kidney injury and renal oxidative stress, 14,15 but also affects mitochondrial dysfunction. 16 ATR has been shown to induce renal mitochondrial dysfunction, but how mitochondrial injury triggers a destructive inflammatory response in the kidney is unclear.…”