Epigenetic Impacts

Bibliography Tag: epigenetic impacts

Benbrook et al., 2023

Benbrook C, Mesnage R, Sawyer W. “Genotoxicity Assays Published since 2016 Shed New Light on the Oncogenic Potential of Glyphosate-Based Herbicides.” Agrochemicals. 2023; 2(1):47-68. https://doi.org/10.3390/agrochemicals2010005

ABSTRACT:

Controversy over the oncogenicity of glyphosate-based herbicides (GBHs) persists seven years after a 2015 IARC Monograph classified glyphosate/GBHs as “probably carcinogenic” to humans. Most regulatory authorities have concluded that technical glyphosate poses little or no oncogenic risk via dietary exposure. The US EPA classified glyphosate as “not likely” to pose cancer risk in 1991, a decision reaffirmed in reports issued in 2017 and 2020. A Federal Circuit Court of Appeals in the US vacated EPA’s assessment of glyphosate human-health risks in 2022 and required EPA to revisit old and take into account new data in its forthcoming, possibly final glyphosate/GBH reregistration decision. Divergent assessments of GBH genotoxicity are the primary reason for differing conclusions regarding GBH oncogenic potential. We assessed whether assays published since completion of the EPA and IARC reviews shed new light on glyphosate/GBH genotoxicity. We found 94 such assays, 33 testing technical glyphosate (73% positive) and 61 on GBHs (95% positive). Seven of 7 in vivo human studies report positive results. In light of genotoxicity results published since 2015, the conclusion that GBHs pose no risk of cancer via a genotoxic mechanism is untenable. FULL TEXT

Benbrook et al., 2021a

Benbrook, Charles, Perry, Melissa J., Belpoggi, Fiorella, Landrigan, Philip J., Perro, Michelle, Mandrioli, Daniele, Antoniou, Michael N., Winchester, Paul, & Mesnage, Robin; “Commentary: Novel strategies and new tools to curtail the health effects of pesticides;” Environmental Health, 2021, 20(1); DOI: 10.1186/s12940-021-00773-4.

ABSTRACT:

BACKGROUND: Flaws in the science supporting pesticide risk assessment and regulation stand in the way of progress in mitigating the human health impacts of pesticides. Critical problems include the scope of regulatory testing protocols, the near-total focus on pure active ingredients rather than formulated products, lack of publicly accessible information on co-formulants, excessive reliance on industry-supported studies coupled with reticence to incorporate published results in the risk assessment process, and failure to take advantage of new scientific opportunities and advances, e.g. biomonitoring and “omics” technologies.
RECOMMENDED ACTIONS: Problems in pesticide risk assessment are identified and linked to study design, data, and methodological shortcomings. Steps and strategies are presented that have potential to deepen scientific knowledge of pesticide toxicity, exposures, and risks.
We propose four solutions:
(1) End near-sole reliance in regulatory decision-making on industry-supported studies by supporting and relying more heavily on independent science, especially for core toxicology studies. The cost of conducting core toxicology studies at labs not affiliated with or funded directly by pesticide registrants should be covered via fees paid by manufacturers to public agencies.
(2) Regulators should place more weight on mechanistic data and low-dose studies within the range of contemporary exposures.
(3) Regulators, public health agencies, and funders should increase the share of exposure-assessment resources that produce direct measures of concentrations in bodily fluids and tissues. Human biomonitoring is vital in order to quickly identify rising exposures among vulnerable populations including applicators, pregnant women, and children.
(4) Scientific tools across disciplines can accelerate progress in risk assessments if integrated more effectively. New genetic and metabolomic markers of adverse health impacts and heritable epigenetic impacts are emerging and should be included more routinely in risk assessment to effectively prevent disease.
CONCLUSIONS: Preventing adverse public health outcomes triggered or made worse by exposure to pesticides will require changes in policy and risk assessment procedures, more science free of industry influence, and innovative strategies that blend traditional methods with new tools and mechanistic insights.

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Milesi et al., 2021

Milesi, M. M., Lorenz, V., Durando, M., Rossetti, M. F., & Varayoud, J. “Glyphosate Herbicide: Reproductive Outcomes and Multigenerational Effects.” Frontiers in Endocrinology, 12. 2021; DOI:10.3389/fendo.2021.672532.

