Bibliography Tag: genotoxicity

Zhang et al., 2021

Zhang, H., Liu, J., Wang, L., & Zhai, Z.; “Glyphosate escalates horizontal transfer of conjugative plasmid harboring antibiotic resistance genes;” Bioengineered, 2021, 12(1), 63-69; DOI: 10.1080/21655979.2020.1862995.


Glyphosate has been frequently detected in water environments because of the wide use for controlling weed in farm lands and urban areas. Presently, the focus of the majority of studies is placed on the toxicity of glyphosate on humans and animals. However, the effects of glyphosate on horizontal transfer of conjugative plasmid carrying antibiotic resistance gene (ARG) are largely unknown. Here, we explored the ability and potential mechanism of glyphosate for accelerating horizontal transfer of conjugative plasmid-mediated ARG. The results showed that glyphosate can effectively boost horizontal transfer rate of conjugative plasmid carrying ARG. The possible mechanism analysis demonstrated that over-production of reactive oxygen species and reactive nitrogen species effectively regulated expression levels of bacterial outer membrane protein and conjugative transfer-related genes, thereby resulting into elevated horizontal transfer rate of plasmid-mediated ARG. In conclusion, this study casts new understanding into the biological effects of glyphosate on ARG. FULL TEXT

Suppa et al., 2020

Suppa, A., Kvist, J., Li, X., Dhandapani, V., Almulla, H., Tian, A. Y., Kissane, S., Zhou, J., Perotti, A., Mangelson, H., Langford, K., Rossi, V., Brown, J. B., & Orsini, L.; “Roundup causes embryonic development failure and alters metabolic pathways and gut microbiota functionality in non-target species;” Microbiome, 2020, 8(1), 170; DOI: 10.1186/s40168-020-00943-5.


BACKGROUND: Research around the weedkiller Roundup is among the most contentious of the twenty-first century. Scientists have provided inconclusive evidence that the weedkiller causes cancer and other life-threatening diseases, while industry-paid research reports that the weedkiller has no adverse effect on humans or animals. Much of the controversial evidence on Roundup is rooted in the approach used to determine safe use of chemicals, defined by outdated toxicity tests. We apply a system biology approach to the biomedical and ecological model species Daphnia to quantify the impact of glyphosate and of its commercial formula, Roundup, on fitness, genome-wide transcription and gut microbiota, taking full advantage of clonal reproduction in Daphnia. We then apply machine learning-based statistical analysis to identify and prioritize correlations between genome-wide transcriptional and microbiota changes.

RESULTS: We demonstrate that chronic exposure to ecologically relevant concentrations of glyphosate and Roundup at the approved regulatory threshold for drinking water in the US induce embryonic developmental failure, induce significant DNA damage (genotoxicity), and interfere with signaling. Furthermore, chronic exposure to the weedkiller alters the gut microbiota functionality and composition interfering with carbon and fat metabolism, as well as homeostasis. Using the “Reactome,” we identify conserved pathways across the Tree of Life, which are potential targets for Roundup in other species, including liver metabolism, inflammation pathways, and collagen degradation, responsible for the repair of wounds and tissue remodeling.

CONCLUSIONS: Our results show that chronic exposure to concentrations of Roundup and glyphosate at the approved regulatory threshold for drinking water causes embryonic development failure and alteration of key metabolic functions via direct effect on the host molecular processes and indirect effect on the gut microbiota. The ecological model species Daphnia occupies a central position in the food web of aquatic ecosystems, being the preferred food of small vertebrates and invertebrates as well as a grazer of algae and bacteria. The impact of the weedkiller on this keystone species has cascading effects on aquatic food webs, affecting their ability to deliver critical ecosystem services. FULL TEXT

van der Plaat et al., 2018

van der Plaat, Diana A., de Jong, Kim, de Vries, Maaike, van Diemen, Cleo C., Nedeljković, Ivana, Amin, Najaf, Kromhout, Hans, Vermeulen, Roel, Postma, Dirkje S., van Duijn, Cornelia M., Boezen, H. Marike, & Vonk, Judith M.; “Occupational exposure to pesticides is associated with differential DNA methylation;” Occupational and environmental medicine, 2018, 75(6), 427; DOI: 10.1136/oemed-2017-104787.


OBJECTIVES: Occupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. a potential mechanism might be through epigenetic mechanisms, like Dna methylation. therefore, we assessed associations between occupational exposure to pesticides and genome-wide Dna methylation sites.

