An approach to the study of the immunity functions of bivalve haemocytes: Physiology and molecular aspects.

The Mediterranean mussel Mytilus galloprovincialis is an ecologically and economically important species. It has been used in programs of monitoring of pollution, since it is sessile organism that is capable of accumulating pollutants in tissues through filter feeding. Due to an increase of pollutants in the environment, marine mussels present physiological alterations that compromise their innate immune system, which can latter lead to opportunistic diseases. The haemocytes are the cells in charge of the immune response in the Mediterranean mussel and in other mollusks. In this review, we summarize the physiological and genetic response capacity of these immune cells to the presence of xenobiotics, pathogens and the interplay. The identification of the basic mechanisms of immunity and their modulation in mussels can give important information for the possible utilization of this species as an invertebrate model for studies on innate immunity, future immunotoxicological studies, and predict changes in the community for the future.

Estrogen regulation of gene expression in the teleost fish immune system.

Elucidating the mechanisms of estrogens-induced immunomodulation in teleost fish is of great importance due to the observed worldwide continuing decrease in pristine environments. However, little is know about the immunotoxicological consequences of exposure to these chemicals in fish, or of the mechanisms through which these effects are mediated. In this review, we summarize the results showing estrogens (natural or synthetic) acting through estrogen receptors and regulating specific target genes, also through microRNAs (miRNAs), leading to modulation of the immune functioning. The identification and characterization of miRNAs will provide new opportunities for functional genome research on teleost immune system and can also be useful when screening for novel molecule biomarkers for environmental pollution.

Impact of phthalates and bisphenols plasticizers on haemocyte immune function of aquatic invertebrates: A review on physiological, biochemical, and genomic aspects.

The invertebrate innate immunity is a crucial characteristic that represents a valuable basis for studying common biological responses to environmental pollutants. Cell defence mechanisms are key players in protecting the organism from infections and foreign materials. Many haemocyte-associated immunological parameters have been reported to be immunologically sensitive to aquatic toxins (natural or artificial). Environmental plastic pollution poses a global threat to ecosystems and human health due to plastic vast and extensive use as additives in various consumer products. In recent years, studies have been done to evaluate the effects of plasticizers on humans and the environment, and their transmission and presence in water, air, and indoor dust, and so forth. Hence, the development of biomarkers that evaluate biological responses to different pollutants are essential to obtain important information on plasticizers' sublethal effects. This review analyses the current advances in the adverse effects of plasticizers (as emerging contaminants), such as immunological response disruption. The review also shows a critical analysis of the effects of the most widely used plasticizers on haemocytes. The advantages of an integrative approach that uses chemical, genetic, and immunomarker assays to monitor toxicity are highlighted. All these factors are imperative to ponder when designing toxicity studies to recognize the potential effects of plasticizers like bisphenol A and phthalates.

Physiological and metabolic approach of plastic additive effects: Immune cells responses.

Human and wildlife are continually exposed to a wide range of compounds and substances, which reach the body through the air, water, food, or personal care products. Plasticizers are compounds added to plastics and can be released to the environment under certain conditions. Toxicological studies have concluded that plasticizers, phthalates, and bisphenols are endocrine disruptors, alter the endocrine system and functioning of the immune system and metabolic process. A functional immune response indicates favourable living conditions for an organism; conversely, a weak immune response could reveal a degraded environment that requires organisms to adapt. There is growing concern about the presence of plastic debris in the environment. In this review, the current knowledge of the action of plasticizers on leukocyte cells will be itemized. We also point out critically the role of some nuclear and membrane receptors as key players in the action of plasticizers on cells possess immune function. We discuss the role of erythrocytes within the immune responses and the alteration caused by plasticizers. Finally, we highlight data evidencing mitochondrial dysfunctions triggered by plasticizing toxic action, which can lead to immunosuppression.

1,1,1-trichloro-2,2-bis (p-chlorophenyl)-ethane (DDT) and 1,1-Dichloro-2,2-bis (p, p'-chlorophenyl) ethylene (DDE) as endocrine disruptors in human and wildlife: A possible implication of mitochondria.

