Epigenetic modifications and human pathologies: cancer and CVD

2010 ◽  
Vol 70 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Susan J. Duthie
Keyword(s):  
Dna Methylation ◽  
Human Cancer ◽  
Dna Methyltransferases ◽  
Water Soluble ◽  
Leafy Vegetables ◽  
Dna Hypomethylation ◽  
Human Diet ◽  
Human Colon Cancer ◽  
Increased Risk ◽  
Risk Of Cancer

Epigenetic changes are inherited alterations in DNA that affect gene expression and function without altering the DNA sequence. DNA methylation is one epigenetic process implicated in human disease that is influenced by diet. DNA methylation involves addition of a 1-C moiety to cytosine groups in DNA. Methylated genes are not transcribed or are transcribed at a reduced rate. Global under-methylation (hypomethylation) and site-specific over-methylation (hypermethylation) are common features of human tumours. DNA hypomethylation, leading to increased expression of specific proto-oncogenes (e.g. genes involved in proliferation or metastasis) can increase the risk of cancer as can hypermethylation and reduced expression of tumour suppressor (TS) genes (e.g. DNA repair genes). DNA methyltransferases (DNMT), together with the methyl donor S-adenosylmethionine (SAM), facilitate DNA methylation. Abnormal DNA methylation is implicated not only in the development of human cancer but also in CVD. Polyphenols, a group of phytochemicals consumed in significant amounts in the human diet, effect risk of cancer. Flavonoids from tea, soft fruits and soya are potent inhibitors of DNMT in vitro, capable of reversing hypermethylation and reactivating TS genes. Folates, a group of water-soluble B vitamins found in high concentration in green leafy vegetables, regulate DNA methylation through their ability to generate SAM. People who habitually consume the lowest level of folate or with the lowest blood folate concentrations have a significantly increased risk of developing several cancers and CVD. This review describes how flavonoids and folates in the human diet alter DNA methylation and may modify the risk of human colon cancer and CVD.

scholarly journals Early Pregnancy Exposure to Ambient Air Pollution among Late-Onset Preeclamptic Cases Is Associated with Placental DNA Hypomethylation of Specific Genes and Slower Placental Maturation

Toxics ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 338
Author(s):  
Karin Engström ◽  
Yumjirmaa Mandakh ◽  
Lana Garmire ◽  
Zahra Masoumi ◽  
Christina Isaxon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Air Pollution ◽  
Early Pregnancy ◽  
Late Onset ◽  
Dispersion Model ◽  
Ambient Air ◽  
Ambient Air Pollution ◽  
Dna Hypomethylation ◽  
Increased Risk

Exposure to ambient air pollution during pregnancy has been associated with an increased risk of preeclampsia (PE). Some suggested mechanisms behind this association are changes in placental DNA methylation and gene expression. The objective of this study was to identify how early pregnancy exposure to ambient nitrogen oxides (NOx) among PE cases and normotensive controls influence DNA methylation (EPIC array) and gene expression (RNA-seq). The study included placentas from 111 women (29 PE cases/82 controls) in Scania, Sweden. First-trimester NOx exposure was assessed at the participants’ residence using a dispersion model and categorized via median split into high or low NOx. Placental gestational epigenetic age was derived from the DNA methylation data. We identified six differentially methylated positions (DMPs, q < 0.05) comparing controls with low NOx vs. cases with high NOx and 14 DMPs comparing cases and controls with high NOx. Placentas with female fetuses showed more DMPs (N = 309) than male-derived placentas (N = 1). Placentas from PE cases with high NOx demonstrated gestational age deceleration compared to controls with low NOx (p = 0.034). No differentially expressed genes (DEGs, q < 0.05) were found. In conclusion, early pregnancy exposure to NOx affected placental DNA methylation in PE, resulting in placental immaturity and showing sexual dimorphism.