ABSTRACT:

Glyphosate base herbicides (GBHs) are the most widely applied pesticides in the world and are mainly used in association with GBH-tolerant crop varieties. Indiscriminate and negligent use of GBHs has promoted the emergence of glyphosate resistant weeds, and consequently the rise in the use of these herbicides. Glyphosate, the active ingredient of all GBHs, is combined with other chemicals known as co-formulants that enhance the herbicide action. Nowadays, the safety of glyphosate and its formulations remain to be a controversial issue, as evidence is not conclusive whether the adverse effects are caused by GBH or glyphosate, and little is known about the contribution of co-formulants to the toxicity of herbicides. Currently, alarmingly increased levels of glyphosate have been detected in different environmental matrixes and in foodstuff, becoming an issue of social concern. Some in vitro and in vivo studies have shown that glyphosate and its formulations exhibit estrogen-like properties, and growing evidence has indicated they may disrupt normal endocrine function, with adverse consequences for reproductive health. Moreover, multigenerational effects have been reported and epigenetic mechanisms have been proved to be involved in the alterations induced by the herbicide. In this review, we provide an overview of: i) the routes and levels of human exposure to GBHs, ii) the potential estrogenic effects of glyphosate and GBHs in cell culture and animal models, iii) their long-term effects on female fertility and mechanisms of action, and iv) the consequences on health of successive generations. FULL TEXT

Ndonwi et al., 2019

Ndonwi EN, Atogho-Tiedeu B, Lontchi-Yimagou E, Shinkafi TS, Nanfa D, Balti EV, Indusmita R, Mahmood A, Katte JC, Mbanya A, Matsha T, Mbanya JC, Shakir A, Sobngwi E. “Gestational Exposure to Pesticides Induces Oxidative Stress and Lipid Peroxidation in Offspring that Persist at Adult Age in an Animal Model.” Toxicological Research, 2019 Jul;35(3):241-248; DOI: 10.5487/TR.2019.35.3.241.

ABSTRACT:

Pesticide exposure may induce biochemical alterations including oxidative stress and lipid peroxidation. However, in the context of developmental origin of health and disease, putative trans-generational effect of exposure to pesticides are insufficiently studied. We therefore aimed to evaluate the biochemical effect of gestational exposure to four pesticides on female Wistar rats and their offspring at adult age. We studied 30 female nulliparous Wistar rats divided into 5 equal groups. Group 1 served as the control group and received distilled water while group 2, 3, 4 and 5 received orally pesticide 1 (imidacloprid), pesticide 2 (chlorpyrifos), pesticide 3 (imidacloprid + lambda cyhalothrin) and pesticide 4 (oxamyl) respectively once daily throughout gestation at a dose equivalent to 1/10 lethal dose 50. The mothers were followed up until one month post gestation. The offspring were followed up from birth until adult age (12 weeks). In all animals at each time point we evaluated malondialdehyde (MDA), oxidative stress and liver function enzymes. There was similar variation of total body weight in all the groups during and after gestation. However, Female Wistar rats of the exposed groups had significant alterations in liver SOD (-30.8% to +64.1%), catalase (-38.8% to -85.7%) and GSH (-29.2% to -86.5%) and; kidney catalase (> 100%), GSH (> 100%). Moreover, MDA, alanine transaminase (ALT) and aspartate transaminase (AST) levels were significantly higher in pesticide exposed rats compared to the control group. Similar alterations in antioxidant enzymes, MDA and liver function enzymes were observed in offspring of treated rats evidenced at weaning and persisting until adult age. Exposure to pesticides causes oxidative stress and lipid peroxidation in exposed female Wistar rats and their offspring. The persistence in offspring at adult age suggests transgenerational adverse effects. FULL TEXT

Maurice et al., 2021

Maurice C, Dalvai M, Lambrot R, Deschênes A, Scott-Boyer M-P, McGraw S, Chan D, Côté N, Ziv-Gal A, Flaws JA, Droit A, Trasler J, Kimmins S, Bailey JL. “Early-Life Exposure to Environmental Contaminants Perturbs the Sperm Epigenome and Induces Negative Pregnancy Outcomes for Three Generations via the Paternal Lineage.” Epigenomes. 2021, 5(2):10; DOI:10.3390/epigenomes5020010

ABSTRACT:

