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SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of resveratrol against neurodevelopment damage by fluoride.Abstract
Rationale: Potential adverse effects of fluoride on neurodevelopment has been extensively explored and mitochondria have been recognized as critical targets. Mitochondrial biogenesis serves a crucial role in maintaining mitochondrial homeostasis and salubrious properties of resveratrol (RSV) has been well-defined. However, the molecular mechanisms governing mitochondrial biogenesis in developmental fluoride neurotoxicity remain unclear and the related therapeutic dietary agent is lacking.
Methods: In vitro neuroblastoma SH-SY5Y cells and in vivo Sprague-Dawley rat model of developmental fluoride exposure were adopted. A total population of 60 children under long-term stable fluoride exposure were also recruited. This work used a combination of biochemical and behavioral techniques. Biochemical methods included analysis of mitochondrial function and mitochondrial biogenesis, as well as mRNA and protein expression of mitochondrial biogenesis signaling molecules, including silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Behavioral studies investigated spatial learning and memory ability of rats.
Results: Both in vivo and in vitro experiments showed that sodium fluoride (NaF) caused mitochondrial dysfunction and impaired mitochondrial biogenesis. Also, NaF elevated SIRT1 levels and suppressed SIRT1 deacetylase activity along with decreased levels of PGC-1?, NRF1 and TFAM, suggestive of dysregulation of mitochondrial biogenesis signaling molecules. Moreover, enhancement of mitochondrial biogenesis by TFAM overexpression alleviated NaF-induced neuronal death through improving mitochondrial function in vitro. Further in vivo and in vitro studies identified RSV, the strongest specific SIRT1 activator, improved mitochondrial biogenesis and subsequent mitochondrial function to protect against developmental fluoride neurotoxicity via activating SIRT1-dependent PGC-1?/NRF1/TFAM signaling pathway. Noteworthy, epidemiological data indicated intimate correlations between disturbed circulating levels of mitochondrial biogenesis signaling molecules and fluoride-caused intellectual loss in children.
Conclusions: Our data suggest the pivotal role of impaired mitochondrial biogenesis in developmental fluoride neurotoxicity and the underlying SIRT1 signaling dysfunction in such neurotoxic process, which emphasizes RSV as a potential therapeutic dietary agent for relieving developmental fluoride neurotoxicity.
EXCERPTS
Animals and experimental designs
… In study-1, female rats were developmentally exposed to fluoride via drinking water freely daily from pre-pregnancy to post-puberty, which covers the critical maternal, perinatal, and pubertal periods. The day of parturition was counted as postnatal day 0 (PND 0). Offspring female rats were still under the same treatments as mother rats till PND60 after the weaning period (PND21) (Figure 1F).
In study-2, offspring female rats were allotted into 4 different groups (n = 20 pups in each group). The treatment schedule was given below (Figure 6A):
- Group I — Control (receiving tap water only till PND 60).
- Group II — Fluoride-treated (100 mg/L NaF via drinking water till PND 60).
- Group III — RSV supplemented (100 mg/L NaF via drinking water till PND 60 + RSV at 200 mg/kg body weight/day by gavage from PND 10 to PND 60).
- Group IV — RSV and NIC supplemented (NaF at a dose of 100 mg/L via drinking water till PND 60 + RSV at 200 mg/kg body weight/day and NIC at 100 mg/kg body weight/day simultaneously by gavage from PND 10 to PND 60).
After corresponding treatments, all offspring rats were euthanized by cervical dislocation for the study of biochemical parameters.
Study population
Baodi district in Tianjin, China is divided into historical high fluoride areas and normal fluoride areas. In 2015, the volunteers aged 8-12 years were selected from local children who are permanent residents since birth. Children from Dakoutun town (high-fluoride districts, n = 30) and students from Lintingkou town (normal-fluoride/control areas, n = 30) were included in this study. Both the two study sites were not in the endemic areas for iodine deficiency disorders, or exposed to other potential neurotoxins like lead, arsenic or mercury.
*Original abstract and full test in html online at https://www.thno.org/v10p4822.htm
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*Original abstract online at https://www.thno.org/v10p4822.htm