METHODS: 1561 subjects of lifelines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood Dna methylation levels were measured using illumina 450K arrays. associations between pesticide exposure and 420 938 methylation sites (cpgs) were assessed using robust linear regression adjusted for appropriate confounders. in addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant cpgs (n=2802).

RESULTS: In total for all analyses, high pesticide exposure was genome-wide significantly (false discovery rate P<0.05) associated with differential Dna methylation of 31 cpgs annotated to 29 genes. twenty of these cpgs were found in subjects with airway obstruction. Several of the identified genes, for example, RYR1, ALLC, PTPRN2, LRRC3B, PAX2 and VTRNA2-1, are genes previously linked to either pesticide exposure or lungrelated diseases. Seven out of 31 cpgs were associated with gene expression levels.

CONCLUSIONS: We show for the first time that occupational exposure to pesticides is genome-wide associated with differential Dna methylation. Further research should reveal whether this differential methylation plays a role in the airway disease pathogenesis induced by pesticides.


Sanchez et al., 2018

Sanchez, M. C., Alvarez Sedo, C., Chaufan, G. R., Romanato, M., Da Cuna, R., Lo Nostro, F., Calvo, J. C., & Fontana, V.; “In vitro effects of endosulfan-based insecticides on mammalian sperm;” Toxicology Research, 2018, 7(1), 117-126; DOI: 10.1039/c7tx00251c.


Endosulfan is an organochloride insecticide extensively used in several countries to protect crops from pests. As several studies indicate that endosulfan can affect human and animal development, the aim of this study was to analyse whether sperm parameters and the process of chromatin decondensation could be altered by endosulfan in mice sperm. Spermatozoa from cauda epididymis were obtained from mature male mice and incubated in the presence of two commercial formulations (CFs) of endosulfan (Master(R) and Zebra Ciagro(R)) or the active ingredient (AI) alone. A significant decrease in the percentage motility and viability of spermatozoa with respect to controls was found. In vitro decondensation was performed in the presence of glutathione and heparin. Spermatozoa incubated with the AI, endosulfan Master(R) and endosulfan Zebra Ciagro(R) showed an increase in chromatin decondensation. In addition, the TUNEL assay showed that DNA fragmentation was significantly higher when sperm were incubated with either one of the CFs when compared to the AI or controls. The ultrastructure analysis of sperm cells showed evident changes in the structure of the plasma and acrosome membranes of sperm incubated with endosulfan AI or the CFs. These results suggest that endosulfan can affect sperm integrity and in vitro chromatin decondensation as well as DNA fragmentation. FULL TEXT

Meftaul et al.; 2020

Meftaul, I. M., Venkateswarlu, K., Dharmarajan, R., Annamalai, P., Asaduzzaman, M., Parven, A., & Megharaj, M.; “Controversies over human health and ecological impacts of glyphosate: Is it to be banned in modern agriculture?;” Environmental Pollution, 2020, 263(Pt A), 114372; DOI: 10.1016/j.envpol.2020.114372.


Glyphosate, introduced by Monsanto Company under the commercial name Roundup in 1974, became the extensively used herbicide worldwide in the last few decades. Glyphosate has excellent properties of fast sorption in soil, biodegradation and less toxicity to nontarget organisms. However, glyphosate has been reported to increase the risk of cancer, endocrine-disruption, celiac disease, autism, effect on erythrocytes, leaky-gut syndrome, etc. The reclassification of glyphosate in 2015 as ‘probably carcinogenic’ under Group 2A by the International Agency for Research on Cancer has been broadly circulated by anti-chemical and environmental advocacy groups claiming for restricted use or ban of glyphosate. In contrast, some comprehensive epidemiological studies involving farmers with long-time exposure to glyphosate in USA and elsewhere coupled with available toxicological data showed no correlation with any kind of carcinogenic or genotoxic threat to humans. Moreover, several investigations confirmed that the surfactant, polyethoxylated tallow amine (POEA), contained in the formulations of glyphosate like Roundup, is responsible for the established adverse impacts on human and ecological health. Subsequent to the evolution of genetically modified glyphosate-resistant crops and the extensive use of glyphosate over the last 45 years, about 38 weed species developed resistance to this herbicide. Consequently, its use in the recent years has been either restricted or banned in 20 countries. This critical review on glyphosate provides an overview of its behaviour, fate, detrimental impacts on ecological and human health, and the development of resistance in weeds and pathogens. Thus, the ultimate objective is to help the authorities and agencies concerned in resolving the existing controversies and in providing the necessary regulations for safer use of the herbicide. In our opinion, glyphosate can be judiciously used in agriculture with the inclusion of safer surfactants in commercial formulations sine POEA, which is toxic by itself is likely to increase the toxicity of glyphosate. FULL TEXT

Williams et al., 2000

Williams, G. M., Kroes, R., & Munro, I. C.; “Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans;” Regulatory Toxicology and Pharmacology, 2000, 31(2 Pt 1), 117-165; DOI: 10.1006/rtph.1999.1371.


