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Bisphenol A 21.11.2024

Bisphenol A

Many chemical and physical environmental factors, depending on the dose and duration of exposure, can cause developmental abnormalities in the embryonic and postnatal periods and can be the cause of a number of diseases in adults. Currently, endocrine disrupting chemicals (EDCs) are attracting particular attention from researchers. They are widely distributed in the environment and are natural or synthetic compounds that, when ingested even in low doses, can interfere with the biosynthesis, storage, release, transfer and/or receptor interaction of endogenous hormones, thereby altering their functions and disrupting the body's internal regulatory system. This, in turn, leads to an increase in the number of pathologies associated with hormonal disorders. In particular, obesity and diabetes mellitus, various oncological diseases (breast, ovarian, prostate and testicular cancer), changes in the reproductive system (cryptorchidism, hypospadias, reduced sperm quality in men, female infertility), as well as cognitive disorders, behavioral deviations and neuropsychological development may develop. According to recent data, only a small fraction of the 900 commercially available EDCs have been screened for potential endocrine disrupting effects.
The primary routes of exposure to EDCs in humans and animals include oral, dermal, and inhalation. The route by which EDCs enter the body determines their bioavailability. Because not all absorbed EDCs can be metabolized, the original compounds become bioavailable. For most EDCs, the unmetabolized compounds, also known as the end toxicant, are the most biologically active form and react with molecules in the body. Once in the bloodstream, the terminal toxicant is able to reach and affect the target cell(s), with the phenotypic consequences of EDCs being highly dependent on the window of exposure. Thus, exposure to EDCs during pregnancy, infancy, early childhood and adolescence is particularly critical for the organism. Because the detoxification mechanism is not fully developed in the developing fetus and neonate, the body is particularly vulnerable to EDCs during these periods. In the prenatal and neonatal periods, primary germ cells also become targets for their effects, which can lead not only to disruption of gametogenesis in children whose mothers were directly exposed to EDCs, but also to the transmission of various phenotypic abnormalities (including predisposition to socially significant diseases) over several generations.
To date, the molecular mechanisms of EDCs exposure are not known. The available evidence suggests that the mechanisms of action of EDCs are quite complex, and research in this area is critical to understanding how adverse phenotypes manifest and to developing intervention and/or prevention strategies.
It should be emphasized that some chemicals may have inherently adverse "biological effects" even though they are considered non-toxic by current standards after appropriate toxicity testing, without considering the possible long-term effects of exposure to such chemicals.
In this context, it is necessary to consider a new concept of toxicity, namely "epigenetic toxicity". Epigenetic toxicity is a phenomenon in which an exogenous chemical affects the epigenome (affects only the activity of genes, but does not change the structure of genes) and has undesirable effects on living organisms, which may explain the prolonged and delayed effects of chemical exposure, as well as predisposition to diseases caused by harmful environmental factors. With the development of new and improved analytical technologies, the number of chemicals that exhibit epigenetic toxicity will continue to increase, as will our understanding of the molecular mechanisms of epigenetic toxicity.
This review examines the molecular mechanisms and biological effects of exposure to the ecotoxicant bisphenol A (BPA), which is a EDCs and is emerging as an epigenetic toxicant.

CHEMICAL PROPERTIES AND OCCURRENCE OF BISPHENOL-A
Bisphenol-A (4,4'-dihydroxy-2,2-diphenylpropane, BPA) is one of the most widely used organic synthetic compounds. It is used in industry in the manufacture of various plastic products, is a component of epoxy resins used as coatings for water pipes and the inside of almost all cans and food and beverage packaging.
and beverages. BPA can leach from containers into food or beverages and then accumulate in humans and animals. It can enter the human body not only through the gastrointestinal tract, but also through the skin, for example through contact with thermal printing paper. Since modern life is "surrounded" by plastic products, the exposure of living organisms to BPA is constant and in varying doses.
PATHOLOGIES ASSOCIATED WITH CHRONIC EXPOSURE TO BISPHENOL A
For several decades, research on the health effects of various doses of BPA has been actively conducted worldwide in laboratory animals and in clinical practice. It has now been established that BPA is hepatotoxic and its exposure can lead to cancer (breast, prostate and thyroid cancers), nervous system pathologies (neurogenesis disorders, strokes, Parkinson's disease), cardiovascular (ischemic heart disease, hypertension, blood clotting disorders), endocrine (diabetes, obesity) and reproductive systems (sexual dysfunction, endometriosis, breast, prostate and testicular changes).
