Epigenetic effects of heavy metals of the environmental by the example of cadmium

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Epigenetic effects of heavy metals of the environmental by the example of cadmium

Ostrovska S. S., Abramov S. V., Dychko E. N., Vyselko A. D.,

Konovalova O. S., Danilchenko A. K.

Dnipro Medical Institute of Traditional and Non-Traditional Medicine (Dnipro, Ukraine)

A review of current research shows the role of noncoding micro-RNAs (miRNAs) of the epigenome in biological processes such as early cell growth, proliferation, differentiation, development, ageing, and apoptosis under environmental factors. Changes in miRNA expression levels depend on the cells' exposure to the toxicant. For example, the expression of miRNA-146a decreases after exposure to Cd but increases after exposure to aluminium. Some of the main epigenetic mechanisms involved in Cd-induced stress responses are described. Current data on epigenetic modifications' role in Cd tolerance development are summarized. They can be used in plant breeding and molecular research to improve resistance to Cd-induced stress. A key direction in this field of epigenetics is understanding the functional significance of changes that occur during embryogenesis to form normal developmental trajectories in adult phenotypes. The facts of how environmental signals trigger the remodelling of embryonic epigenetic configurations, and phenotype changes that can be inherited over several generations are demonstrated. The effect of Cd on miRNA expression in placental samples was evaluated to better characterise intrauterine disorders. In humans, environmental factors, including heavy metals, organic pollutants, and drugs, adversely affect the function of miRNAs in the placenta. Specific miRNAs against the background of oxidative stress are identified as potential biomarkers in human malignant tumours, expanding their potential as therapeutic targets.

Key words: epigenetic modifications, noncoding miRNAs, gene expression, cadmium, epigenetic mechanisms as preventive, diagnostic and therapeutic markers. epigenetic modification epigenome

Connection of the publication with planned research works.

This work is a fragment of the scientific topic of the Department of Medical Biology: "Development and morphofunctional state of organs and tissues of experimental animals and humans in normal ontogenesis under the influence of external factors", state registration number 0111U009598.

Introduction

Exposure to environmental toxicants, especially heavy metals (HMs) such as cadmium (Cd), is of global concern due to their widespread distribution. The concentration of heavy metals (HM) in soil, air and water increases and exceeds natural levels due to metal mining and production, agricultural and other anthropogenic activities. They pollute groundwater and soil and can actively enter plants, entering food chains through crops [1, 2]. Data on the exact mechanisms of action of environmental HM are of primary importance in health risk assessments, and the results of clinical and epidemiological studies on humans are used to determine the relationship between their effects and the occurrence of diseases [3, 4].

The effect of environmental HM on the epigenome has attracted considerable interest in the last few decades [5]. Epigenetics studies changes in the chemical composition of nucleotides or associated histone proteins rather than changes in the genetic code or the DNA sequence itself. Mechanisms of epigenetics include DNA methylation and demethylation, histone modifications, and non-coding RNAs such as miRNAs. Under environmental factors, violating gene expression patterns regulated by epigenetics can lead to developing autoimmune processes, cancer and other diseases [6]. Given the critical role of epigenetics in regulating gene and protein expression, including epigenetic changes (EC) induced by environmental HM in the health risk assessment process is currently fundamental [7].

The aim of the study

Analysis of current scientific data regarding the interaction of environmental factors, using the example of the heavy toxic metal Cd, with the epigenome, which includes non-coding microRNAs (miRNAs) that influence gene activity, can modulate their expression, and this, in turn, leads to is a violation of protein synthesis in cells and the development of many pathological changes.

Main part

Compared to the many studies in the field of genetics, research in the field of epigenetics has appeared relatively recently. Unlike genetic changes, which are difficult to reverse, pharmaceutical drugs can reverse epigenetic aberrations. Therefore, epigenetics tools are used as preventive, diagnostic and therapeutic markers. With the development of drugs that affect specific epigenetic mechanisms and are involved in regulating gene expression, epigenetic tools are an effective approach applied in the clinic to treat diseases [8].

There is more and more evidence environmental HM can manifest their toxicity through miRNAs, causing aberrant changes in their expression, which are directly related to various pathophysiological conditions and signalling pathways [9]. In this regard, the review focuses mainly on the role of non-coding miRNAs in these processes. Since the first discovery about 20 years ago, thousands of miRNAs have been discovered in various biological species. MiRNAs are endogenous RNAs of approximately 23 nucleotides in length that play an essential role in gene regulation in plants, animals, and humans by pairing with target matrix RNA (mRNA) genes to control their posttranscriptional expression. Detection of miRNAs, identification of their target genes in mRNA, and conclusions about the functions of miRNAs are essential strategies for understanding their role in normal biological processes and disease development [10].