scholarly journals Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 764 ◽  
Author(s):  
Wa Zhang ◽  
David Klinkebiel ◽  
Carter J. Barger ◽  
Sanjit Pandey ◽  
Chittibabu Guda ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Genomic Instability ◽  
Human Cancer ◽  
Disease Free Survival ◽  
Gene Expression Signature ◽  
Dna Methyltransferases ◽  
Dna Demethylation ◽  
Dna Hypomethylation ◽  
Proliferation Markers

A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been investigated in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO (+) EOC tumors displayed a proliferative gene expression signature, including FOXM1 and CCNE1 overexpression. Furthermore, DNA hypomethylation in these tumors was enriched within genomic blocks (hypomethylated blocks) that overlapped late-replicating regions, lamina-associated domains, PRC2 binding sites, and the H3K27me3 histone mark. Increased proliferation coupled with hypomethylated blocks at late-replicating regions suggests a passive hypomethylation mechanism. This hypothesis was further supported by our observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO (+) EOC after normalization to canonical proliferation markers, including MKI67. Finally, GDHO (+) EOC tumors had elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at the DNA hypomethylated blocks. Together, these findings implicate a passive DNA demethylation mechanism in ovarian cancer that is associated with genomic instability and poor prognosis.

scholarly journals CHK Methylation Is Elevated in Colon Cancer Cells and Contributes to the Oncogenic Properties

2021 ◽  
Vol 9 ◽  
Author(s):  
Shudong Zhu ◽  
Yan Zhu ◽  
Qiuwen Wang ◽  
Yi Zhang ◽  
Xialing Guo
Keyword(s):  
Dna Methylation ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Human Colon ◽  
Dna Methyltransferases ◽  
Colon Cancer Cells ◽  
Normal Colon ◽  
Human Colon Cancer ◽  
Colon Cells ◽  
Matrigel Invasion

Src is an important oncogene that plays key roles in multiple signal transduction pathways. Csk-homologous kinase (CHK) is a kinase whose molecular roles are largely uncharacterized. We previously reported expression of CHK in normal human colon cells, and decreased levels of CHK protein in colon cancer cells leads to the activation of Src (Zhu et al., 2008). However, how CHK protein expression is downregulated in colon cancer cells has been unknown. We report herein that CHK mRNA was decreased in colon cancer cells as compared to normal colon cells, and similarly in human tissues of normal colon and colon cancer. Increased levels of DNA methylation at promotor CpG islands of CHK gene were observed in colon cancer cells and human colon cancer tissues as compared to their normal healthy counterparts. Increased levels of DNA methyltransferases (DNMTs) were also observed in colon cancer cells and tissues. DNA methylation and decreased expression of CHK mRNA were inhibited by DNMT inhibitor 5-Aza-CdR. Cell proliferation, colony growth, wound healing, and Matrigel invasion were all decreased in the presence of 5-Aza-CdR. These results suggest that increased levels of DNA methylation, possibly induced by enhanced levels of DNMT, leads to decreased expression of CHK mRNA and CHK protein, promoting increased oncogenic properties in colon cancer cells.

Repetitive DNA Hypomethylation in Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2703-2703
Author(s):  
Sonia Fabris ◽  
Valentina Bollati ◽  
Laura Mosca ◽  
Valeria Pegoraro ◽  
Domenica Ronchetti ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Human Cancer ◽  
Wide Spectrum ◽  
Rank Correlation ◽  
Global Dna Methylation ◽  
Dna Hypomethylation ◽  
Alu Elements