1,1,1-trichloro-2,2-bis (p-chlorophenyl)-ethane (DDT) and its main metabolite 1,1-Dichloro-2,2-bis (p, p'-chlorophenyl) ethylene (DDE) act as endocrine disruptors in humans and wildlife. Immunomodulatory functions have also been attributed to both xenobiotics. DDT was banned in the 1970s due to its toxicity, but it is still produced and used for indoor residual spraying with disease vector control purposes. Due to their persistence and lipophilic properties, DDT and DDE can bioaccumulate through the food chain, being stored in organisms' adipose depots. Their endocrine disruptor function is mediated by agonist or antagonist interaction with nuclear receptors. Present review aimed to provide an overview of how DDT and DDE exposure impacts reproductive and immune systems with estrogen-disrupting action in humans and wildlife. Studies showing DDT and DDE impact on mitochondrial function and apoptosis pathway will also be reviewed, suggesting the hypothesis of direct action on mitochondrial steroid receptors.

Dose-Dependent Response to the Environmental Pollutant Dichlorodipheniletylhene (DDE) in HepG2 Cells: Focus on Cell Viability and Mitochondrial Fusion/Fission Proteins.

Dichlorodiphenyldichloroethylene (DDE), the primary persistent metabolite of dichlorodiphenyltrichloroethane (DDT), has toxic effects on cells, but its dose-dependent impact on mitochondrial proteins involved in mitochondrial fusion and fission processes associated with cell viability impairment has not yet been analysed. Mitochondrial fusion and fission processes are critical to maintaining the mitochondrial network and allowing the cell to respond to external stressors such as environmental pollutants. Fusion processes are associated with optimizing mitochondrial function, whereas fission processes are associated with removing damaged mitochondria. We assessed the effects of different DDE doses, ranging between 0.5 and 100 µM, on cell viability and mitochondrial fusion/fission proteins in an in vitro hepatic cell model (human hepatocarcinomatous cells, HepG2); the DDE induced a decrease in cell viability in a dose-dependent manner, and its effect was enhanced in conditions of coincubation with dietary fatty acids. Fusion protein markers exhibited an inverted U-shape dose-response curve, showing the highest content in the 2.5-25 µM DDE dose range. The fission protein marker was found to increase significantly, leading to an increased fission/fusion ratio with high DDE doses. The low DDE doses elicited cell adaption by stimulating mitochondrial dynamics machinery, whereas high DDE doses induced cell viability loss associated with mitochondrial dynamics to shift toward fission. Present results are helpful to clarify the mechanisms underlying the cell fate towards survival or death in response to increasing doses of environmental pollutants.

Guanine Content of MicroRNAs is Associated with their Tumor- Suppressive and Oncogenic Roles in Lung and Breast Cancers.

BACKGROUND: microRNAs (miRNAs, miRs) are small noncoding RNAs that negatively regulate gene expression at the post-transcriptional level and fine-tune gene functions. Global repression of miRNAs expression in different types of human tumors, after exposure to cigarette smoke, or to the hormone estrogen, have been shown to be associated with guanine (G) enrichment in the terminal Loops (TLs) of their precursors. METHODS: We integrated the G content of miRNA mature forms and precursor miRNA TLs with their described function in the literature, using the PubMed database. Gene Ontology term analysis was used to describe the pathways in which the G-enriched miRNA targets are involved. RESULTS: Herein, we show an association between the relative G enrichment of precursor miRNAs' TLs and their tendency to act as tumor suppressor miRs in human lung and breast cancers. Another association was observed between the high G content of the miRNAs 5-mature forms and their tendency to act as oncomiRs. CONCLUSION: The results support previous findings showing that the G sequence content is an important feature determining miRNA expression and function, and opens the way for future cancer investigations in this direction.

Multidisciplinary haematology as prognostic device in environmental and xenobiotic stress-induced response in fish.