The field of toxicoepigenomics, which studies the relationship between epigenetic changes (ECs) and disease status in response to exposure to HM, is currently at the forefront of the science of environmental hygiene [5]. EC data are successfully used as biomarkers of environmental factors' effects, including disease predictors. EC can be hereditary, i.e. cause inherited phenotypic changes without changing the DNA sequence, for example, those obtained in response to exposure to toxicants on the mother during pregnancy [11].

EC studies in plants are aimed at identifying miR- NAs that are widely involved in plant development and morphogenesis by controlling splicing, translational expression or DNA methylation in mRNA targets, as well as defining the profiles of miRNA expression patterns and their role in responses to biotic and abiotic factors, caused by the environment [12].

The miRNA-393/target module was identified, which is a conserved miRNA family present in many plants which mainly targets genes encoding auxin receptors. Auxin, primarily indole-3-acetic acid (IAA), is a versatile signalling molecule that regulates many aspects of plant growth, development, and stress response. In this, miR- NAs are the central regulators of auxin response pathways, influencing their perception by plants. The combination of miRNAs and autoregulation of auxin signalling pathways, as well as interactions with other hormones, create a regulatory network that controls signal transduction to maintain homeostasis. This module is informative for genetic manipulation of optimal conditions for the growth and development of crops and is also used to increase yields using molecular selection [13].

Altered expression of miRNAs involved in the growth and development of several plants exposed to abiotic stress conditions such as drought, salinity, temperature extremes, nutrient deprivation and exposure to HM has been reported. These miRNAs are key targets for genetic manipulation aimed at creating resistance to these factors [14]. The regulation of miRNA expression stimulates the biosynthesis of therapeutically significant compounds, such as the production of vincristine and vinblastine (antitumor drugs obtained from pink periwinkle (Cataranthus roseus)) [15]. The fact that plant food miRNAs can survive digestion and subsequently affect gene expression in various organs of the consumer's body is a cause for concern [16].

In plants, miRNAs play a vital regulatory role in biotic and abiotic stresses, including stress caused by Cd [17]. To understand the mechanism of Cd-induced stress, genetic mechanisms that are important for plant stress tolerance have been identified. In this regard, ECs have great potential. Some of the main epigenetic mechanisms involved in Cd-induced stress responses are described. It includes chromatin remodelling, DNA meth- ylation, histone acetylation, and miRNA dysregulation. Current data on their role in Cd tolerance development and can be used in plant breeding, and molecular research to improve resistance to Cd-induced stress are summarized [18].

For the general population, the main route of Cd intake is food. Rice (Oryza sativa) grains contaminated with Cd pose a severe health risk to more than half of the world's population, for whom rice is the staple food. The role of miRNA-166 in modulating Cd tolerance and its accumulation in rice was analyzed. The expression levels of miRNA-166 in root and leaf tissues were significantly higher at the reproductive stage than at the seedling stage. After exposure to Cd, the expression of miRNA-166 in the roots of rice seedlings decreased. Overexpression of miRNA-166 increased Cd tolerance, associated with a reduction in Cd-induced oxidative stress (OS). Moreover, overexpression of miRNA-166 reduced Cd translocation from roots to shoots and its accumulation in grains. It has been shown that miRNA-166 targets the genes that encode the synthesis of proteins of the HD-Zip family in plants. In rice, the activity of the OsHB4 gene, which encodes the synthesis of proteins of this family, increased after exposure to Cd but was suppressed by overexpression of miRNA-166. Activation of OsHB4 increased sensitivity to Cd and its accumulation in leaves and grains. In contrast, inhibition of OsHB4 function by siRNA-166 enhanced Cd tolerance. These results indicate a critical role of miRNA-166 in Cd accumulation and tolerance by regulating the function of OsHB4, a target gene for miRNA-166 and a target gene for Cd [19]. In another rice research, the study of altered expression of miRNAs after exposure to Cd revealed 19 new miRNAs associated with the activation of the synthesis of 11 unknown proteins. After exposure to Cd, activation of miRNA-319 and miRNA-393 was observed, while the expression of miRNA-398 was suppressed. The activity of miRNA in plant homeostasis depends on the localization of the influencing factor inside the plant. In roots, exposure to Cd leads to inhibition of miRNA- 390 expression. Many miRNAs are involved in processes that promote growth, minimize OS, and protect plants from toxicants [20].