Abstract Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells characterized by a wide spectrum of genetic and epigenetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear elements-1 (LINE-1) and Alu repetitive elements (approximately 500.000 and 1.4 million in the human genome) has been associated with chromosomal instability. Additionally, satellite alfa DNA (SAT-alpha DNA) hypomethylation has been reported to be associated to karyotypic instability in human cancer, possibly playing a role in centromere function. So far, the LINE-1/Alu and centromeric SAT-alpha DNA methylation patterns have not been investigated in the context of the different clinical and molecular MM subtypes. Global DNA methylation changes were investigated in a panel of 53 newly diagnosed, untreated MMs, 7 plasma cell leukemias (PCL) and 11 healthy subjects as controls. DNA was extracted from purified plasma cells, treated with bisulfite and analyzed by bisulfite-PCR and Pyrosequencing. Methylation of LINE-1 and Alu elements was shown to correlate with total 5mC content and thus used to estimate global DNA methylation. MMs showed a decrease of Alu (21.1%) and LINE-1 (70.0%) methylation average levels compared with controls (25.2% and 79.5% respectively). Lower median methylation levels were also found in centromeric SAT-alpha DNA of MMs (77.95%) compared to controls (89.5%). The median methylation level of PCLs was lower than MMs (16.7% versus 21.1% for Alu; 45.5% versus 70.0% for LINE-1; and 33.3% versus 77.9% for SATalpha DNA). Notably, a statistically significant association between SAT-alpha DNA and LINE-1 methylation (Spearman’s rank correlation, ρ = 0.94; P &lt; 0.001) was found in MM. The comparison between methylation pattern and different molecular MM subgroups by means of non parametric tests, revealed that LINE-1 and SAT-alpha DNA methylation was significantly lower in the nonhyperdiploid versus hyperdiploid (HD) tumors (P = 0.01 and 0.02 respectively). Alu and SAT-alpha were significantly lower in the MMs with t(4;14) (P = 0.02 and 0.004 respectively). Finally, in the context of translocation/cyclin D (TC) classification, a statistically significant differences inside the five different groups were found for SAT-alpha DNA methylation (P = 0.008, Kruskal-Wallis test). These findings may provide insights into the molecular mechanisms of MM pathogenesis and suggest that our approach may contribute toward a more exhaustive stratification of the disease.

scholarly journals MTHFR C677T and A1298C Polymorphisms in Breast Cancer, Gliomas and Gastric Cancer: A Review

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 587
Author(s):  
Igor Petrone ◽  
Paula Sabbo Bernardo ◽  
Everton Cruz dos Santos ◽  
Eliana Abdelhay
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Dna Methylation ◽  
Mthfr C677t ◽  
Water Soluble ◽  
Mthfr Polymorphisms ◽  
Methyl Donor ◽  
Vitamin B9 ◽  
Increased Risk ◽  
The Impact

Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes. Dietary folate is converted into tetrahydrofolate, a vital methyl donor for most methylation reactions, including DNA methylation. 5,10-methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which produces a methyl donor for the remethylation of homocysteine to methionine. MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis. MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer. Breast cancer, gliomas and gastric cancer are highly heterogeneous and aggressive diseases associated with high mortality rates. The impact of MTHFR polymorphisms on these tumors remains controversial in the literature. This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer. Additionally, we highlight the relevance of ethnic and dietary aspects of population-based studies and histological stratification of highly heterogeneous tumors. Finally, this review discusses these aspects as potential factors responsible for the controversial literature concerning MTHFR polymorphisms.

scholarly journals Multifaceted Roles of DNA Methylation in Neoplastic Transformation, from Tumor Suppressors to EMT and Metastasis

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 922 ◽  
Author(s):  
Laura Casalino ◽  
Pasquale Verde
Keyword(s):  
Dna Methylation ◽  
Cancer Cell ◽  
Tumor Suppressors ◽  
Epigenetic Modification ◽  
Dna Methyltransferases ◽  
Potential Contribution ◽  
Epigenetic Changes ◽  
Dna Hypomethylation ◽  
Mesenchymal Transition

