Effects of a glyphosate‐based herbicide on the uterus of adult ovariectomized rats

Abstract

Glyphosate is the active ingredient of several herbicide formulations. Different reports suggest that glyphosate-based herbicides (GBHs) may act as endocrine disruptors. We evaluated the potential estrogenic effects of a GBH formulation using the uterotrophic assay. Adult ovariectomized rats were sc injected for 3 consecutive days with: saline solution (vehicle control), 2.10 g E /kg/day (uterotrophic dose; UE ), 2.10 g E /kg/day (nonuterotrophic dose; NUE ), or 0.5, 5, or 50 mg GBH/kg/day of the. Twenty-four hours after the last injection, the uterus was removed and weighed and processed for histopathology and mRNA extraction. Epithelial cell proliferation and height and expression of estrogen-responsive genes were evaluated (estrogen receptors, ERα and ERβ; progesterone receptor, PR; complement 3, C3). Uterine weight and epithelial proliferation were not affected by GBH. However, the luminal epithelial cell height increased at GBH0.5. ERα mRNA was downregulated by all GBH doses and E groups, whereas PR and C3 mRNA were diminished by GBH0.5. GBH5-, GBH50-, and UE -treated rats showed downregulated ERα protein expression in luminal epithelial cells, while the receptor was upregulated in the stroma. GBH upregulated ERβ (GBH0.5-50) and PR (GBH5) expressions in glandular epithelial cells, similar effect to that of NUE group. These results indicate that, although the uterine weight was not affected, GBH modulates the expression of estrogen-sensitive genes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1191-1201, 2017.

Glyphosate-based herbicide enhances the uterine sensitivity to estradiol in rats

“…On the contrary, other studies showed that glyphosate (the active ingredient of formulations) promotes cell proliferation in hormone-dependent breast cancer cells by activating the ESR1 (Thongprakaisang et al 2013, Mesnage et al 2017. Similarly, we and other authors have shown that glyphosate and GBHs can modulate the expression of both ER subtypes in the rat uterus (Varayoud et al 2017) as well as induce ESR1 and ESR2 protein expression in T47D breast cancer cells (Thongprakaisang et al 2013). In the present study, we observed that postnatal exposure to GBH enhanced ESR1 and ESR2 expression in the rat uterus after E2 treatment.…”

Organ Toxicity and Estrogen Like Effects of Cuminum Cyminum.L Seed Essential Oil: A Hormonal, Histopathological and Immunohistochemical Study in Female Mice

“…cyminum essential oil at dose levels of 250,500 and 1000 mg/ day was orally administered to female mice for 14 days caused marked elevation in the body weight , uterus and estradiol levels(p<0.001) whereas the progesterone levels were decreased significantly in all dose groups including 25 mg/kg after 28 days study (p=0.001) . Phytoestrogen properties of cumin extract has been previously described (25)and it was identified useful in treating postmenopausal osteoporosis and estrogen-related disorders in bilaterally ovariectomized rat as an osteoprotective product comparable with estradiol (26).This study suggests the phyotoestrogenic effects of cumin essential oil which should be confirmed by later studies using specific models. On the other side, another study showed a marked reduction in sperm density in the cauda epididymis and testes and sperm motility in the cauda epididymis as well as fertility reduction, significant decreases in the number of testicular cells, secondary spermatocytes and round spermatids (27) with its endocrine disruptive effects.…”

Re-registration Challenges of Glyphosate in the European Union

“…caused a testosterone-disruptor effect (Romano et al, 2012). In addition, nephrotoxicity (Hamdaoui et al, 2016), hepatotoxicity (ElShenawy, 2009;Haskovic et al, 2016;Tang et al, 2017;Lozano et al, 2018), neurotoxicity on dopaminergic markers (Hernández-Plata et al, 2015;Martínez et al, 2018), and on the immature rat hippocampus (Cattani et al, 2014), effects on intestine peristalsis (Chłopecka et al, 2014(Chłopecka et al, , 2017, sperm quality (Abarikwu et al, 2015;Dai et al, 2016) and reproductive toxicity (Owagboriaye et al, 2017), estrogenic effects (Vandenberg et al, 2012;Varayoud et al, 2017) and the effect of neonatal exposure to female adult reproductive performance (Ingaramo et al, 2016 have been demonstrated. Liver dysfunction observed in rats correlated with gut microbiome disturbances identified in a recent study : longterm effects of Roundup Grand Travaux Plus R at 3 doses (corresponding to glyphosate concentrations of 50 ng/l, 100 µg/l, and 2.25 g/l) on the gut microbiota in Sprague-Dawley rats were observed by determining 141 bacteria families by highthroughput sequencing, of which alteration of the Firmicutes to Bacteroidetes ratio was recorded at different levels in females (but not in males).…”

“…Repeated 4-week intranasal administration of Glifoglex R in male CF-1 mice (∼2 mg/nostrils/day) affected the central nervous system (probably by altering neurotransmission pathways), caused neurobehavioral effects (by decreasing the ambulatory activity and increase in thigmotaxis, indicating higher anxiety levels), and impaired recognition memory as early as after 6 h (Baier et al, 2017). Results on hormonal effects of glyphosate-based herbicides on rats indicate modulation of the expression of estrogen-sensitive genes in the exposed animals with non-monotonic dose-response curves , indicating the need for hazard-based considerations in risk assessment (Vandenberg et al, 2012;Varayoud et al, 2017). A recent meta-analysis of eight previous studies on reproductive toxicity on males, carried out between 1992 and 2016, on sperm counts in rodents (Kunming and B6C3F mice and Sprague Dawley, Wistar and Fischer F344 rats) upon glyphosate administration at 40-50,000 mg/kg resulted in decreased sperm concentrations showing that glyphosatebased herbicides exerts reprotoxicity to male rodents.…”