Postnatal exposure to a glyphosate-based herbicide modifies mammary gland growth and development in Wistar male rats

Altamirano, Gabriela A.; Delconte, Melisa B.; Gómez, Ayelén L.; Ingaramo, Paola I.; Bosquiazzo, Verónica L.; Luque, Enrique H.; Muñoz-de-Toro, Mónica; Kass, Laura

doi:10.1016/j.fct.2018.05.011

Cited by 34 publications

(10 citation statements)

References 62 publications

(71 reference statements)

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“…Glyphosate may act as an endocrine disrupting chemical (EDC) because it has been found recently to alter sex hormone production. Several in vivo studies of male rats exposed to glyphosate have reported significantly lower testosterone levels [94][95][96], spermatid numbers [94], altered sperm and testicular morphology [94,95], greater development of the mammary gland [97], and a surge in mast cell infiltration and proliferation accompanied by increased estrogen receptor (ESR1) [97]. In ovarian granulosa cells, glyphosate exposure resulted in decreased cell proliferation and estradiol production [98], which may contribute to lymphomagenesis [93].…”

Section: Endocrine Disruptionmentioning

confidence: 99%

Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence

Zhang

Rana

Shaffer

et al. 2019

Mutation Research/Reviews in Mutation Research

257

122

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Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that included the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% CI, confidence interval: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we determined a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed available animal and mechanistic studies, which provided supporting evidence for the carcinogenic potential of GBH. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly *

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Section: Endocrine Disruptionmentioning

confidence: 99%

Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence

Zhang

Rana

Shaffer

et al. 2019

Mutation Research/Reviews in Mutation Research

257

122

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“…Since the late 1970s, the volume of GBHs applied has increased around 100-fold [31]. The widespread exposure of human population to GBHs has raised public health concerns, including potential effects on the endocrine system, for example by inhibiting aromatase enzyme activity [14, 39] and/or by activating estrogen receptors (ERs) [1, 21, 46, 49]. In vitro, the reduction in aromatase activity has been reported in placental and embryonic human cells treated with low concentrations of Roundup [5, 39] and other formulations [14].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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BackgroundGlyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be “safe” (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats.MethodsGlyphosate alone and Roundup Bioflow, a commercial brand of GBHs, were administered in drinking water at 1.75 mg/kg bw/day to F0 dams starting from the gestational day (GD) 6 (in utero) up to postnatal day (PND) 120. After weaning, offspring were randomly distributed in two cohorts: 8 M + 8F/group animals belonging to the 6-week cohort were sacrificed after puberty at PND 73 ± 2; 10 M + 10F/group animals belonging to the 13-week cohort were sacrificed at adulthood at PND 125 ± 2. Effects of glyphosate or Roundup exposure were assessed on developmental landmarks and sexual characteristics of pups.ResultsIn pups, anogenital distance (AGD) at PND 4 was statistically significantly increased both in Roundup-treated males and females and in glyphosate-treated males. Age at first estrous (FE) was significantly delayed in the Roundup-exposed group and serum testosterone concentration significantly increased in Roundup-treated female offspring from the 13-week cohort compared to control animals. A statistically significant increase in plasma TSH concentration was observed in glyphosate-treated males compared with control animals as well as a statistically significant decrease in DHT and increase in BDNF in Roundup-treated males. Hormonal status imbalances were more pronounced in Roundup-treated rats after prolonged exposure.ConclusionsThe present pilot study demonstrate that GBHs exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs in both males and females, delay of FE and increased testosterone in female.Electronic supplementary materialThe online version of this article (10.1186/s12940-019-0453-y) contains supplementary material, which is available to authorized users.

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“…Even if still controversial, the ability of G to activate ER in vitro has been demonstrated ( 34 , 36 ), and confirmations also came from experimental animals, showing ERα activation following herbicide exposure in male and female rats ( 37 , 38 ). The possible role of ER in G-immunotoxicity is strengthened by the ability of estrogens to influence Th1 and Th2 responses, with a promotion toward Th2 activity ( 39 ), and to allergic airway inflammation ( 40 ).…”

Section: Discussionmentioning

confidence: 98%

Direct Effects of Glyphosate on In Vitro T Helper Cell Differentiation and Cytokine Production

et al. 2022

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Glyphosate (G) is the active ingredient of the most used herbicides worldwide. Its use is currently very debated, as several studies indicating its hazard and toxicity are emerging. Among them, there is evidence of adverse effects on the immune system. The aim of this work was to investigate if G could directly affect immune cells. Peripheral blood mononuclear cells (PBMC) obtained from healthy donors were used as experimental model. PBMC were expose to G and stimulated with PMA/ionomycin, T helper (Th) cell differentiation and cytokine production were assessed by flow cytometry and enzyme-linked immunosorbent assay, respectively. A reduction of Th1/Th2 ratio, mainly due to a decrease in Th1 cells, was observed following G exposure. Results show an enhancement of IL-4 and IL-17A production, and a reduction of IFN-γ. Based on literature evidence that suggest G being an endocrine disruptor, we investigated the role of nuclear estrogen receptors (ER). ERα/ERβ inhibition by ICI 182,780 abolished the effects of G on IFN-γ and IL-4 release, suggesting a role of ER in the observed effects. To further characterize the mechanism of action of G, miRNAs, both in exosome and intracellular, were investigated. A statistically significant increase in miR-500a-5p was observed following G treatment. The blockage of miR-500a-5p, using a specific antagomir, prevented G-induced reduction of IFN-γ production. Finally a relationship between miR-500a-5p up-regulation and ER was observed. Overall, these results suggest that G can directly act on T cells, altering T cell differentiation and cytokines production.

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Postnatal exposure to a glyphosate-based herbicide modifies mammary gland growth and development in Wistar male rats

Cited by 34 publications

References 62 publications

Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence

Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence

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

Direct Effects of Glyphosate on In Vitro T Helper Cell Differentiation and Cytokine Production

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