Among the major mechanisms involved in tumorigenesis, DNA methylation is an important epigenetic modification impacting both genomic stability and gene expression. Methylation of promoter-proximal CpG islands (CGIs) and transcriptional silencing of tumor suppressors represent the best characterized epigenetic changes in neoplastic cells. The global cancer-associated effects of DNA hypomethylation influence chromatin architecture and reactivation of repetitive elements. Moreover, recent analyses of cancer cell methylomes highlight the role of the DNA hypomethylation of super-enhancer regions critically controlling the expression of key oncogenic players. We will first summarize some basic aspects of DNA methylation in tumorigenesis, along with the role of dysregulated DNA methyltransferases and TET (Ten-Eleven Translocation)-family methylcytosine dioxygenases. We will then examine the potential contribution of epimutations to causality and heritability of cancer. By reviewing some representative genes subjected to hypermethylation-mediated silencing, we will survey their oncosuppressor functions and roles as biomarkers in various types of cancer. Epithelial-to-mesenchymal transition (EMT) and the gain of stem-like properties are critically involved in cancer cell dissemination, metastasis, and therapeutic resistance. However, the driver vs passenger roles of epigenetic changes, such as DNA methylation in EMT, are still poorly understood. Therefore, we will focus our attention on several aspects of DNA methylation in control of EMT and metastasis suppressors, including both protein-coding and noncoding genes.

scholarly journals SDC mediates DNA methylation-controlled clock pace by interacting with ZTL in Arabidopsis

2021 ◽  
Vol 49 (7) ◽  
pp. 3764-3780
Author(s):  
Wenwen Tian ◽  
Ruyi Wang ◽  
Cunpei Bo ◽  
Yingjun Yu ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Dna Methyltransferases ◽  
Feedback Loops ◽  
Circadian Clocks ◽  
Fine Tuning ◽  
Dna Hypomethylation ◽  
Proteolytic Cascade ◽  
Molecular Bases

Abstract Molecular bases of eukaryotic circadian clocks mainly rely on transcriptional-translational feedback loops (TTFLs), while epigenetic codes also play critical roles in fine-tuning circadian rhythms. However, unlike histone modification codes that play extensive and well-known roles in the regulation of circadian clocks, whether DNA methylation (5mC) can affect the circadian clock, and the associated underlying molecular mechanisms, remains largely unexplored in many organisms. Here we demonstrate that global genome DNA hypomethylation can significantly lengthen the circadian period of Arabidopsis. Transcriptomic and genetic evidence demonstrate that SUPPRESSOR OF drm1 drm2 cmt3 (SDC), encoding an F-box containing protein, is required for the DNA hypomethylation-tuned circadian clock. Moreover, SDC can physically interact with another F-box containing protein ZEITLUPE (ZTL) to diminish its accumulation. Genetic analysis further revealed that ZTL and its substrate TIMING OF CAB EXPRESSION 1 (TOC1) likely act downstream of DNA methyltransferases to control circadian rhythm. Together, our findings support the notion that DNA methylation is important to maintain proper circadian pace in Arabidopsis, and further established that SDC links DNA hypomethylation with a proteolytic cascade to assist in tuning the circadian clock.

scholarly journals Promotor Hypomethylation Mediated Upregulation of miR-23b-3p Targets PTEN to Promote Bronchial Epithelial-Mesenchymal Transition in Chronic Asthma

2022 ◽  
Vol 12 ◽  
Author(s):  
Yimin Guo ◽  
Xiaoqing Yuan ◽  
Luna Hong ◽  
Qiujie Wang ◽  
Shanying Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Epithelial Mesenchymal Transition ◽  
Airway Remodeling ◽  
Dna Methyltransferases ◽  
Chronic Asthma ◽  
Dna Hypomethylation ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Specific Pcr

