The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system

Manservisi, Fabiana; Lesseur, Corina; Panzacchi, Simona; Mandrioli, Daniele; Falcioni, Laura; Bua, Luciano; Manservigi, Marco; Spinaci, Marcella; Galeati, Giovanna; Mantovani, Alberto; Lorenzetti, Stefano; Miglio, Rossella; Martino‐Andrade, Anderson Joel; Kristensen, David M.; Perry, Melissa J.; Swan, Shanna H.; Chen, Jia; Belpoggi, Fiorella

doi:10.1186/s12940-019-0453-y

Cited by 76 publications

(56 citation statements)

References 51 publications

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“…It remains to be determined whether Glyphosate or Roundup alter the peripheral and central actions of gonadal and adrenal hormones in the mother. Previous research on human cell lines, human breast cancer cells and rodents has shown that glyphosate‐based herbicides in formulation can disrupt steroid secretion, oestrogen receptors and aromatase activity, albeit the exact mechanisms remain to be determined. The physiological and behavioural effects of glyphosate observed in the present study could be linked to endocrine disruption, and future work will aim to investigate this possibility.…”

Section: Future Directionsmentioning

confidence: 99%

Glyphosate and glyphosate‐based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome

Dechartres

Pawluski

Guéguen

et al. 2019

J Neuroendocrinology

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Glyphosate is found in a large array of non‐selective herbicides such as Roundup® (Monsanto, Creve Coeur, MO, USA) and is by far the most widely used herbicide. Recent work in rodent models suggests that glyphosate‐based herbicides during development can affect neuronal communication and result in altered behaviours, albeit through undefined mechanisms of action. To our knowledge, no study has investigated the effects glyphosate or its formulation in herbicide on maternal behaviour and physiology. In the present study, relatively low doses of glyphosate (5 mg kg‐1 d‐1), Roundup® (5 mg kg‐1 d‐1 glyphosate equivalent), or vehicle were administered by ingestion to Sprague‐Dawley rats from gestational day (GD) 10 to postpartum day (PD)22. The treatments significantly altered licking behaviour toward pups between PD2 and PD6. We also show in the dams at PD22 that Roundup exposure affected the maturation of doublecortin‐immunoreactive new neurones in the dorsal dentate gyrus of the hippocampus of the mother. In addition, the expression of synaptophysin was up‐regulated by glyphosate in the dorsal and ventral dentate gyrus and CA3 regions of the hippocampus, and down‐regulated in the cingulate gyrus. Although a direct effect of glyphosate alone or its formulation on the central nervous system is currently not clear, we show that gut microbiota is significantly altered by the exposure to the pesticides, with significant alteration of the phyla Bacteroidetes and Firmicutes. This is the first study to provide evidence that glyphosate alone or in formulation (Roundup) differentially affects maternal behaviour and modulates neuroplasticity and gut microbiota in the mother.

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Section: Future Directionsmentioning

confidence: 99%

Glyphosate and glyphosate‐based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome

Dechartres

Pawluski

Guéguen

et al. 2019

J Neuroendocrinology

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“…Many studies have reported that commercially formulated pesticide products are more toxic than their active ingredient. This has been shown multiple times for glyphosate-based herbicides (Adam et al 1997;Manservisi et al 2019;Mesnage et al 2013), and also for other classes of pesticides such as insecticides or fungicides (Mesnage et al 2014). This difference in toxic effects is generally due to the toxicity of surfactants and other compounds that constitute the adjuvant mixture in commercial pesticide formulations , although it cannot be excluded that these surfactants can also potentiate glyphosate penetration in tissues (Anadón et al 2009).…”

Section: Discussionmentioning

confidence: 98%

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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“…Newly published reports are demonstrating previously unrecognized health impacts of glyphosate exposure, including a meta analysis of epidemiologic studies showing a link between glyphosate based herbicide expsoure and increased risk of Non-Hodgkin Lymphoma [11] and a long-term low dose toxicologic assessment that showed glyphosate and Roundup had developmental and endocrinological impacts in sprague dawley rats [12].…”

Section: Discussionmentioning

confidence: 99%

Historical evidence of glyphosate exposure from a US agricultural cohort

et al. 2019

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In response to the recent review by Gillezeau et al., The evidence of human exposure to glyphosate: A review , Environmental Health 1/19/19 , here we report additional glyphosate biomonitoring data from a repository of urine samples collected from United States farmers in 1997–98. To determine if glyphosate exposure could be identified historically, we examined urine samples from a biorepository of specimens collected from US dairy farmers between 1997 and 98. We compared samples from farmers who self-reported glyphosate application in the 8 h prior to sample collection to samples from farm applicators who did not report using glyphosate. Of 18 applicator samples tested, 39% showed detectable levels of glyphosate (mean concentration 4.04 μg/kg; range:1.3–12) compared to 0% detections among 17 non glyphosate applicator samples ( p -value < 0.01). One of the applicator samples that tested positive for glyphosate also tested positive for AMPA. Concentrations of glyphosate were consistent with levels reported in the prior occupational biomonitoring studies reviewed by Gillezeau et al. Accurately detecting both glyphosate and AMPA in this small sample of Wisconsin farmers demonstrates a) glyphosate exposures among farmers were occurring 20 years ago, which was prior to the widespread planting of genetically engineered glyphosate tolerant crops first approved in 1996; and b) liquid chromatography tandem mass spectrometry (LC-MS/MS) can be used for sensitive characterization in cryopreserved urine samples. These data offer an important historical benchmark to which urinary levels from current and future biomonitoring studies can be compared.

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The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system

Cited by 76 publications

References 51 publications

Glyphosate and glyphosate‐based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome

Glyphosate and glyphosate‐based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome

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

Historical evidence of glyphosate exposure from a US agricultural cohort

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