Today, approximately 400 million people worldwide are considered to be diabetic. In addition to genetic factors, lifestyle and poor diet, as well as unavoidable chronic exposure to xenobiotics, are considered possible causes contributing to the development of this disease. Experimental studies have shown that BPA affects glucose metabolism through various mechanisms, including insulin resistance, pancreatic beta-cell dysfunction, adipogenesis, inflammation, and oxidative stress, supporting a link between BPA exposure and the development of diabetes. It has been shown in OS-2 cell cultures that BPA can cause mitochondrial dysfunction due to oxidative stress and affect lipid metabolism, such as in HER02 and ¡N8-1 cells. It is hypothesized that BPA exposure may contribute to other diabetes risk factors that lead to obesity, regulate eating behavior, or alter adipocyte differentiation.
BPA exposure has been associated with chronic respiratory disease such as asthma. For example, elevated urinary levels of BPA have been found in children with asthma. In addition, prenatal exposure to BPA has been found to increase the risk of has been found to increase the risk of respiratory distress in children during the neonatal period, although the adverse effects of BPA are then reduced during the first three years after birth.
Men and women exposed to BPA have been found to have an increased risk of developing coronary atherosclerosis. Patients with severe coronary artery stenosis have been found to have higher urinary BPA concentrations than people without atherosclerosis. Carriers of some genetic polymorphisms associated with reduced cellular response to oxidative stress were found to be more susceptible to cardiovascular and respiratory diseases. It should be noted that one of the possible molecular mechanisms of BPA action may be its effect specifically on oxidative stress.
BPA may lead to changes in brain structure and to mental and neurological disorders. For example, mice and rats exposed to BPA were more aggressive than controls. Moreover, this was observed only at certain ages and was not associated with an increase in testosterone concentrations. Studies in laboratory animals have shown that prenatal exposure to BPA affects brain development. High doses of BPA reduced the proliferative activity of multipotent neural stem cells, while low doses accelerated the differentiation and migration of neurons. This further resulted in abnormal neocortical architecture and corticotelamic projection, impaired neurotransmitter system and behavior in the postnatal period and in adulthood. In addition, after BPA exposure in the early postnatal period, vacuolization, pycnosis (compaction of the cell nucleus with further cell death), edema, degenerative changes, reduction in size and number of cells in the large cerebral hemispheres and cerebellum, and impaired sexual differentiation in the hypothalamus were observed.
In cultured hypothalamic cells of rat embryos, BPA affected the development of dendrites and synapses by increasing the levels of presynaptic synapsin protein I and microtubulin-associated protein 2. BPA has been implicated in cognitive disorders, autism, schizophrenia, Parkinson's disease, and Alzheimer's disease.
Epidemiological studies have shown that BPA may cause reproductive system and sexual behavior problems in both men and women, although no reproductive or hormonal abnormalities have been found. However, recent data do not conclusively show that adult exposure to low doses of BPA affects reproductive health. This may be because the published studies have examined different populations (and groups).
different populations (and groups), different doses of BPA, and different study designs and methods of measuring BPA in biological fluids.
Many studies have found an association between BPA exposure during pregnancy and fetal malformations. There is evidence that if the mother consumed foods containing BPA, the toxicant was detected not only in her serum, follicular fluid, and amniotic fluid, but also in the fetal serum. This suggests that BPA can cross the placenta (even at low doses), accumulate in the fetus, and cause adverse effects throughout the prenatal period. In addition, analysis of BPA levels in the body has shown that a reduced ability to metabolize the chemical in mothers often coincides with the occurrence of developmental defects in the fetus.
For example, intrauterine exposure to BPA was found to cause genital abnormalities in boys in about 40% of cases, as well as prematurity and low birth weight (especially in male infants), leading Welshos et al. to refer to BPA-induced birth defects and developmental abnormalities as "large effects of small exposures."