Chronic asthma is characterized by airway inflammation and irreversible airway remodeling. Epithelial-mesenchymal transition (EMT) is a typical pathological change of airway remodeling. Our previous research demonstrated miR-23b inhibited airway smooth muscle proliferation while the function of miR-23b-3p has not been reported yet. Besides, miRNA is regulated by many factors, including DNA methylation. The function of miR-23b-3p and whether it is regulated by DNA methylation are worth exploring. Balb/c mice were given OVA sensitization to develop the asthmatic model. Expression of miR-23b-3p and EMT markers were measured by RT-qPCR, WB and immunohistochemistry (IHC). DNA methylation was detected by methylation-specific PCR (MSP) and the MassARRAY System. Asthmatic mice and TGF-β1-stimulated bronchial epithelial cells (BEAS-2B) showed EMT with increased miR-23b-3p. Overexpression of miR-23b-3p promoted EMT and migration, while inhibition of miR-23b-3p reversed these transitions. DNA methyltransferases were decreased in asthmatic mice. MSP and MassARRAY System detected the promotor of miR-23b showed DNA hypomethylation. DNA methyltransferase inhibitor 5’-AZA-CdZ increased the expression of miR-23b-3p. Meanwhile, PTEN was identified as a target gene of miR-23b-3p. Our results indicated that promotor hypomethylation mediated upregulation of miR-23b-3p targets PTEN to promote EMT in chronic asthma. miR-23b-3p and DNA methylation might be potential therapeutic targets for irreversible airway remodeling.

The revival of DNA methylation

2000 ◽  
Vol 113 (22) ◽  
pp. 3887-3888
Author(s):  
B. Malfoy
Keyword(s):  
Dna Methylation ◽  
Cpg Island ◽  
Current Knowledge ◽  
Human Cancer ◽  
Cpg Islands ◽  
Regulation Of Gene Expression ◽  
Dna Methyltransferases ◽  
Immune Recognition ◽  
Age Related

Current Topics in Microbiology and Immunology. Vol. 249: DNA Methylation and Cancer edited by P. A. Jones and P. K. Vogt Springer-Verlag (2000) pp. 170. ISBN 3–540-66608-7 75.50/$129.00 After a long period of relative confidentiality, the DNA methylation field has become a major research domain over the last few years. In this context, the importance of DNA methylation in human cancer has only become apparent over the last 5 to10 years. This small book (9 articles) provides a comprehensive overview of the main data and, more interestingly, presents the new concepts emerging from the recent extensive work, essentially performed over 2–3 years. The article written by B. Hendrich and A. Bird gives an overview of our current knowledge about the proteins implicated in DNA methylation, including DNA-methyltransferases and methylated-DNA-binding-proteins. It should be noted that the discovery of several of these proteins is a direct consequence of the human genome sequencing program, since they were first found ‘in silico’ by searching the databases. The specific properties of each of these partners of DNA methylation are beginning to be identified. Their implication in the regulation of histone acetylation suggests some possible mechanisms for regulation of gene expression. These models take into account, in particular, the remodeling of the chromatin structure. The value of mouse models in the understanding of the role of these proteins is discussed by P. W. Laird in another article. The present limitations of these approaches, essentially due to the non-viability of homozygous mutant mice for the main DNA-methyltransferase (Dnmt1) could be passed in the near future by the generation of conditional knockouts. Three articles by J. G. Herman and S. B. Baylin, M. F. Chan, G. Liang and P. A. Jones and J. P. Issa focus on the role of CpG island methylation in cancer and aging. These small stretches of DNA are frequently located around the transcription-start sites of approximately half of all human genes. For virtually all of these genes, with the exception of genes of the inactive X chromosome and some imprinted genes, these regions are maintained free of methylation in normal cells regardless of whether these genes are transcribed. It has been recognized that the CpG islands of a growing number of genes, either known to be involved in carcinogenesis (p16, E-cadherin, hMLH1,.) or candidate tumor supressor genes (p15, GST-Π,.) are methylated in many types of human cancer. The implication of the hypermethylation of CpG islands in tumor progression is discussed in its various aspects. In particular, the article by Chan et al. highlights the necessity to not oversimplify the relationships between methylation/inactivation and demethylation/activation. Moreover, extending his work on cancer, J. P. Issa shows that specific genes are affected by age-related methylation (EGFR, ER,.) and that such hypermethylation has disastrous consequences for the integrity of aged tissues. The article of A. P. Feinberg covers another area in this field and discusses the role of DNA methylation in imprinting and proposes a model for a role for the of loss of imprinting in cancer. Two articles investigate the action of tumor causing agents: the exogenous carcinogens and the Epstein-Barr virus (EBV). G. P. Pfeifer, M. S. Tang and M. F. Denissenko present the now well known effect of the deamination of methylcytosine on the formation of mutations. However, they insist on the finding that cytosine methylation can increase the rates of mutation by enhancing the binding of chemical carcinogens to DNA. This mechanisms is likely to have important implications for both chemical and ultra violet light induced carcinogenesis. K. D. Robertson summarize his work on the consequences of the inactivation of EBV genes on the virus' life cycle. The use of demethylating agents, like azacytidine, for reactivation of Cp-derived antigens, which could result in specific immune recognition of the tumor, is an interesting idea; however, as analyzed by M. (ABSTRACT TRUNCATED)

