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    • Furthermore the higher expression levels of DNMT seemed to

    2021-09-08

    Furthermore, the higher expression levels of DNMT1 seemed to be responsible for the elevated levels of methylation in the GSTP1 and TXNRD2 promoters in HMC. In the DNA methyltransferase family, the functions of DNMT1 and DNMT3, including 3a and 3b, were the most ubiquitously expressed in cells. DNMT1 encodes the enzyme that is the most abundant DNA methyltransferase in mammalian EI1 mg and is considered the key maintenance methyltransferase, while DNMT3 mostly functions in de novo methylation. Aberrant methylation patterns induced by DNMT1 have been discovered in the initiation of many diseases, such as tumor or developmental abnormalities. Previously, there have also been studies proving the role of DNMT1 in addressing the possible influence of elevated oxidative stress on genome-wide DNA methylation levels [40]. Wu et al. reported that reactive oxygen species might induce site-specific hypermethylation via either the overexpression of DNMTs or the formation of a new DNMT-containing complex that better catalyzes this modification [41]. Our study discovered that, compared to LECs from ARC cases, LECs from HMC cases showed higher expression of DNMT1 at both the mRNA and protein levels, where the LECs were in a condition with higher levels of oxidative stress. Similar to our findings, DNMT1 was found to be upregulated in oxidative stress-related conditions, such as in an Alzheimer disease model in mice [42]. In our hypothesis, the elevated level of oxidative stress would damage the LECs in highly myopic eyes; thus, by treating LECs with H2O2, we aimed to simulate the microenvironment of HMC in terms of oxidative stress. We analyzed the regulation of methylation and gene expression of GSTP1 and TXNRD2 in response to H2O2 treatment. Our results indicated that H2O2 induction resulted in complex effects. In the present experiment, during a period of 8 days of H2O2 treatment, we observed increased expression of these two genes in the middle stage (from day 2 to day 6), followed by a sharp decrease at the late stage (day 6 to day 8) of the treatment period (Fig. 8E). One explanation of this finding would be that under oxidative stress, the expression of these two antioxidant genes would first increase to defend against the high-oxygen environment; on the other hand, the oxidative stress would chronically increase the methylation levels of the gene promoters possibly through upregulation of DNMT1, resulting in a decrease in transcription products of GSTP1 and TXNRD2. This implies that in highly myopic eyes, higher concentrations of oxygen due to earlier vitreous liquefaction are more likely to have a chronic effect, as they might not only cause direct oxidative damage to the lens but also simultaneously lead to impairment of antioxidant capacity through epigenetic regulation.
    Acknowledgements The authors sincerely appreciate the patients for participation. This research was funded by research grants from the National Natural Science Foundation of China (Grant nos. 81470613, 81870642, 81100653, 81670835, and 81270989), Shanghai High Myopia Study Group, International Science and Technology Cooperation Foundation of Shanghai (Grant no. 14430721100), Shanghai Talent Development Fund (Grant no. 201604), Shanghai Youth Doctor Support Program (Grant no. 2014118), and Outstanding Youth Medical Talents Program of Shanghai Health and Family Planning Commission (Grant no. 2017YQ011).
    Introduction Toxic electrophiles are certainly a prominent one on a long list of assaults and insults to the human body. One key source of these electrophiles is pesticides, chemical substances commonly used to control disease vectors (Hernández et al., 2013). Humans are exposed to pesticides mostly through residues in food, water and air (which result from extensive pesticide use in modern agricultural practices to enhance food production), applications to public areas (which aim at controlling disease vectors to ensure public health), careless handling (which results from pesticide use in gardens and lawns to improve the growth of ornamental plants), and occupational exposures to workers in production plants (Hernández et al., 2013; Alavanja et al., 2004). Although pesticides have been highly beneficial to modern agriculture and public health, their impact on human health has attracted substantial attention only in recent years (Hu et al., 2015). The mechanism of toxicity of various pesticides, including organophosphates (OP), organochlorines (OC), N-methylcarbamates (NMC), pyrethroids, neonicotinoids, triazines, paraquat, and dithiocarbamates (DTC), has been chiefly through oxidative stress by which many disease conditions are induced (Hernández et al., 2013). Perhaps more worrisome, fetuses and babies could be relatively prone to the toxic effects of pesticides as there exists evidence in the relevant scientific literature of pesticide residues present in placenta, fetal organs, subcutaneous fat tissues, umbilical cord blood, and other body fluids (Martı´nez et al., 1993; Waliszewski et al., 2000; Perera et al., 2003; Souza et al., 2005). Even more so, it has been well established that the enterohepatic clearance system of the fetus is immature (Myren et al., 2007) and that the bodily defense system of neonates is not fully developed (Beath, 2003; Grijalva and Vakili, 2013).