In addition, there is evidence that fetal exposure to low doses of BPA alters cell proliferation, affects apoptosis (cell death), and the timing of mammary gland development, which may further predispose to breast cancer in adulthood. In this case, exposure to BPA during pregnancy in combination with a high-fat diet significantly increases the risk of breast cancer in the offspring. It is hypothesized that BPA may promote breast oncogenesis through direct stimulation of estrogen-dependent tumor cell growth and/or through molecular alterations of fetal glands without associated morphological changes. It should be noted that BPA may also affect ovarian cell proliferation and apoptosis and disrupt ovarian steroidogenesis by altering steroidogenic enzymes, which in turn may contribute to ovarian tumor progression.
Recent evidence suggests that exposure to low, environmentally relevant doses of BPA during embryogenesis also affects prostate cells, increasing susceptibility to precancerous lesions of this organ and hormonal disturbances in adulthood. It is believed that prostate cells are more sensitive to the effects of BPA during the embryonic period than in adulthood. A number of studies have shown that BPA can enhance the proliferation and migration of prostate cancer cells and induce DNA adducts in this pathology.
At present, the molecular mechanisms by which BPA affects the fetus and induces the development of ovarian, breast, and prostate cancers in adults remain unclear and require further research. It has been suggested that BPA may interact directly with steroid hormone receptors (estrogen - BN and androgen - DO), which play a critical role in the onset and progression of these pathologies. In particular, BNa and BNr are expressed from day 12 of embryonic development in the mesenchyme surrounding the embryonic rudiment and regulate the growth of the mammary ducts both before and after birth. Therefore, exposure to BPAs during these periods may be critical for the development of breast cancer in adulthood. Studies show that the mechanisms of action of BPA in prostate cancer are much more complex than in breast and ovarian cancer.
In general, two main conclusions can be drawn about the association of BPA with different pathologies: 1) BPA is a typical xenoestrogen, and its estrogenic, estrogenic
is involved in the carcinogenesis of various organs and in the development of endocrine and/or hormone-dependent diseases; 2) exposure to BPA (even at low doses) during critical periods of ontogenesis (prenatal, neonatal, adolescent) can lead to long-term adverse effects in adulthood.
MOLECULAR MECHANISMS OF BISPHENOL A EXPOSURE IN LIVING ORGANISMS. ASSOCIATION WITH CHRONIC DISEASE
The mechanisms by which BPA may have adverse effects on human and animal organisms remain an open question. It is now generally accepted that BPA acts not only as a mutagen, but also as an endocrine disruptor and an agent that affects DNA methylation and histone modifications. These mechanisms are not mutually exclusive, although the epigenetic mechanisms of action of BPA are still poorly understood, but most likely depend on its endocrine activity.

Bisphenol A-induced genetic damage
BPA has been shown to be genotoxic and cytotoxic in several human and animal cell lines. It causes cell cycle disruptions (both in mitosis and meiosis) and leads to gene, chromosome and genomic mutations. For example, cases of aneuploidy due to impaired chromosome segregation during cell division have been described in the Chinese hamster V79 (lung fibroblasts) and Syrian hamster SHE (embryonic cells) cell lines. BPA is a frequent cause of DNA damage, DNA adduct formation, and apoptosis. For example, culturing cells in the presence of BFA induced apoptosis in the ER-positive breast adenocarcinoma cell line MCF-7, the ER-negative human embryonic kidney cell line HEK293, and the male mouse germ cell line GC-2. It was found that the rate of DNA adduct formation depends on the dose of BFA exposure, i.e. the higher the dose, the faster such compounds are formed. For example, in the human prostate cell line, DNA adducts were formed within 24 hours of exposure to high doses of BPA, whereas they were formed within 2 months of exposure to low doses of this ecotoxicant.
It is thought that the mutagenic effect of BPA, like any other xenobiotic, may be due to the formation of free radicals, electrophiles, nucleophiles, and redox reagents that accumulate and disrupt the plasma membrane and cellular components. Genetic damage caused by BPA exposure, in particular, can lead to changes in the proteome (quantitative and qualitative changes in protein synthesis) of the mammary glands, which may be the cause of birth defects, miscarriages, female and male infertility, and the development of many other pathologies mentioned above.
Mechanisms of action of bisphenol A as an endocrine disruptor
BPA is a xenoestrogen, but not an estrogen mimic. Its effect on the body as a synthetic hormone is largely explained by the fact that, like steroid hormones, it has phenolic groups so that nuclear estrogen receptors (ERa and ERP, as well as ERy, recently discovered in bone) perceive BPA as a signal to initiate the estrogen pathway to activate transcription of estrogen-sensitive genes. In vertebrates, this toxicant can alter hormonal balance by interacting directly with ERa, ERP, and ERy receptors or by affecting enzymes that enable the metabolism of these hormones. For example, BPA may affect ERP-mediated transcription of target genes by inhibiting ERP degradation and ubiquitination.
