editorial genetic and epigenetic effects of environmental...

EditorialGenetic and Epigenetic Effects of EnvironmentalMutagens and Carcinogens

Alessandra Pulliero,1 Jia Cao,2 Luciana dos Reis Vasques,3 and Francesca Pacchierotti4

1Department of Health Sciences, University of Genoa, Via Antonio Pastore 1, 16132 Genoa, Italy2Toxicology Institute, Preventive Medical College, Third Military Medical University, Chongqing 400038, China3Department of Genetics and Evolutionary Biology, Institute of Bioscience, University of Sao Paulo, 05508-090 Sao Paulo, SP, Brazil4Laboratory of Toxicology UT-BIORAD, ENEA, CR Casaccia, Via Anguillarese 301, 00123 Rome, Italy

Correspondence should be addressed to Alessandra Pulliero; [email protected]

Received 21 June 2015; Accepted 22 June 2015

Copyright © 2015 Alessandra Pulliero et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Identifying the effects of environmental exposures on humanhealth is a major objective of life sciences and biomedi-cal research. In environmental health, the recognition thatexposures could produce DNAmutations represents a majorlandmark for risk assessment and prevention [1]. Conse-quently, chemical agents have been categorized according totheir ability to alter the DNA sequence. Such informationhas been fundamental to determine environmental risksand shape current regulatory efforts for exposure reduction.Recent evidences suggest that the molecular influence ofthe environment may extend beyond the interaction withthe DNA sequence [2]. Epigenetics is the study of heritablechanges in gene expression that occur without changes inDNA sequence [3]. This is particularly fascinating becauseepigenetics involves factors that cause chemical changes tooccur in our genomes. Epigenetic mechanisms, with particu-lar reference tomicroRNAalterations,DNAmethylation, andhistone modifications, can change genome function underexogenous influence. MicroRNAs are posttranscriptionalregulators of gene expression involved in carcinogenesis,metastasis, and invasion. Thus, microRNAs are potentiallyuseful as diagnostic and prognostic biomarkers as well asanticancer therapeutic targets. Many microRNAs undergoaltered expression as consequence of exposure to carcinogensand these changesmay be useful in cancer prevention [4].Therelationship between exposure to environmental carcinogensand epigenetics revealed that toxicants modify epigeneticstates. Accordingly, the alteration of microRNA expression

is a general mechanism playing an important pathogenicrole in linking exposure to environmental toxic agents withtheir pathological consequences. The underlying molecularmechanism involves both p53-microRNA interconnectionand alterations of Dicer function [5]. MicroRNAs have beenalso implicated in transgenerational epigenetic inheritancevia the gametes. Other epigenetic mechanisms, like DNAmethylation, are susceptible to environmental influence inboth somatic and germ cells modulating themechanisms andthe risk of chemically induced genetic and epigenetic effects.The present special issue provides a comprehensive overviewof the current status of this interesting field of research.It comprises manuscripts reporting novel data as well asstate-of-the-art reviews. We have composed a balanced issuecombining in vitro studies, as well as studies performed inhumans. The issue is started by a comprehensive review byM. Romani et al., describing the mechanisms of epigeneticcontrol and their role in disease development, the influenceof the environment, lifestyle, and nutritional habits influenceon epigenetic markers, and how these factors are relatedto the development of cancer and other noncommunicablediseases. Diet is a major exposure daily route to manytoxic substances including endocrine disruptors such asbisphenol A. The epigenome of mammalian female germcells and oocyte development is modified by low bisphenolA concentrations with functional consequences on geneexpression, chromosome dynamics in meiosis, and oocytedevelopment. These important aspects are described by U.

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015, Article ID 608054, 3 pageshttp://dx.doi.org/10.1155/2015/608054