Reviews on the safety of glyphosate and Roundup herbicide that have been conducted by several regulatory agencies and scientific institutions worldwide have concluded that there is no indication of any human health concern. Nevertheless, questions regarding their safety are periodically raised. This review was undertaken to produce a current and comprehensive safety evaluation and risk assessment for humans. It includes assessments of glyphosate, its major breakdown product [aminomethylphosphonic acid (AMPA)], its Roundup formulations, and the predominant surfactant [polyethoxylated tallow amine (POEA)] used in Roundup formulations worldwide. The studies evaluated in this review included those performed for regulatory purposes as well as published research reports. The oral absorption of glyphosate and AMPA is low, and both materials are eliminated essentially unmetabolized. Dermal penetration studies with Roundup showed very low absorption. Experimental evidence has shown that neither glyphosate nor AMPA bioaccumulates in any animal tissue. No significant toxicity occurred in acute, subchronic, and chronic studies. Direct ocular exposure to the concentrated Roundup formulation can result in transient irritation, while normal spray dilutions cause, at most, only minimal effects. The genotoxicity data for glyphosate and Roundup were assessed using a weight-of-evidence approach and standard evaluation criteria. There was no convincing evidence for direct DNA damage in vitro or in vivo, and it was concluded that Roundup and its components do not pose a risk for the production of heritable/somatic mutations in humans. Multiple lifetime feeding studies have failed to demonstrate any tumorigenic potential for glyphosate. Accordingly, it was concluded that glyphosate is noncarcinogenic. Glyphosate, AMPA, and POEA were not teratogenic or developmentally toxic. There were no effects on fertility or reproductive parameters in two multigeneration reproduction studies with glyphosate. Likewise there were no adverse effects in reproductive tissues from animals treated with glyphosate, AMPA, or POEA in chronic and/or subchronic studies. Results from standard studies with these materials also failed to show any effects indicative of endocrine modulation. Therefore, it is concluded that the use of Roundup herbicide does not result in adverse effects on development, reproduction, or endocrine systems in humans and other mammals. For purposes of risk assessment, no-observed-adverse-effect levels (NOAELs) were identified for all subchronic, chronic, developmental, and reproduction studies with glyphosate, AMPA, and POEA. Margins-of-exposure for chronic risk were calculated for each compound by dividing the lowest applicable NOAEL by worst-case estimates of chronic exposure. Acute risks were assessed by comparison of oral LD50 values to estimated maximum acute human exposure. It was concluded that, under present and expected conditions of use, Roundup herbicide does not pose a health risk to humans.

Balderrama-Carmona et al., 2019

Balderrama-Carmona, A. P., Valenzuela-Rincon, M., Zamora-Alvarez, L. A., Adan-Bante, N. P., Leyva-Soto, L. A., Silva-Beltran, N. P., & Moran-Palacio, E. F.; “Herbicide biomonitoring in agricultural workers in Valle del Mayo, Sonora Mexico;” Environmental Science and Pollution Research International, 2019; DOI: 10.1007/s11356-019-07087-6.


Valle del Mayo is an important agricultural area at the northwest of Mexico where up to 20,000 L of a mix composed of glyphosate and tordon is used in drains and canals. This study was carried out in order to evaluate the cellular damage caused by glyphosate, aminomethylphosphonic acid (AMPA), and picloram in agricultural workers. Biomonitoring was performed through the quantification of herbicides in urine using HPLC (high-performance liquid chromatography) to then evaluate the cellular damage in exposed people by means of an evaluation of micronuclei and cellular proliferation in lymphocyte cultures. The urine samples (n = 30) have shown a concentration of up to 10.25 mug/L of picloram and 2.23 mug/L of AMPA; no positive samples for glyphosate were reported. The calculation of the external dose reveals that agricultural workers ingest up to 146 mg/kg/day; however, this concentration does not surpass the limits that are allowed internationally. As for the results for the micronuclei test, 53% of the workers showed cellular damage, and the nuclear division index test reported that there was a significant difference (P < 0.05) between the exposed and the control population, which indicated that the exposure time to pesticides in the people of Valle del Mayo can induce alterations which can cause chronic damage. FULL TEXT

Crump et al., 2020

Crump, K., Crouch, E., Zelterman, D., Crump, C., & Haseman, J.; “Accounting for Multiple Comparisons in Statistical Analysis of the Extensive Bioassay Data on Glyphosate;” Toxicology Science, 2020; DOI: 10.1093/toxsci/kfaa039.