Due to the grasshopper effect, the Arctic food chain in Canada is contaminated with persistent organic pollutants (POPs) of industrial origin, including polychlorinated biphenyls and organochlorine pesticides. Exposure to POPs may be a contributor to the greater incidence of poor fetal growth, placental abnormalities, stillbirths, congenital defects and shortened lifespan in the Inuit population compared to non-Aboriginal Canadians. Although maternal exposure to POPs is well established to harm pregnancy outcomes, paternal transmission of the effects of POPs is a possibility that has not been well investigated. We used a rat model to test the hypothesis that exposure to POPs during gestation and suckling leads to developmental defects that are transmitted to subsequent generations via the male lineage. Indeed, developmental exposure to an environmentally relevant Arctic POPs mixture impaired sperm quality and pregnancy outcomes across two subsequent, unexposed generations and altered sperm DNA methylation, some of which are also observed for two additional generations. Genes corresponding to the altered sperm methylome correspond to health problems encountered in the Inuit population. These findings demonstrate that the paternal methylome is sensitive to the environment and that some perturbations persist for at least two subsequent generations. In conclusion, although many factors influence health, paternal exposure to contaminants plays a heretofore-underappreciated role with sperm DNA methylation contributing to the molecular underpinnings involved. FULL TEXT

Lorenz et al., 2019

Lorenz, V., Milesi, M. M., Schimpf, M. G., Luque, E. H., & Varayoud, J.; “Epigenetic disruption of estrogen receptor alpha is induced by a glyphosate-based herbicide in the preimplantation uterus of rats;” Molecular and Cellular Endocrinology, 2019, 480, 133-141; DOI: 10.1016/j.mce.2018.10.022.

ABSTRACT:

Previously, we have shown that perinatal exposure to a glyphosate-based herbicide (GBH) induces implantation failures in rats. Estrogen receptor alpha (ERalpha) is critical for successful implantation. ERalpha transcription is under the control of five promoters (E1, OT, O, ON, and OS), which yield different transcripts. Here, we studied whether perinatal exposure to a GBH alters uterine ERalpha gene expression and prompts epigenetic modifications in its regulatory regions during the preimplantation period. Pregnant rats (F0) were orally treated with 350mg glyphosate/kg bw/day through food from gestational day (GD) 9 until weaning. F1 females were bred, and uterine samples were collected on GD5 (preimplantation period). ERalpha mRNA levels and its transcript variants were evaluated by RT-qPCR. Enzyme-specific restriction sites and predicted transcription factors were searched in silico in the ERalpha promoter regions to assess the methylation status using the methylation-sensitive restriction enzymes-PCR technique. Post-translational modifications of histones were studied by the chromatin immunoprecipitation assay. GBH upregulated the expression of total ERalpha mRNA by increasing the abundance of the ERalpha-O transcript variant. In addition, different epigenetic changes were detected in the O promoter. A decrease in DNA methylation was observed in one of the three sites evaluated in the O promoter. Moreover, histone H4 acetylation and histone H3 lysine 9 trimethylation (H3K9me3) were enriched in the O promoter in GBH-exposed rats, whereas H3K27me3 was decreased. All these alterations could account for the increase in ERalpha gene expression. Our findings show that perinatal exposure to a GBH causes long-term epigenetic disruption of the uterine ERalpha gene, which could be associated with the GBH-induced implantation failures. FULL TEXT

Rattan and Flaws, 2019

Rattan, S., & Flaws, J. A.; “The epigenetic impacts of endocrine disruptors on female reproduction across generationsdagger;” Biology of Reproduction, 2019, 101(3), 635-644; DOI: 10.1093/biolre/ioz081.

ABSTRACT:

Humans and animals are repeatedly exposed to endocrine disruptors, many of which are ubiquitous in the environment. Endocrine disruptors interfere with hormone action; thus, causing non-monotonic dose responses that are atypical of standard toxicant exposures. The female reproductive system is particularly susceptible to the effects of endocrine disruptors. Likewise, exposures to endocrine disruptors during developmental periods are particularly concerning because programming during development can be adversely impacted by hormone level changes. Subsequently, developing reproductive tissues can be predisposed to diseases in adulthood and these diseases can be passed down to future generations. The mechanisms of action by which endocrine disruptors cause disease transmission to future generations are thought to include epigenetic modifications. This review highlights the effects of endocrine disruptors on the female reproductive system, with an emphasis on the multi- and transgenerational epigenetic effects of these exposures. FULL TEXT

Alexander et al., 2017

Alexander, M., Koutros, S., Bonner, M. R., Barry, K. H., Alavanja, M. C. R., Andreotti, G., Byun, H. M., Chen, L., Beane Freeman, L. E., Hofmann, J. N., Kamel, F., Moore, L. E., Baccarelli, A., & Rusiecki, J.; “Pesticide use and LINE-1 methylation among male private pesticide applicators in the Agricultural Health Study;” Environ Epigenet, 2017, 3(2), dvx005; DOI: 10.1093/eep/dvx005.