It should be noted that nuclear receptors ERa and ERP are functionally and genetically distinct, they differ in affinity, specificity, and have different spatial and temporal modes of expression. In this regard, cells of different types may respond differently to the same estrogenic stimuli depending on the ratio and expression of the two receptor subtypes in the cell, so that the "pathogenic" effect of BPA may be different in different tissue types. By mimicking natural sex hormones, BPA can disrupt endocrine regulation and cause various alterations in estrogen target organs, including the brain, ovary, thyroid, mammary gland, prostate, and others. Thus, the interaction of BPA with steroid hormone receptors may be responsible for hormone-related cancers of the ovary, breast, and prostate.
At present, the existence of additional membrane receptors for estrogens in the brain (similar to catecholaminergic receptors found in the pancreas) is thought to explain the mechanism of estrogen influence on cognitive functions, pain development, fine motor functions, emotional behavior, and neuroprotective effects in Parkinson's and Alzheimer's diseases, multiple sclerosis, depression, schizophrenia, and stroke. In this regard, the presence of BPA in the body may have its negative effects on these processes.
In addition, data are presented on the effect of BPA directly on the expression of genes - receptors of hormones, especially estrogen. For example, it has been shown in the culture of rat cerebellum and human neuroblastoma cells, as well as in human cell lines H295R (adrenal cortex, angiotensin-11-sensitive, steroid-producing line), HEK293 (embryonic kidney cells), HERO2 (liver carcinoma).
BPA is classified as an endocrine disruptor because it can interact with classical and non-classical membrane estrogen receptors. BPA can act on metabotropic receptors, which transmit chemical signals to O-protein coupled receptors (e.g., GPR30) and enzyme coupled receptors, leading to disruption of the regulatory pathways of androgens, glucocorticoids, thyroid hormone, prolactin, insulin, and the dopaminergic system. In addition, BPA adversely affects the body through "non-steroidal pathways" by affecting the activity of genes involved in cell and tissue differentiation.
BPA can induce functional effects not only through steroid hormone receptor activation, but also through the NF-kB, 8TAT3, P13K/AKT, and MARK signaling pathways. This xenobiotic may also affect sodium, potassium, calcium and chloride ion channels, ionotropic glutamate receptors, nicotinic and GABA receptors, thereby altering excitability and signaling in neurons. In addition, BPA exposure may increase the activity of oxidative stress markers and decrease the activity of antioxidant markers. In this regard, it has been suggested that, for example, in the neonatal period, BPA-induced hypothyroidism may affect the thyroid-brain axis through the formation of free radicals, which in turn may disrupt the plasma membrane and cellular components, leading to delays in brain development.
Since there is evidence that estrogen pathway proteins affect the epigenetic status of target genes (both at the level of DNA methylation and chromatin proteins) by altering the level of their transcriptional activity, it is reasonable to assume that BPA exposure has similar epigenetic mechanisms. To date, a limited number of studies have been published on the epigenetic consequences of BPA exposure on the developing organism. The data obtained confirm that this xenoestrogen can indeed induce changes in the DNA methylation status of expressed genes.

Epigenetic effects of bisphenol A and gene expression
The relationship between xenobiotic exposure and changes in the epigenome is being actively investigated. Three major epigenetic mechanisms are known to regulate gene activity that may be involved in the development of pathologies associated with CVRES exposure. These are DNA methylation and hydroxymethylation, various histone post-translational modifications (methylation, acetylation, phosphorylation, ubiquitinylation, sumoylation, and ADP-ribosylation of histones), and non-coding RNA. It should be emphasized that these epigenetic regulatory mechanisms do not operate in isolation but interact in a complex regulatory network. Different combinations of these modifications can significantly affect the state of chromatin and lead to both transcriptional silencing and increased transcriptional activity.