Data on the ability of sunflower (Helianthus annuus L), Indian mustard (Brassica juncea) and eucalyptus ca- maldulensis (Eucalyptus camaldulensis) to remove Cd from contaminated soil and water due to epigenetic factors are given [21]. The identification of miRNAs and corresponding mRNA target genes, induced in response to Cd stress in rapeseed (Brassica napus), was carried out. In this plant's example, miRNA's participation in the regulation of transcription factors, protection against biotic stress, and ion cell metabolism in response to Cd exposure has been demonstrated [22]. After exposure to this heavy metal, miRNA-268 reduces plant growth activity. An increase in their expression level is associated with an increased content of hydrogen peroxide and malondialdehyde, which are indicators of increased OS [18]. Improvements in research technologies in epig- enomics allow the identification of additional miRNAs in plants that may be involved in effective regulatory responses after exposure to HM.

ECs caused by Cd in aquatic organisms were studied. Its exposure leads to an inverse correlation between miRNA-122 expression and metallothionein levels in ti- lapia (a fish). Its elevated level is useful for alleviating Cd-induced cellular stress. A similar study on Daphnia pulex (the first crustacean whose genome was deciphered) demonstrated a positive correlation between miRNA-210 and hypoxia after its exposure. It is assumed that Cd and hypoxia increase the generation of reactive oxygen species (ROS) by enhancing the activity of ERK,

Akt, and hypoxia-inducible factor 1a (HIFla) genes, followed by increased expression of miRNA-210 [23].

The role of epigenetic modifications in embryogen- esis is determined by the ability of epigenetic factors to modulate the expression of embryonic development genes in response to environmental signals. Epigenetic mechanisms (DNA methylation, histone modification, and miRNA expression) have a unique impact on vertebrate development; in this aspect, zebrafish (Danio rerio) are widely used as a vertebrate model organism in studies of the developmental process due to their high fecundity and rapid organogenesis [24]. The zebrafish model allows us to understand the interaction between EC dynamics and various biological effects. A key focus in this field of epigenetics is understanding the functional significance of changes occurring during embryogenesis for the formation of typical developmental trajectories and adult phenotypes. The facts of how environmental signals trigger the remodelling of embryonic epigenetic configurations and phenotype changes, which can be inherited over several generations, have been demonstrated [25, 26]. The advantage of zebrafish for studying the transgenerational effect of xenobiotics on key epigenetic processes, including miRNA expression, is emphasized [27]. A comparative approach between zebrafish and mammalian models showed that changes in gene expression profiles are strictly associated with EC [28].

Traditional animal models for biological research, such as mice, reveal specific miRNA expression patterns that may be potential early biomarkers of the harmful effects of environmental toxicants, including carcinogens, and miRNA-134, miRNA-132, and miRNA-124-1 are biomarkers for rapid screening of potential chemical carcinogens [10].

It was compared the effect of HM and changes in the expression of miRNA in the placenta of newborns, which is known to be the primary regulator of the intrauterine medium and damage to which can lead to adverse consequences for the health of the offspring. The effect of Cd on miRNA expression in placental samples was evaluated to characterise intrauterine abnormalities better. In humans, environmental factors, including HM, organic pollutants, and drugs, adversely affect the function of miRNAs in the placenta. Identification of a panel of expressed miRNAs revealed 112 miRNAs consistently expressed in more than 70% of placental samples in response to Cd exposure. Placental miRNA profiles signalled the intrauterine influence of environmental factors [29].

There is a significant relationship between the change in miRNA expression profiles induced by HM and the development of diseases. However, in humans, the interpretation of miRNA response data to Cd is complicated because this metal can exist in the body for years, within 7-16 years or even 45 years, while minor exposure to Cd leads to its bioaccumulation in human tissues. To the extent tissues concentrate Cd, toxic reactions increase [9].

ECs play a critical role in several stages of biological processes, such as early cell growth, proliferation, differentiation, development, senescence, and apoptosis. Changes in miRNA expression levels depend on the cells' exposure to the toxicant. For example, the expression of miRNA-146a decreases after exposure to Cd but increases after exposure to aluminium. There are specific variations of miRNA response throughout the spectrum of HM [30].

Thus, the given review shows that miRNAs, as an epigenetic mechanism, have great potential in regulating vital processes in the development and growth of plants, animals, and humans. The central and absolute dogma of genetics, which is that information in cells flows in only one direction, from DNA to RNA and then to proteins, is now essentially debunked by the role of the environment in modulating gene expression.

Conclusions

The presented research results indicate that miRNAs, as one of the epigenetic mechanisms, have great potential in regulating the vital development and growth processes of plants, animals, and humans.

Prospects for further research.

The Discovery of new miRNAs, identification of their target genes in mRNA, and conclusions about the functions of miRNAs are essential strategies for understanding their role in normal biological processes and disease development.

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