Glyphosate is a widely used herbicide worldwide. In 2015, the International Agency for Research on Cancer (IARC) reviewed glyphosate cancer bioassays and human studies and declared that the evidence for carcinogenicity of glyphosate is sufficient in experimental animals. We analyzed ten glyphosate rodent bioassays, including those in which IARC found evidence of carcinogenicity, using a multi-response permutation procedure that adjusts for the large number of tumors eligible for statistical testing and provides valid false-positive probabilities. The test statistics for these permutation tests are functions of p-values from a standard test for dose-response trend applied to each specific type of tumor. We evaluated three permutation tests, using as test statistics the smallest p-value from a standard statistical test for dose-response trend and the number of such tests for which the p-value is less than or equal to 0.05 or 0.01. The false-positive probabilities obtained from two implementations of these three permutation tests are: smallest p-value: 0.26, 0.17, p-values </= 0.05: 0.08, 0.12, p-values </= 0.01: 0.06, 0.08. In addition, we found more evidence for negative dose-response trends than positive. Thus, we found no strong evidence that glyphosate is an animal carcinogen. The main cause for the discrepancy between IARC’s finding and ours appears to be that IARC did not account for the large number of tumor responses analyzed and the increased likelihood that several of these would show statistical significance simply by chance. This work provides a more comprehensive analysis of the animal carcinogenicity data for this important herbicide than previously available. FULL TEXT

Dimitrov et al., 2006

Dimitrov, B. D., Gadeva, P. G., Benova, D. K., & Bineva, M. V.; “Comparative genotoxicity of the herbicides Roundup, Stomp and Reglone in plant and mammalian test systems;” Mutagenesis, 2006, 21(6), 375-382; DOI: 10.1093/mutage/gel044.


The genotoxicities of the herbicides Roundup (glyphosate), Stomp (pendimethaline) and Reglone (diquat), were compared in plant (Crepis capillaris L.) and mouse bone marrow test systems using chromosomal aberrations and micronuclei. Roundup did not induce chromosomal aberrations or micronuclei in either test system. Reglone also did not induce chromosomal aberrations in either test system; however, it increased micronucleus frequency in both plant cells and mouse bone marrow polychromatic erythrocytes (PCEs). The responses of the two test systems to Stomp were quite different. Stomp did not induce chromosomal aberrations in the plant cells, but increased their incidence in mouse cells; Stomp increased the frequency of micronuclei in both test systems. The induction of micronuclei in plant cells may have been due to the spindle-destroying effect of the herbicide, since all concentrations of Stomp produced C-mitoses. The increased chromosomal aberration frequency in mouse bone marrow cells observed at later sampling times after administration of Stomp into animals suggests that the induction of aberrations may be due to biosynthesis of genotoxic metabolites. This conclusion was supported by the coincidence between the frequencies of chromosomal aberrations and of micronucleated PCEs in mouse cells. These data indicate that plant and animal assays are differentially responsive to some pesticides, and these differences may be due to metabolism and their responses to mitotic spindle disruption. FULL TEXT

Curl et al., 2020

Curl, C. L., Spivak, M., Phinney, R., & Montrose, L.; “Synthetic Pesticides and Health in Vulnerable Populations: Agricultural Workers;” Current Environmental Health Reports, 2020, 7(1), 13-29; DOI: 10.1007/s40572-020-00266-5.


PURPOSE OF REVIEW: This review aims to summarize epidemiological literature published between May 15, 2018, and May 14, 2019, that examines the relationship between exposure to synthetic pesticides and health of agricultural workers.

RECENT FINDINGS: Current research suggests that exposure to synthetic pesticides may be associated with adverse health outcomes. Agricultural workers represent a potentially vulnerable population, due to a combination of unique social and cultural risk factors as well as exposure to hazards inherent in agricultural work. Pesticide exposure among agricultural workers has been linked to certain cancers, DNA damage, oxidative stress, neurological disorders, and respiratory, metabolic, and thyroid effects.

SUMMARY: This review describes literature suggesting that agricultural workers exposed to synthetic pesticides are at an increased risk of certain cancers and neurological disorders. Recent research on respiratory effects is sparse, and more research is warranted regarding DNA damage, oxidative stress, metabolic outcomes, and thyroid effects. FULL TEXT