ABSTRACT:

Cancer risk may be associated with DNA methylation (DNAm) levels in Long Interspersed Nucleotide Element 1 (LINE-1), a surrogate for global DNAm. Exposure to certain pesticides may increase risk of particular cancers, perhaps mediated in part through global DNAm alterations. To date, human data on pesticide exposure and global DNAm alterations are limited. The goal of this study was to evaluate alterations of LINE-1 DNAm by pesticides in a variety of classes. Data from 596 cancer-free male participants enrolled in the Agricultural Health Study (AHS) were used to examine associations between use of 57 pesticides and LINE-1 DNAm measured via Pyrosequencing in peripheral blood leucocytes. Participants provided information on pesticide use at three contacts between 1993 and 2010. Associations of ever/never pesticide use and lifetime days of application (years of use x days per year) and LINE-1 DNAm level were assessed using linear regression, adjusting for potential confounders (race, age at blood draw, and frequency of drinking alcohol) and other moderately correlated pesticides. After adjustment, ever application of 10 pesticides was positively associated and ever application of eight pesticides was negatively associated with LINE-1 DNAm. In dose-response analyses, increases in five pesticides (imazethapyr, fenthion, EPTC, butylate, and heptachlor) were associated with increasing LINE-1 DNAm (ptrend < 0.05) and increases in three pesticides (carbaryl, chlordane, and paraquat) were associated with decreasing LINE-1 DNAm (ptrend < 0.05). This study provides some mechanistic insight into the pesticide-cancer relationship, which may be mediated in part by epigenetics. FULL TEXT

Wang et al., 2020

Wang, G. H., Berdy, B. M., Velasquez, O., Jovanovic, N., Alkhalifa, S., Minbiole, K. P. C., & Brucker, R. M.; “Changes in Microbiome Confer Multigenerational Host Resistance after Sub-toxic Pesticide Exposure;” Cell Host & Microbe, 2020; DOI: 10.1016/j.chom.2020.01.009.

ABSTRACT:

The gut is a first point of contact with ingested xenobiotics, where chemicals are metabolized directly by the host or microbiota. Atrazine is a widely used pesticide, but the role of the microbiome metabolism of this xenobiotic and the impact on host responses is unclear. We exposed successive generations of the wasp Nasonia vitripennis to subtoxic levels of atrazine and observed changes in the structure and function of the gut microbiome that conveyed atrazine resistance. This microbiome-mediated resistance was maternally inherited and increased over successive generations, while also heightening the rate of host genome selection. The rare gut bacteria Serratia marcescens and Pseudomonas protegens contributed to atrazine metabolism. Both of these bacteria contain genes that are linked to atrazine degradation and were sufficient to confer resistance in experimental wasp populations. Thus, pesticide exposure causes functional, inherited changes in the microbiome that should be considered when assessing xenobiotic exposure and as potential countermeasures to toxicity. FULL TEXT

Chung and Herceg, 2020

Chung, F. F., & Herceg, Z.; “The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome;” Environmental Health Perspectives, 2020, 128(1), 15001; DOI: 10.1289/EHP6104.

ABSTRACT:

BACKGROUND: It has been estimated that a substantial portion of chronic and noncommunicable diseases can be caused or exacerbated by exposure to environmental chemicals. Multiple lines of evidence indicate that early life exposure to environmental chemicals at relatively low concentrations could have lasting effects on individual and population health. Although the potential adverse effects of environmental chemicals are known to the scientific community, regulatory agencies, and the public, little is known about the mechanistic basis by which these chemicals can induce long-term or transgenerational effects. To address this question, epigenetic mechanisms have emerged as the potential link between genetic and environmental factors of health and disease.

OBJECTIVES: We present an overview of epigenetic regulation and a summary of reported evidence of environmental toxicants as epigenetic disruptors. We also discuss the advantages and challenges of using epigenetic biomarkers as an indicator of toxicant exposure, using measures that can be taken to improve risk assessment, and our perspectives on the future role of epigenetics in toxicology.

DISCUSSION: Until recently, efforts to apply epigenomic data in toxicology and risk assessment were restricted by an incomplete understanding of epigenomic variability across tissue types and populations. This is poised to change with the development of new tools and concerted efforts by researchers across disciplines that have led to a better understanding of epigenetic mechanisms and comprehensive maps of epigenomic variation. With the foundations now in place, we foresee that unprecedented advancements will take place in the field in the coming years.

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Bibliography Index