2 BioMed Research International

Eichenlaub-Ritter and F. Pacchierotti underlying that thereare specific timewindows, during which profound chromatinremodeling occurs and maternal imprints are established orprotected that appear particularly vulnerable to epigeneticderegulation by bisphenol A. Indeed, the BPA exposurehas long lasting consequences on the female reproductivehealth, reducing fertility and potentially leading to offspringdefects. At the same time, certain components of the dietcan modify the epigenetic pattern through natural bioactivecomponents that can act on DNA methylation or histonemodification or, as in the case of exogenous miRNA that canbe direct epigenetic actors. Althoughmuch effort has focusedon the gene-environment axis, there is a growing bodyof information suggesting that environmental influencesextend beyond the DNA sequences of our genes. Epigeneticsincludes the study of the protein constituents of chromatin,the interaction of microRNAs with the genome, and theprotein andDNAmodifications that appear to define biologicstates in local regions of chromosomes. However, only morerecently the role of noncoding RNAs (ncRNAs) in epigeneticprocesses has been highlighted. This topic is discussed inP. Arrigo and A. Pulliero’s paper dealing with the effect ofenvironmental chemical stress on nuclear noncoding RNAinvolved in epigenetic control. This paper summarizes howa chemical mutagen can interfere with the conformationof specific regulatory domains in ncRNAs. The majority ofhuman cellular RNA consists of rRNA (∼90% of total RNA).The total number of RNA molecules is estimated to beabout 107 per cell, and ncRNAs include snRNA, snoRNA,and miRNA. The overexpression of lncRNAs can potentiallymeasure the cytotoxicity signals of various environmentalstresses [6]. Knowing the location of such ncRNAs could helpin selecting the best candidates for starting the ncRNA-basedgene therapy trials. For example, the fact that miRNA alteredexpression in cancer cells has a pathogenic effect provides therationale for usingmiRNAs as potential therapeutic targets incancer. It is interesting to note how the chemical entity couldinduce a slight change in the conformation that is criticalfor molecular recognition in the process of RNA editing.Environmental exposures to potentially aneugenic agents,including therapeutic exposures and exposures associatedwith lifestyle habits, influence the epigenetic alterations. InIndia, the health of approximately 62 million people is at riskdue to high concentration of fluoride in drinking water/diet.The paper of A. P. Daiwile et al. describes the expressionprofiling of short noncoding RNAs, in particular miRNAsand snoRNAs, carried out in sodium fluoride (NaF) treatedhuman osteosarcoma cells to understand their possible rolein the development of fluorosis. They found that epigeneticmodifications in miRNAs and C/D box snoRNAs that canregulate the key genes are involved in the development offluorosis, suggesting the possible involvement ofmiR-124 andmiR-155 in the development of fluorosis. The special issueis continued by three contributions describing mutationsand epigenetic events important in our understanding ofmolecularmechanisms associatedwith exposure-disease out-comes.The review byO. Torres-Bugarin et al. provides stronginformation that sustains the observation that increasedmicronuclei frequencies are observed in association with

the presence of any autoimmune disease condition. Theauthors propose that micronuclei could be used as an earlybiomarker of disease progression and/or response to therapy.The effect of toxicological agents on genes is an area thatwarrants further research as a major public health issue. Inparticular, pollution in Asia is a growing concern also inoccupational places. Consequently, human molecular epi-demiological studies have explored the association betweenpolymorphisms of DNA repair genes and chromosomaldamage by 1,3-butadiene in current exposure workers. Thepaper by M. Xiang et al. focuses on genetic polymorphismsof DNA repair genes and chromosomal damage. In theirpaper, they provide evidence for DNA repair genes (XRCC1,MGMT, APE1, and ADPRT) that modify the genetic instabil-ity induced by 1,3-butadiene, group 1 carcinogen, and widelyused as an industrial chemical and also present in autoe-mission. Newly developed biomarkers (MNi: micronuclei;NPBs: nucleoplasmic bridges; NBUDs: nuclear buds) in thecytokinesis-blocked micronucleus cytome assay were usedto detect chromosomal damage, showing that 1,3-butadieneexposed workers have increased frequencies of MNi andNPBs compared to control subjects. Actually, the effect oncell transformation ofmany environmental factors, which arereported in epidemiological studies to be associated with acertain risk for a given cancer type,might well bemediated byepimutations.Thepaper by S.A.Gross andK.M. Fedaknicelysummarizes the role of such epimutations applying a weightof evidence approach to evaluate molecular characteristicsfor environmental carcinogens as well as associated diseaseoutcomes. The authors consider the example of benzene asan environmental carcinogen and myelodysplastic syndromeas a causative disease endpoint. Using the weight of evi-dence method, they find overlapping polymorphisms in themetabolic enzymes GST and NQO1. Additional mutationsincluding RUNX1 and glycophorin A, epigenetic eventsassociated with DNMT3a, and polymorphism in interleukincytokines induce dysregulation of the hematopoietic sys-tem in benzene-exposed workers. The weight of evidenceapproach illustrated by S. A. Gross andK.M. Fedak is a usefultool for sorting, categorizing, and prioritizing themostmean-ingful information. Using such a framework, researchers candetermine ways to take advantage of best practices in iden-tifying exposure scenarios and defining biomarkers relevantto the exposure-disease paradigm. In addition, certain toxicmetals (i.e., cadmium, nickel, arsenic, and chromium) havebeen identified as persistent environmental pollutants due totheir indestructible chemical and physical properties. Whilethe ability of some metal compounds to cause cancer inexposed workers has been known for a long time, epigenetic-based research has recently shed light upon mechanismsinvolved in metal-induced carcinogenesis [7]. For example,recent research has shown that cadmium exposure stim-ulates cellular proliferation, increases oxidative stress andDNA damage, and induces global DNA hypomethylation[8]. C. Urani et al., in the experimental study, provide newinformation on the novel mechanisms for cadmium toxicityand biological effects and, along with those already reportedin the literature, open new intriguing interpretations oncadmium-induced carcinogenicity. The authors show that

