https://linkinghub.elsevier.com/retriev ... 25)00188-9
PFPC Commentary:Abstract
The aim of the study is to explore the regulatory effect of nuclear factor erythroid 2-related factor 2 (Nrf2) on iron overload and lipid peroxidation in pathogenesis of liver injury induced by fluorosis.
METHODS Liver function of the individuals residing in endemic fluorosis area and the rats were examined by biochemical analysis. The histopathological changes of rat liver were observed under light and electron microscopes. The parameters relating iron overload and lipid peroxidation were determined by biochemical and molecular biological methods. HepG2-cells were treated with overexpressed plasmid or siRNA of Nrf2.
RESULTS The results showed that the disfunction of liver was related to the severity of dental fluorosis in population of fluorosis area and the changed liver function and histopathology were observed in rats with chronic fluorosis. Fluoride exposure induced iron overload, exhibiting the high levels of Nrf2, total iron and ferrous ion, the changed protein and mRNA levels of FTL, FPN1, hepcidin and S100A9; and the stimulated lipid peroxidation, including the increased MDA and ROS, and the decreased GSH, GPX4 and SLC7A11 in rat liver and HepG2-cells. Interestingly, overexpression of Nrf2 attenuated the changes of iron overload and peroxidative injury of cultural cells exposed to fluoride, and while silencing Nrf2 enhanced these hepatic damages by fluoride.
CONCLUSION Our results indicated that fluoride exposure caused iron overload and lipid oxidative injury in liver, which was involved in the impairment of liver function. Nrf2 may play a protective role in alleviating the liver injury by regulating iron overload and lipid peroxidation induced by chronic fluorosis.
- Nrf-2 is regulated by thyroid hormone (T3)(Cornejo et al., 2013; Stryhn et al., 2023; Romanque et al., 2011).
- Nrf-2 activation is mediated by the Gq/11 pathway (PKC) (Numazawa et al., 2003; Sun et al., 2020).
Once again, we have a professor who is well familiar with the effects of fluoride on thyroid hormone metabolism - namely, Zhi-Zhong Guan - who completely neglects to consider the implications of thyroid hormone signalling. In 1988, Guan co-authored a widely cited study demonstrating the synergistic actions of fluoride and iodine deficiency on the rat thyroid (Guan et al., 1988).
The present study shows the same type of antagonism, but in the liver: fluoride exposure disrupts iron and redox homeostasis, triggers oxidative injury, and induces a compensatory Nrf2 response - a downstream pattern entirely consistent with impaired Gq/11 and T3 regulation.
That this endocrine dimension was ignored is astonishing. Guan’s own earlier work laid out the thyroidal component clearly. The thyroid-Nrf2-iron regulatory axis is not marginal here - it is central to the physiology being disrupted.
It is also noteworthy that Prof. Guan rotates as an Editor-in-Chief of the journal Fluoride, which has published many reports on fluoride effects on thyroid hormone metabolism over the last few decades. How could this have been missed?
Unfortunately, these two studies are only the tip of the iceberg. Although extensive research has documented the essential role of thyroid hormone in neurodevelopment, liver disease, and many other major public health concerns, when it comes to fluoride, results are still described as “not completely understood” or “unclear.”
Despite more than 170 years of research and hundreds of studies showing how fluoride disrupts thyroid hormone metabolism and its associated pathways, science continues to look the other way.
This persistent failure to integrate thyroid physiology into fluoride research reflects not a lack of evidence, but a profound failure of the scientific discourse surrounding it.
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