A Comprehensive, Integrated Review and Evaluation of the Scientific Evidence Relating to the Safety of the Herbicide 2,4-D

1992 ◽  
Vol 11 (5) ◽  
pp. 559-664 ◽  
Author(s):  
Ian C. Munro ◽  
George L. Carlo ◽  
Joan C. Orr ◽  
Kelly G. Sund ◽  
Ross M. Wilson ◽  
...  
Keyword(s):  
Human Cancer ◽  
Scientific Evidence ◽  
Critical Evaluation ◽  
Reproductive Toxicity ◽  
Large Body ◽  
Epidemiological Studies ◽  
Forestry Workers ◽  
Increased Risk ◽  
User Groups ◽  
Risk Of Cancer

The safety of 2,4-D to farm and forestry workers, commercial applicators and the general public has been of continuing concern because certain epidemiological studies of groups potentially exposed to 2,4-D have suggested a relationship between 2,4-D use and increased risk of soft tissue sarcoma, Hodgkin's disease or non-Hodgkin's lymphoma. This review on 2,4-D is unique in that the approach taken was to integrate data from worker exposure studies, whole animals, metabolic and other relevant laboratory studies with the epidemiological findings to assess the extent to which there is scientific support for the hypothesis that 2,4-D exposure is associated with any increased risk of human cancer. The case-control epidemiological studies that have been the source of the cancer risk hypothesis are inconclusive. Problems in assessing exposure based on patients' memories make these studies difficult to interpret. Cohort studies of exposed workers do not generally support the specific hypothesis that 2,4-D causes cancer. Taken together, the epidemiological studies provide, at best, only weak evidence of an association between 2,4-D and the risk of cancer. Importantly, the cancer hypothesis is not supported by other data. A critical evaluation of the exposure data indicates that exposure to 2,4-D in user groups is intermittent and much lower than the doses tested chronically in long-term animal studies that have not shown evidence of tumor induction. Moreover, the structure of 2,4-D does not suggest it would be a carcinogen. 2,4-D is a simple organic acid, that is largely excreted unchanged, and there is no evidence that it is metabolized to critically reactive metabolites or accumulates in tissues. This evidence is supported by a large body of negative studies on genotoxicity, which taken together with the metabolic studies, clearly indicates that 2,4-D is highly unlikely to be a genotoxic carcinogen. Furthermore, 2,4-D has no known hormonal activity and does not induce proliferative changes in any tissue or organ, indicating that it does not possess any of the characteristics of non-genotoxic animal carcinogens. Thus the available mechanistic studies provide no plausible basis for a hypothesis of carcinogenicity. In this review, data relating to potential neurotoxicity, immunotoxicity and reproductive toxicity also were evaluated. There is no evidence that 2,4-D adversely affects the immune system and neurotoxic and reproductive effects only have been associated with high toxic doses that would not be encountered by 2,4-D users. Historical exposures to 2,4-D by user groups, particularly farmers, forestry workers and commercial applicators, would be higher than those sustained under present rigorous standards for application which involve the use of protective clothing and other measures to reduce exposure. Proposed label changes indicate that in the future exposures will be even further reduced. Viewed in this context, the available data indicate that the potential public health impact of 2,4-D, including the risk of human cancer, was negligible in the past and would be expected to be even smaller in the present and future.

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