Fluoride-induced iron overload contributes to hepatic oxidative damage in mouse and the protective role of Grape seed proanthocyanidin extract

Abstract

-Emerging evidence has demonstrated that iron overload plays an important role in oxidative stress in the liver. This study aimed to explore whether fluoride-induced hepatic oxidative stress is associated with iron overload and whether grape seed proanthocyanidin extract (GSPE) alleviates oxidative stress by reducing iron overload. Forty Kunming male mice were randomly divided into 4 groups and treated for 5 weeks with distilled water (control), sodium fluoride (NaF) (100 mg/L), GSPE (400 mg/kg bw), or NaF (100 mg/L) + GSPE (400 mg/kg bw). Mice exposed to NaF showed typical poisoning changes of morphology, increased aspartate aminotransferase and alanine aminotransferase activities in the liver. NaF treatment also increased MDA accumulation, decreased GSH-Px, SOD and T-AOC levels in liver, indicative of oxidative stress. Intriguingly, all these detrimental effects were alleviated by GSPE. Further study revealed that NaF induced disorders of iron metabolism, as manifested by elevated iron level with increased hepcidin but decreased ferroportin expression, which contributed to hepatic oxidative stress. Importantly, the iron dysregulation induced by NaF could be normalized by GSPE. Collectively, these data provide a novel insight into mechanisms underlying fluorosis and highlight the potential of GSPE as a naturally occurring prophylactic treatment for fluoride-induced hepatotoxicity associated with iron overload.

Grape Seeds Proanthocyanidins: An Overview of In Vivo Bioactivity in Animal Models

“…Chronic fluoride intoxication could cause toxicity to the liver [42]. In this regards, earlier research demonstrated that iron overload is implicated in fluoride-induced oxidative damage in vitro attenuated by GSPE which protected the cells against oxidative stress [42].…”

“…Chronic fluoride intoxication could cause toxicity to the liver [42]. In this regards, earlier research demonstrated that iron overload is implicated in fluoride-induced oxidative damage in vitro attenuated by GSPE which protected the cells against oxidative stress [42]. A more recent study showed that 400 mg/kg BW/day of GSPE significantly decreased levels of ALT, AST, MDA and iron content in liver tissue and increased the GSH-Px, SOD, T-AOC levels in fluoride-induced iron overload Kunming male mice [42].…”

“…In this regards, earlier research demonstrated that iron overload is implicated in fluoride-induced oxidative damage in vitro attenuated by GSPE which protected the cells against oxidative stress [42]. A more recent study showed that 400 mg/kg BW/day of GSPE significantly decreased levels of ALT, AST, MDA and iron content in liver tissue and increased the GSH-Px, SOD, T-AOC levels in fluoride-induced iron overload Kunming male mice [42]. Despite the mechanism involved in the GSPE liver protection related to fluoride-mediated hepatic oxidative damage is not being fully elucidated, proanthocyanidins from grape seeds have iron-chelating effects that can prevent the production of free radicals normally caused by iron overload [42].…”

Disrupted Iron Storage in Dental Fluorosis

“…Their characterization may help to reconstitute the history of ameloblast activity alterations and thus to use enamel defects as an early marker of exposure to environmental toxicants altering the development of teeth and other organs. The present study is focused on fluoride, which is widely present in the human environment and which presents many cell effects (Liu et al 2018), including disruption of iron metabolism (Niu et al 2018). Fluoride protects against caries essentially via topical actions, but when absorbed in excess, fluoride may also lead to altered enamel structural properties associated with enamel gene expression modulations (Fejerskov et al 1994; Aoba and Fejerskov 2002).…”

“…The most external part of enamel is in contact with maturation-stage ameloblasts, which express and contain high concentrations of ferritin heavy chain (Fth) associated with the light chain (Ftl) to form the core subunit of ferritin, responsible for cellular iron storage (Wen and Paine 2013). Interestingly, ferritin expression has been reported to be regulated by fluoride in hepatocytes (Niu et al 2018), suggesting a possible regulation in ameloblasts.…”