Sodium Fluoride Affects DNA Methylation of Imprinted Genes in Mouse Early Embryos

Zhao, Lei; Zhang, Sheng; An, Xinglan; Tan, Wenxi; Tang, Bo; Zhang, Xueming; Li, Ziyi

doi:10.1159/000442067

Cited by 15 publications

(6 citation statements)

References 18 publications

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“…(SNRPN) (Mayer et al, 2000;Higashimoto et al, 2003;Broad et al, 2009;Hammoud et al, 2010;Zheng et al, 2011;Zhao et al, 2015;Bruno et al, 2018). However, failure in the maintenance of imprinted gene methylation patterns in the germline might occur, and this has been associated with low sperm quality and pregnancy rate and impaired post-fertilization development (Rotondo et al, 2013;Kitamura et al, 2015;McSwiggin and O'Doherty, 2018).…”

Section: Dna Methylation In Germ Cell Developmentmentioning

confidence: 99%

Epigenetics of Male Infertility: The Role of DNA Methylation

Rotondo

Lanzillotti

Mazziotta

et al. 2021

Front. Cell Dev. Biol.

114

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In recent years, a number of studies focused on the role of epigenetics, including DNA methylation, in spermatogenesis and male infertility. We aimed to provide an overview of the knowledge concerning the gene and genome methylation and its regulation during spermatogenesis, specifically in the context of male infertility etiopathogenesis. Overall, the findings support the hypothesis that sperm DNA methylation is associated with sperm alterations and infertility. Several genes have been found to be differentially methylated in relation to impaired spermatogenesis and/or reproductive dysfunction. Particularly, DNA methylation defects of MEST and H19 within imprinted genes and MTHFR within non-imprinted genes have been repeatedly linked with male infertility. A deep knowledge of sperm DNA methylation status in association with reduced reproductive potential could improve the development of novel diagnostic tools for this disease. Further studies are needed to better elucidate the mechanisms affecting methylation in sperm and their impact on male infertility.

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Section: Dna Methylation In Germ Cell Developmentmentioning

confidence: 99%

Epigenetics of Male Infertility: The Role of DNA Methylation

Rotondo

Lanzillotti

Mazziotta

et al. 2021

Front. Cell Dev. Biol.

114

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“…In part, these end points, e.g., the induction of oxidative stress or histopathology of the myocardium are not covered by the standard guidelines. Furthermore, fluoride exposure was shown to alter DNA methylation in early mouse embryos (Zhao et al 2015;Zhu et al 2014). The respective studies are quite heterogeneous with respect to experimental settings (e.g., animal model, dose levels) and end points examined.…”

Section: Developmental Toxicitymentioning

confidence: 99%

“…For subacute studies, a default factor of 0.12 for rats and 0.18 for mice should be used. In case the authors only reported F -concentration in drinking water, conversion factors of 0.05/0.09 (rats/mice) were used for adult animals/the parental generation and conversion factors of 0.12/0.18 (rats/mice) for the pups or short-term exposure of young animals Furthermore, only a single high dose was investigated in some studies, which was identified as the LOAEL; therefore, no dose-response assessment was possible (Bouaziz et al 2007;Zhao et al 2015).…”

Section: Developmental Toxicitymentioning

confidence: 99%

Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses

et al. 2020

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Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.

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“…NaF also disturbs the methylation pattern of imprinted genes in embryos during pregnancy . In addition, fluoride induces abnormal methylation of imprinted genes, such as H19 , Peg3, and IGF2 . This study, conducted with a fluorosis population and with human osteoblasts in culture, demonstrated that fluoride induces hypermethylation of the p16 gene.…”

Section: Discussionmentioning

confidence: 69%

Aberrant methylation‐induced dysfunction of p16 is associated with osteoblast activation caused by fluoride

Qiu

et al. 2018

Environmental Toxicology

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Chronic exposure to fluoride continues to be a public health problem worldwide, affecting thousands of people. Fluoride can cause abnormal proliferation and activation of osteoblast and osteoclast, leading to skeletal fluorosis that can cause pain and harm to joints and bones and even lead to permanent disability. Nevertheless, there is no recognized mechanism to explain the bone lesions of fluorosis. In this work, we performed a population study and in vitro experiments to investigate the pathogenic mechanism of skeletal fluorosis in relation to methylation of the promoter of p16. The protein coded by the p16 gene inhibits cdk (cyclin-dependent kinase) 4/cdk6-mediated phosphorylation4 of retinoblastoma gene product and induces cell cycle arrest.The results showed that hypermethylation of p16 and reduced gene expression was evident in peripheral blood mononuclear cells of patients with fluorosis and correlated with the level of fluoride exposure. Studies with cell cultures of osteoblasts revealed in response to sodium fluoride (NaF) treatment, there was an induction of p16 hypermethylation and decreased expression, leading to increased cell proliferation, a longer S-phase of the cell cycle, and development of skeletal fluorosis. Further, the methylation inhibitor, 5-aza-2-deoxycytidine, reversed the p16 hypermethylation and expression in response to NaF. These results reveal a regulatory role of p16 gene methylation on osteoblasts activation during the development of skeletal fluorosis. K E Y W O R D S coal-burning fluorosis, DNA methylation, osteoblast activation, p16 gene, skeletal fluorosis

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Sodium Fluoride Affects DNA Methylation of Imprinted Genes in Mouse Early Embryos

Cited by 15 publications

References 18 publications

Epigenetics of Male Infertility: The Role of DNA Methylation

Epigenetics of Male Infertility: The Role of DNA Methylation

Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses

Aberrant methylation‐induced dysfunction of p16 is associated with osteoblast activation caused by fluoride

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