These covalent modifications do not cause classical genetic mutations, are highly labile, and are the most sensitive targets for both direct and indirect (metabolites) effects of ecotoxicants on the epigenome of living organisms, even at low doses. Disruptions in any of the above epigenetic regulatory mechanisms are associated with increased risk of disease, and abnormal epigenetic regulation that occurs in primary germ cells provides a mechanism for epigenetic inheritance of abnormal phenotypes over a number of generations, including inheritance of predisposition to a number of socially important diseases.
The first studies of epigenetic changes induced by xenobiotic exposure were conducted using a model of coat color change in agouti viable yellow (Avy) mice. It was shown that maternal diets with different levels of methyl group sources (e.g., folic acid) affected the level of methylation of the IAP retrotransposon upstream of the agouti gene, thereby affecting the level of gene transcription and leading to coat color changes in the offspring. A similar effect was observed when pregnant females were exposed to BPA. This ecotoxicant was found to reduce IAP methylation of the Avy and CapblAP genes (bringing the gene from an inactive to a pathologically active state). In addition, hypomethylation of the imprinted genes Igf2r, Peg3, and H19 was also observed in mice with elevated BPA levels, leading to increased mRNA levels of these proteins, which in turn suppressed oocyte maturation due to abnormal spindle assembly during meiosis. The authors concluded that BPA exposure during embryogenesis may alter cellular processes and developmental pathways through epigenetic mechanisms, thereby altering the phenotype of the offspring.
In laboratory mice, exposure to low doses of BPA during the preimplantation period can affect DNA methylation not only during fragmentation but also at later stages of embryonic development. Thus, BPA caused a dose-dependent decrease in DNA methylation in one- and two-cell embryos and in blastocysts, which was accompanied by an inhibition of fragmentation. In contrast, a slight increase in the level of whole-genome DNA methylation was observed in embryos at the 9th day of development, i.e., the period of early organogenesis. At the same time, both hypomethylation and hypermethylation of DNA were detected as early as day 12 of embryonic development, depending not only on the body part (tissue type) but also on the weight of the embryos. The data obtained confirm that preimplantation development is a highly sensitive period to BPA exposure. This is due to the active reprogramming processes associated primarily with the differential nature of changes in DNA methylation throughout the genome. Apparently, this process is likely to involve various repetitive DNA sequences that are also involved in the regulation of gene activity, chromosomal organization and nuclear architecture.
It appeared that BPA could reduce the level of genome-wide DNA methylation in conjunction with decreased expression of the DNA methyltransferase Dnmt1, which is thought to be due to impaired estrogenic mechanisms. In males, a decrease in the level of complete genomic methylation of LINE1 DNA sequences in semen was observed after BPA exposure, which was inversely related to the level of BPA in urine.
in urine, but this was not observed for LINE1 methylation in blood cells. All these data point to epigenetic changes mediated by DNA methylation as one of the possible mechanisms for the adverse effects of BPA on gametogenesis and fertility.
In addition, prenatal exposure to BPA caused disruptions in the expression of genes critical for brain development, including basic (helix-loop-helix) transcription factors, which may be due to epigenetic changes in CpG islands associated with the promoters of these genes. For example, exposure of developing cortical neurons in mice, rats, and humans to BPA decreased mRNA levels of the chloride potassium transporter 2 (Kss2) gene. This was probably due to increased binding activity of methyl-CpG-binding protein 2 (MECP2, MBD2) to the cytosine-phosphate-guanine shores of the Kss2 gene promoter and decreased interaction with acetylated histone H3K9 surrounding the transcription initiation site. Sex differences were observed: the effect of BPA was stronger in females than in males. Decreased expression of DNA methyltransferases and hypomethylation of genes related to lipid synthesis were also detected after BPA exposure in the cell lines Hepa1-6 (mouse hepatoma) and BeWo (trophoblasts, human choriocarcinoma).
BPA can not only cause DNA hypomethylation but also increase DNA methylation levels. Hypermethylated DNA was found in the tail tissue of the offspring of a mouse perinatally exposed to very low doses of BPA, i.e. the second-generation offspring. Experiments in laboratory animals have shown that this toxicant leads to the persistent expression of certain genes, including genes for lactoferrin, epidermal growth factor, proto-oncogenes (c-fos and c-jun), and inhibits the process of methylation.