The variations of haematological parameters hematocrit, hemoglobin concentration, leukocyte and erythrocyte count have been used as pollution and physiological indicators of organic dysfunction in both environmental and aquaculture studies. These parameters are commonly applied as prognostic and diagnostic tools in fish health status. However, there are both extrinsic and intrinsic factors to consider when performing a blood test, because a major limitation for field researchers is that the "rules" for animal or human haematology do not always apply to wildlife. The main objective of this review is to show how some environmental and xenobiotic factors are capable to modulating the haematic cells. Visualizing the strengths and limitations of a haematological analysis in the health assessment of wild and culture fish. Finally, we point out the importance of the use of mitochondrial activities as part of haematological evaluations associated to environment or aquaculture stress.

microRNAs Downregulation in Cancer is Associated with Guanine Enrichment in the Terminal Loop Sequences of their Precursors.

BACKGROUND: microRNAs (miRNAs) are small noncoding segments of RNA that negatively regulate gene expression at the post-transcriptional level and fine-tune gene functions. A global repression in miRNA expression is a phenomenon observed in different types of cancer. In this study we aimed to reveal a possible association of miRNAs downregulation in cancer, with the guanine (G) content in the terminal loop (TL) sequences of their precursors. METHODS: Lists of most significantly downregulated miRNAs in different tumor types, obtained from previously published microarray experiments, were selected for bioinformatics analysis. The complete precursor, TL, and mature miRNA sequences, were analyzed for evaluation of nucleotide composition and motif enrichment. RESULTS: Herein, we show an association of miRNAs downregulation in cancer, with G enrichment in the TL sequences of their precursors. High G (and GG) content was mostly found in repressed miRNAs of breast, lung and ovary cancers, predominantly in poorly differentiated tumors. The mature sequences of repressed miRNAs had significantly low G content and were enriched with an ACA motif. CONCLUSION: This study suggests a new link between G enrichment of precursor miRNAs TLs and carcinogenesis, and the possible association of specific sequence motifs with the regulation of their expression.

A potential microRNA regulation of immune-related genes in invertebrate haemocytes.

Bivalve mollusks have been employed as sentinel organisms in environmental health programs due to their sedentary lifestyle, filter-feeding behavior and their ability to accumulate pathogens or toxin molecules inside tissues. Endocrine disrupting chemicals (EDCs) can be up taken and bioaccumulated, and due to sensibility of mollusks to these EDCs, being able to cause immune alterations. Recently, microRNAs (miRNAs) were shown to be involved in modulation and buffering developmental processes against the effects of environmental alterations and pathogenic microorganisms. Moreover, it is suggested that this miRNAs are incorporated into the estrogen-controlled immune network, regulating mechanism of immune gene expression at the posttranscriptional level, modulating immune responses as phagocytosis, redox reaction and apoptosis in bivalve haemocytes. Thus, miRNAs can be used as biomarkers that specifically elucidate immunotoxic effects caused by exogenous biotic or abiotic factors, and can act as useful tools in integrated monitoring environmental health programs. In this review, we aim to describe the investigations that have been carried out on miRNAs in bivalve mollusks, especially those associated with immune responses against infectious agents and xenobiotic exposure.

Modulation of mitochondrial functions by xenobiotic-induced microRNA: From environmental sentinel organisms to mammals.

Mitochondria play a crucial role in energetic metabolism, signaling pathways, and overall cell viability. They are in the first line in facing cellular energy requirements in stress conditions, such as in response to xenobiotic exposure. Recently, a novel regulatory key role of microRNAs (miRNAs) in important signaling pathways in mitochondria has been proposed. Consequently, alteration in miRNAs expression by xenobiotics could outcome into mitochondrial dysfunction, reactive oxygen species overexpression, and liberation of apoptosis or necrosis activating proteins. The aim of this review is to show the highlights about mitochondria-associated miRNAs in cellular processes exposed to xenobiotic stress in different cell types involved in detoxification processes or sensitive to environmental hazards in marine sentinel organisms and mammals.

Omega-3 Fatty Acids and Insulin Resistance: Focus on the Regulation of Mitochondria and Endoplasmic Reticulum Stress.

