Acute exposure to a glyphosate-containing herbicide formulation inhibits Complex II and increases hydrogen peroxide in the model organism Caenorhabditis elegans

Burchfield, Shelbie; Bailey, Denise C.; Todt, Callie E.; Denney, Rachel D.; Negga, Rekek; Fitsanakis, Vanessa A.

doi:10.1016/j.etap.2018.12.019

Cited by 40 publications

(26 citation statements)

References 42 publications

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“…The detrimental impact of GBHs on mitochondrial activity has already been demonstrated in Caenorhabditis elegans, as exposing these animals to 3% TouchDown (expressed as % glyphosate; TouchDown Hitech, formulation of 52.3% glyphosate) leads to a decrease in mitochondrial respiration, oxygen consumption and ATP production, and an increase in intracellular levels of hydrogen peroxide 40 . These toxic effects have been suggested to be exerted through the impairment of the electron transport chain function via inhibition of Complex II (succinate dehydrogenase) 40,41 . Moreover, Roundup has been demonstrated to reduce the activity of mitochondrial succinate dehydrogenase in an immature mouse Sertoli TM4 cell line at a concentration as low as 0.001%, with heavier toxic effect than glyphosate alone 42 .…”

Section: Discussionmentioning

confidence: 99%

Effects of Roundup and its main component, glyphosate, upon mammalian sperm function and survival

Nerozzi

Recuero

Galeati

et al. 2020

Sci Rep

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The wide use of glyphosate-based herbicides (GBHs) has become a matter of concern due to its potential harmful effects on human health, including men fertility. This study sought to investigate, using the pig as a model, the impact of pure glyphosate and its most known commercial formulation, Roundup, on sperm function and survival. With this purpose, fresh commercial semen doses were incubated with different concentrations (0-360 µg/mL) of glyphosate (GLY; exp. 1) or Roundup, at the equivalent GLY concentration (exp. 2), at 38 °C for 3 h. Glyphosate at 360 µg/mL significantly (P < 0.05) decreased sperm motility, viability, mitochondrial activity and acrosome integrity but had no detrimental effect at lower doses. On the other hand, Roundup did significantly (P < 0.05) reduce sperm motility at ≥ 5 µg/mL GLY-equivalent concentration; mitochondrial activity at ≥ 25 µg/mL GLYequivalent concentration; and sperm viability and acrosome integrity at ≥ 100 µg/mL GLY-equivalent concentration as early as 1 h of incubation. In a similar fashion, GLY and Roundup did not inflict any detrimental effect on sperm DNA integrity. Taken together, these data indicate that, while both glyphosate and Roundup exert a negative impact on male gametes, Roundup is more toxic than its main component, glyphosate. Abbreviations CASA Computer-assisted sperm analysis JC1 5,5′,6,6′-Tetrachloro-1,1′,3,3′tetraethylbenzimidazolylcarbocyanine iodide GLY Glyphosate GBHs Glyphosate-based herbicides MMP Mitochondrial membrane potential PI Propidium iodide PNA Lectin from Arachis hypogaea 3Rs Replacement, reduction and refinement SCSA Sperm chromatin structure assay Glyphosate (GLY) is the active ingredient of all glyphosate-based herbicides (GBHs), including the most famous commercial formulation, Roundup (R). Despite GBHs being currently used worldwide, not only does this massive usage represent a risk for farmers but also for the general population, as environmental contamination with glyphosate affects water and food consumption 1,2. For this reason, the use of GBHs has become a matter of concern for public health, and much debate has been raised about their potential carcinogenicity and negative impact on neurologic, gastroenteric, endocrine and reproductive systems 3-9. Previous research has confirmed that, at low doses, glyphosate acts as an endocrine disruptor in mammals altering hormonal function 10,11. In particular, it has been suggested that GBHs can interfere with steroidogenesis

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Section: Discussionmentioning

confidence: 99%

Effects of Roundup and its main component, glyphosate, upon mammalian sperm function and survival

Nerozzi

Recuero

Galeati

et al. 2020

Sci Rep

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“…Given their implication in oxidative stress, GBHs are inclined to alter energy metabolism and cellular biochemical processes as well. Indeed, in C. elegans exposed to environmentally-relevant concentrations of Touchdown V R , a reduction in oxygen consumption and complex II activity was noted, suggesting a decrease in mitochondrial respiration; but complex IV seems unscathed, with its activity even increased (Burchfield et al 2019). This observation could indicate that GBHs affect mitochondrial respiration upstream of complex IV.…”

Section: Cellular Effectsmentioning

confidence: 99%

“…In Caenorhabditis elegans, increased hydrogen peroxide (H 2 O 2 ) production was observed after Touchdown V R exposure (Burchfield et al 2019). Environmentally-realistic concentrations of GBHs also lower the activity of anti-oxidant enzymes, i.e.…”

Section: Cellular Effectsmentioning

confidence: 99%

“…This observation could indicate that GBHs affect mitochondrial respiration upstream of complex IV. Both the proton gradient and the ATP levels were reduced in C. elegans (Burchfield et al 2019), as a result of complex dysfunctions. A decrease in the activity of both complex II and III, as well as in mitochondrial membrane potentials, was observed in rat liver cells (Peixoto 2005).…”

