Zhao 2019
| Data type(s) | Animal bioassay, Epidemiology, In vitro |
|---|---|
| Full citation | Zhao Q, Niu Q, Chen J, Xia T, Zhou G, Li P, Dong L, Xu C, Tian Z, Luo C, Liu L, Zhang S, Wang A. 2019. Roles of mitochondrial fission inhibition in developmental fluoride neurotoxicity: Mechanisms of action in vitro and associations with cognition in rats and children. Arch Toxicol: 93(3): 709-726. |
| Abstract | Fluoride neurotoxicity is associated with mitochondrial disruption. Mitochondrial fission/fusion dynamics is crucial to maintain functional mitochondria, yet little is known about how fluoride perturbs this dynamics and whether such perturbation contributes to impaired neurodevelopment. Here in human neuroblastoma SH-SY5Y cells treated with sodium fluoride (NaF, 20, 40 and 60 mg/L), mitochondrial fission suppression exerted a central role in NaF-induced mitochondrial abnormalities and the resulting autophagy deficiency, apoptosis augmentation, and compromised neuronal survival. Mechanically, pharmacological inhibition of mitochondrial fission exacerbated NaF-induced mitochondrial defects and cell death through promoting apoptosis despite partial autophagy restoration. Conversely, genetic enhancement of mitochondrial fission alleviated NaF-produced detrimental mitochondrial and cellular outcomes by elevating autophagy and inhibiting apoptosis. Further suppressing autophagy was harmful, while blocking apoptosis was beneficial for cellular survival in this context. Consistently, using Sprague-Dawley rats developmentally exposed to NaF (10, 50, and 100 mg/L) from pre-pregnancy until 2 months of delivery to mimic human exposure, we showed that perinatal exposure to environmentally relevant levels of fluoride caused learning and memory impairments, accompanied by hippocampal mitochondrial morphological alterations manifested as fission suppression and fusion acceleration, along with defective autophagy, excessive apoptosis and neuronal loss. Intriguingly, the disturbed circulating levels of identified mitochondrial fission/fusion molecules were closely associated with intellectual loss in children under long-term environmental drinking water fluoride exposure. Collectively, our results suggest that mitochondrial fission inhibition induces mitochondrial abnormalities, triggering abnormal autophagy and apoptosis, thus contributing to neuronal death, and that the mitochondrial dynamics molecules may act as promising indicators for developmental fluoride neurotoxicity. |
| Reference hyperlink | |
| Literature review tags | Mechanistic StudyHuman StudyAnimal Study |
| COI reported | Authors report they have no COI |
| Funding source | This work was supported by grants from the State Key Program of National Natural Science of China (Grant No. 81430076), the National Natural Science Foundation of China (Grants No. 81502785 and No. 81773388) and the Fundamental Research Funds for the Central Universities (HUST 2016YXMS221 and HUST 2015ZDTD052). |
| Study identifier | 33793 |
| Author contacted? | true |
| Author contact details | Authors were contacted in June 2019 for additional information for risk of bias evaluation. Additional information provided by the authors informed the rating decision for the following risk-of-bias domains: Selection, Attrition, Detection (exposure assessment), Detection (outcome assessment). |
| Summary/extraction comments | Animal data: Figure 5b, c, d, e, h; Human data: Figure 7a Zhao 2019, Zhou 2019, and Zhao 2020 all appear to use the same population of 8-12 year olds from Lintingkou and Dakoutun towns in Tianjin; population numbers vary slightly |
Risk of bias
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Animal bioassay experiments
| Name | Type | Comments |
|---|---|---|
| Developmental drinking water, Sprague Dawley rats | Developmental | 40 female and 20 male Sprague–Dawley rats (180–220 g) were obtained from the Laboratory Animal Center of Hubei Provincial Center for Disease Control and Prevention. Standardized pellet diet and drinking water were available ad libitum. All rats were kept in a controlled environment at (23–27)°C, 55–60% humidity, conforming to a 12 h light/dark cycle. The experimental protocols were approved by the Ethics Review Committee for Animal Research at Archives of Toxicology (2019) 93:709–726 711 1 3 Huazhong University of Science and Technology and were implemented exactly as specified. After 1-week acclimation, rats of the same sex were ranked by weight and divided randomly into the following four groups: one control group (tap water, containing less than 1.0 mg/L F−), and three NaF-treated groups (NaF was administered orally via drinking water; dosages were set as 10, 50, and 100 mg/L NaF (corresponding to 4.52, 22.6 and 45.2 mg/L F−, respectively) ). After 2 months of NaF exposure, rats in each group were chosen randomly for mating according to the ratio of male-to-female as 1:2. Then the pregnant female rats were kept in separate cages throughout gestation and subsequent weaning of pups, during which the corresponding NaF exposure still continued. The day of birth was considered as postnatal day 0 (PND 0). On PND 21, the offsprings were re-caged to five single sex pups in one cage and exposed to the same NaF concentration as the adult rats did until PND 60 (2 months of age). |