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been suggested to play a key role in insulin resistance development. Reactive oxygen species (ROS) production and lipid accumulation due to mitochondrial dysfunction seemed to be important mechanisms leading to cellular insulin resistance. Moreover, mitochondria are functionally and structurally linked to ER, which undergoes stress in conditions of chronic overnutrition, activating the unfolded protein response, which in turn activates the principal inflammatory pathways that impair insulin action. Among the nutrients, dietary fats are believed to play key roles in insulin resistance onset. However, not all dietary fats exert the same effects on cellular energy metabolism. Dietary omega 3 polyunsaturated fatty acids (PUFA) have been suggested to counteract insulin resistance development by modulating mitochondrial bioenergetics and ER stress. In the current review, we summarized current knowledge on the role played by mitochondrial and ER stress in inflammation and insulin resistance onset, focusing on the modulation role of omega 3 PUFA on these stress pathways. Understanding the mechanisms by which omega 3 PUFA modulates cellular metabolism and insulin resistance in peripheral tissues may provide additional details on the potential impact of omega 3 PUFA on metabolic function and the management of insulin resistance in humans.

Environmental Pollutants Effect on Brown Adipose Tissue.

Brown adipose tissue (BAT) with its thermogenic function due to the presence of the mitochondrial uncoupling protein 1 (UCP1), has been positively associated with improved resistance to obesity and metabolic diseases. During recent years, the potential influence of environmental pollutants on energetic homoeostasis and obesity development has drawn increased attention. The purpose of this review is to discuss how regulation of BAT function could be involved in the environmental pollutant effect on body energy metabolism. We mainly focused in reviewing studies on animal models, which provide a better insight into the cellular mechanisms involved in this effect on body energy metabolism. The current literature supports the hypothesis that some environmental pollutants, acting as endocrine disruptors (EDCs), such as dichlorodiphenyltrichoroethane (DDT) and its metabolite dichlorodiphenylethylene (DDE) as well as some, traffic pollutants, are associated with increased obesity risk, whereas some other chemicals, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), had a reverse association with obesity. Noteworthy, the EDCs associated with obesity and metabolic disorders impaired BAT mass and function. Perinatal exposure to DDT impaired BAT thermogenesis and substrate utilization, increasing susceptibility to metabolic syndrome. Ambient particulate air pollutions induced insulin resistance associated with BAT mitochondrial dysfunction. On the other hand, the environmental pollutants (PFOS/PFOA) elicited a reduction in body weight and adipose mass associated with upregulation of UCP1 and increased oxidative capacity in brown-fat mitochondria. Further research is needed to better understand the physiological role of BAT in response to exposure to both obesogenic and anti-obesogenic pollutants and to confirm the same role in humans.

Estrogen Repression of MicroRNAs Is Associated with High Guanine Content in the Terminal Loop Sequences of Their Precursors.

Widespread microRNA (miRNA) repression is a phenomenon observed in mammals after exposure to cigarette smoke and in many types of cancer. A comprehensive reduction in miRNA expression after treatment with the hormone estrogen has also previously been described. Here, we reveal a conserved association of miRNA downregulation after estrogen exposure in zebrafish, mouse, and human breast cancer cell line, with a high guanine content in the terminal loop sequences of their precursors, and offer a possible link between estrogen-related miRNA-adducts formation and carcinogenesis. We also show common gene expression patterns shared by breast cancer tumors and estrogen-treated zebrafish, suggesting that this organism can be used as a powerful model system for the study of human breast cancer.

A potential role for estrogen in cigarette smoke-induced microRNA alterations and lung cancer.

Alteration in the expression of microRNAs (miRNAs) is associated with oncogenesis and cancer progression. In this review we aim to suggest that elevated levels of estrogens and their metabolites inside the lungs as a result of cigarette smoke exposure can cause widespread repression of miRNA and contribute to lung tumor development. Anti-estrogenic compounds, such as the components of cruciferous vegetables, can attenuate this effect and potentially reduce the risk of lung cancer (LC) among smokers.

Estrogen repression of microRNA as a potential cause of cancer.

MicroRNAs (miRNAs) are endogenous small molecules that regulate gene expression and have been implicated in the pathogenesis of many human diseases, including cancer. This review describes the results that show a global repression in miRNA expression in various tumors and cancer cell lines. Intriguingly, recent discoveries have shown a widespread downregulation of miRNA after exposure to the steroid hormone estrogen. The integration of the results suggests that estrogen-dependent repression of miRNA is a potential cause of cancer.