BioMed Research International 3

HepG2 cells, exposed to 10 𝜇M cadmium for 24 hrs, increasemicroarray expression profiling of labile zinc after cadmiumexposure. In addition, the downregulation of miR-34a andmiR-200a, both implicated in the epithelial-mesenchymaltransition, supports the role played by zinc in affectinggene expression at the posttranscriptional level. Research onepimutations is also a rapidly growing area. These changesmay involve modification of DNA bases and histones, suchas methylation, ubiquitination, or acetylation.The regulationof transcription and genome stability by epigenetic systems iscrucial for the proper development of mammalian embryos.Y. Arai et al. confirm the hypothesis that combined exposureto chemicals (diethyl phosphate,mercury, cotinine, selenium,and octachlorodipropyl ether) detected at low concentrationsin maternal peripheral and cord blood samples affect embry-oid body formation and neural differentiation from humaninduced pluripotent stem cells (hiPSCs). C. E. Cross et al.add another detail reporting that short-term exposure ofvillous first trimester trophoblasts to low concentrations ofH2O2significantly alters miRNA profile and expression of

genes implicated in placental development. The last sectionof this special issue comprises two papers describing thefeatures of DNA methylation and the exposure to a varietyof chemical stressors, occurring during the prenatal or theadult life. The first paper by F. Pacchierotti and M. Spanoreviews the literature on the impact of chemicals and lifestylefactors onDNAmethylation in germ cells. Studies on rodentsshow that DNAmethylation can be altered by many differentkinds of exposures during the fetal as well as the adultlife. Still these studies suffer from some limitations: fewexperiments were conducted on the female germline; theanalyses were rarely extended to a genomewide scale; onlyin a few cases the functional impact of epigenetic changeswas investigated; dose-response relationships were scarcelyconsidered. Nevertheless, their results are very importantbecause they establish proof of principle demonstration thata variety of exogenous stressors may alter DNA methylationat developmentally important imprinted or metabolic genesand warrant future investigations on human mother-childcohorts and biomonitoring epigenetic analyses on semencollected from human exposed cohorts. In a final paper, Y.Liu et al. demonstrated for the first time that 50Hz ELF-EMFexposure can induce the alterations of genomewide methyla-tion and the expression of DNMTs in spermatocyte-derivedGC-2 cells. Indeed, the epigenetics plays an important role inthe biological effects of 50Hz ELF-EMF exposure.

Understanding the mechanistic basis of how epigeneticregulation is achieved is fundamental to placing this level ofbiologic regulation in the toolbox of environmental healthscience andmedicine. Based on these contributions, itmay bestated that the genetic and epigenetic effects of environmentalmutagens and carcinogens are subject of innovative research.

Acknowledgment

The authors of the papers included in this special issue haveprovided new inputs to establishing a synergistic interactionbetween environmental exposure and genetic predisposition

and epigenetic effects in the diseases risk, and we are gratefulto them for their contributions.

Alessandra PullieroJia Cao

Luciana dos Reis VasquesFrancesca Pacchierotti

References

[1] G. N. Wogan, “Molecular epidemiology in cancer risk assess-ment and prevention: recent progress and avenues for futureresearch,” Environmental Health Perspectives, vol. 98, pp. 167–178, 1992.

[2] R. L. Jirtle andM. K. Skinner, “Environmental epigenomics anddisease susceptibility,”Nature Reviews Genetics, vol. 8, no. 4, pp.253–262, 2007.

[3] A. P.Wolffe andM. A.Matzke, “Epigenetics: regulation throughrepression,” Science, vol. 286, no. 5439, pp. 481–486, 1999.

[4] A. Izzotti, “Molecular medicine and the development of cancerchemopreventive agents,” Annals of the New York Academy ofSciences, vol. 1259, no. 1, pp. 26–32, 2012.

[5] A. Izzotti and A. Pulliero, “The effects of environmental chem-ical carcinogens on the microRNA machinery,” InternationalJournal of Hygiene and Environmental Health, vol. 217, no. 6, pp.601–627, 2014.

[6] F. Doolittle, T. D. P. Brunet, S. Linquist, and T. R. Gregory,“Distinguishing between ‘Function’ and ‘Effect’ in genomebiology,” Genome Biology and Evolution, vol. 6, no. 5, pp. 1234–1237, 2014.

[7] J. E. Klaunig, L. M. Kamendulis, and Y. Xu, “Epigenetic mech-anisms of chemical carcinogenesis,” Human and ExperimentalToxicology, vol. 19, no. 10, pp. 543–555, 2000.

[8] D. Huang, Y. Zhang, Y. Qi, C. Chen, and W. Ji, “GlobalDNA hypomethylation, rather than reactive oxygen species(ROS), a potential facilitator of cadmium-stimulated K562 cellproliferation,” Toxicology Letters, vol. 179, no. 1, pp. 43–47, 2008.

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