Section: Cellular Effectsmentioning

confidence: 99%

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The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity

Peillex

Pelletier

2020

Journal of Immunotoxicology

174

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Glyphosate, or N-phosphomethyl(glycine), is an organophosphorus compound and a competitive inhibitor of the shikimate pathway that allows aromatic amino acid biosynthesis in plants and microorganisms. Its utilization in broad-spectrum herbicides, such as RoundUp V R , has continued to increase since 1974; glyphosate, as well as its primary metabolite aminomethylphosphonic acid, is measured in soils, water, plants, animals and food. In humans, glyphosate is detected in blood and urine, especially in exposed workers, and is excreted within a few days. It has long been regarded as harmless in animals, but growing literature has reported health risks associated with glyphosate and glyphosate-based herbicides. In 2017, the International Agency for Research on Cancer (IARC) classified glyphosate as "probably carcinogenic" in humans. However, other national agencies did not tighten their glyphosate restrictions and even prolonged authorizations of its use. There are also discrepancies between countries' authorized levels, demonstrating an absence of a clear consensus on glyphosate to date. This review details the effects of glyphosate and glyphosate-based herbicides on fish and mammal health, focusing on the immune system. Increasing evidence shows that glyphosate and glyphosate-based herbicides exhibit cytotoxic and genotoxic effects, increase oxidative stress, disrupt the estrogen pathway, impair some cerebral functions, and allegedly correlate with some cancers. Glyphosate effects on the immune system appear to alter the complement cascade, phagocytic function, and lymphocyte responses, and increase the production of pro-inflammatory cytokines in fish. In mammals, including humans, glyphosate mainly has cytotoxic and genotoxic effects, causes inflammation, and affects lymphocyte functions and the interactions between microorganisms and the immune system. Importantly, even as many outcomes are still being debated, evidence points to a need for more studies to better decipher the risks from glyphosate and better regulation of its global utilization.

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“…One of the most studied aspect of glyphosate toxicology is its oxidative stress inducing properties. Glyphosate is known to affect mitochondria in mammalian cells, generating oxidative stress (Burchfield et al 2019;El-Shenawy 2009). Caecal metabolomics in our study showed that glyphosate affected gamma-glutamyl amino acid metabolism in the microbiome (Figure 2).…”

Section: Discussionmentioning

confidence: 60%

Shotgun metagenomics and metabolomics reveal glyphosate alters the gut microbiome of Sprague-Dawley rats by inhibiting the shikimate pathway

Mesnage

Teixeira

Mandrioli

et al. 2019

Preprint

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There is intense debate as to whether glyphosate can interfere with aromatic amino acid biosynthesis in microorganisms inhabiting the gastrointestinal tract, which could potentially lead to negative health outcomes. We have addressed this major gap in glyphosate toxicology by using a multi-omics strategy combining shotgun metagenomics and metabolomics. We tested whether glyphosate (0.5, 50, 175 mg/kg bw/day), or its representative EU commercial herbicide formulation MON 52276 at the same glyphosate equivalent doses, has an effect on the rat gut microbiome in a 90day subchronic toxicity test. Clinical biochemistry measurements in blood and histopathological evaluations showed that MON 52276 but not glyphosate was associated with statistically significant increase in hepatic steatosis and necrosis.Similar lesions were also present in the liver of glyphosate-treated groups but not in the control group. Caecum metabolomics revealed that glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase in the shikimate pathway as evidenced by an accumulation of shikimic acid and 3-dehydroshikimic acid. Levels of caecal microbiome dipeptides involved in the regulation of redox balance (γglutamylglutamine, cysteinylglycine, valylglycine) had their levels significantly increased. Shotgun metagenomics showed that glyphosate affected caecum microbial community structure and increased levels of Eggerthella spp. and Homeothermacea spp.. MON 52276, but not glyphosate, increased the relative abundance of Shinella zoogleoides. Since Shinella spp. are known to degrade alkaloids, its increased abundance may explain the decrease in solanidine levels measured with MON 52776 but not glyphosate. Other glyphosate formulations may have different effects since Roundup® GT Plus inhibited bacterial growth in vitro at concentrations at which MON 52276 did not present any visible effect. Our study highlights the power of a multiomics approach to investigate effects of pesticides on the gut microbiome. This revealed the first biomarker of glyphosate effects on rat gut microbiome. Although more studies will be needed to ascertain if there are health implications arising from glyphosate inhibition of the shikimate pathway in the gut microbiome, our findings can be used in environmental epidemiological studies to understand if glyphosate can have biological effects in human populations. Graphical Abstract

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Acute exposure to a glyphosate-containing herbicide formulation inhibits Complex II and increases hydrogen peroxide in the model organism Caenorhabditis elegans

Cited by 40 publications

References 42 publications

Effects of Roundup and its main component, glyphosate, upon mammalian sperm function and survival

Effects of Roundup and its main component, glyphosate, upon mammalian sperm function and survival

The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity

Shotgun metagenomics and metabolomics reveal glyphosate alters the gut microbiome of Sprague-Dawley rats by inhibiting the shikimate pathway

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