It was found that exposure to BPA in the neonatal period causes hypermethylation of the promoter of the estrogen receptor gene in the testes of rats. Exposure of human mammary epithelial primary culture cells to low doses of BPA leads to increased methylation of CpG islets of DNA of the lysosomal-associated membrane protein 3 (LAMP3) gene and suppression of transcription of this gene, which suggests a role of BPA in increasing the risk of breast cancer development. The epigenetic mechanism of regulation of BPA effects in breast carcinogenesis is also indicated by data on increased expression of trimethylated histone H3 by lysine EZH2 after the action of this xenoestrogen. BPA can also increase the transcription level of the cytokine gene of the tumor necrosis factor family (TNFSF11, RANKL) and the gene family encoding secreted
signaling proteins (WNT-4), which are essential in embryogenesis, regulate proliferation, participate in mammary stem cell carcinogenesis, and play an important role in bone metabolism. It appears that BPA can increase the expression level of microRNA-146a, which is important in the immune response, so regulation of the epigenetic program and microRNAs may be one avenue for the study and possibly therapy of cancers associated with BPA exposure.
It has been shown that BPA exposure during pregnancy (in mice and rats) can induce sex-dependent, dose-dependent, and region-specific (by brain region) changes in the expression of genes encoding estrogen receptors (ERa, ERP, and ERRy) in the brains of first-generation offspring at puberty. In parallel with changes in estrogen-associated receptors, there were dose-dependent changes in the mRNA level of DNMT1 and DNMT3A DNA-methyltransferases genes in the juvenile cortex (in males) and hypothalamus (in females), as well as in the ERa gene methylation level.
In addition, such offspring (males) showed changes in glucocorticoid regulation, namely increased DNA methylation in the Fkbp5 gene and decreased levels of this protein in the hippocampus, which resulted in behavioral abnormalities and stress response in these animals. Exposure to BPA during the prenatal and neonatal periods also impairs the expression of methyl-CrO-binding protein 2 in hypothalamic cells, which may be responsible for abnormalities in normal hypothalamic development and function.
Thus, all of these data point to the interrelationship of two regulatory systems - epigenetic and receptor (hormonal) - and underscore the importance of research on the effects of BPA exposure on human and animal health. Obviously, methodological differences in the conduct of studies on the effects of BPA on living organisms (in vivo and in vitro studies, different study subjects, different routes of exposure and experimental doses of BPA, exposure to single compounds and mixtures) give rise to alternative hypotheses about the molecular mechanisms of action of this xenoestrogen. For example, mice and rats are different models for understanding the mechanisms of human disease. In addition, it should be noted that the same dose of BPA may or may not result in hypo- or hypermethylation of DNA, depending on subtle differences in the organism's response to exposure, developmental stage, cell differentiation and tissue type.
CONCLUSION
Data from epidemiologic studies indicate potentially deleterious chronic effects of BPA on human and animal ontogenesis, so it is necessary to limit as much as possible the penetration of BPA (even in low doses) into the body, especially during pregnancy, taking into account its possible long-term negative effects on health. We would like to emphasize that some individuals have a low risk of developing pathologies caused by exposure to harmful environmental factors, while others are much more susceptible to such influences. This is largely due to genetic features, although at the present stage the contribution of individual epigenomic differences cannot be ruled out. The results of many studies indicate that the molecular mechanisms of xenobiotic exposure extend far beyond the interaction with the DNA sequence. Clearly, more research and the development of new test systems are needed to assess the true dose-effect relationships and mechanisms of action of ecotoxicants in the development of the pathologies reported in this review. Studies of epigenomic/epigenetic modifications, especially DNA methylation, are needed to develop preventive measures for the negative effects of xenobiotics. Such studies should preferably be conducted at different levels of organization - from molecular (DNA, chromatin), cellular and tissue to the organism as a whole - in experimental models in vivo and in vitro, taking into account different susceptibility to adverse effects of BPA.
Another crucial aspect to be addressed is that epimutations resulting from BFAs during early embryogenesis may alter normal gene expression, which may be maintained in adults and transmitted through germ cells to the next generation, thereby leading to intergenerational inheritance of abnormal phenotypes. In addition, it cannot be overlooked that we are actually exposed to a mixture of pollutants and, as a consequence, additive and synergistic effects occur, including BPA with other common compounds. In conclusion, we would also like to emphasize that the approaches used in ecotoxicology, based only on DNA nucleotide sequence analysis, are currently insufficient to fully explain the risks of diseases, which may be modulated by non-genetic or extra-genetic mechanisms.


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