Glyphosate-based herbicide worsens alterations induced by cafeteria diet on rat uterus.

Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17ß-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.

Disruption of developmental programming with long-term consequences after exposure to a glyphosate-based herbicide in a rat model.

Glyphosate-based herbicides (GBHs) have been associated with endocrine disrupting effects on reproductive organs. We examined whether postnatal exposure to GBH affects developmental programming of the uterus with long-term consequences. Female Wistar pups received vehicle (control) or GBH (2 mg of glyphosate/kg/day) from postnatal day (PND) 1 to PND7, where the developing uterus is highly sensitive to endocrine disruption. Short-, mid- and long-term effects were evaluated on PND8, PND120 and PND600, respectively. GBH induced hyperplasia and epigenetic alterations in the uterus of neonatal females (PND8). DNA hypermethylation, enrichment of H3K9me3 and reductions of H3K27me3 at regulatory regions of the morphoregulatory gene Hoxa10 resulted in gene downregulation. In young adult females (PND120), GBH increased 17ß-estradiol (E2) and decreased progesterone (P4) serum levels, altering estrous cyclicity. Aged females (PND600) exposed to GBH developed leiomyoma and pre-neoplastic glandular lesions in the uterus. Vaginal rhabdomyosarcoma and intrahepatic bile duct adenoma were also observed. In conclusion, neonatal exposure to GBH altered the expression and induced hypermethylation of the Hoxa10 gene in uterine tissue at early life, and increased E2/P4 ratio serum level at middle-age. We propose that epigenetic reprogramming of Hoxa10 in association with hormonal imbalance could be among the possible mechanisms underlying the long-term adverse effects detected in GBH-exposed rats.

AHR agonistic effects of 6-PN contribute to potential beneficial effects of Hops extract.

Hops (Humulus lupulus) is used as an alternative to hormone replacement therapy due to the phytoestrogen, 8-prenylnaringenin (8-PN). To examine the potential risks/benefits of hops extract and its compounds (8-PN and 6-prenylnaringenin, 6-PN), we aimed to evaluate the estrogen receptor α (ERα) and aryl hydrocarbon receptor (AHR) signaling pathways in human endometrial cancer cells. Hops extract, 8-PN and 6-PN showed estrogenic activity. Hops extract and 6-PN activated both ERα and AHR pathways. 6-PN increased the expression of the tumor suppressor gene (AHRR), and that of genes involved in the estrogen metabolism (CYP1A1, CYP1B1). Although 6-PN might activate the detoxification and genotoxic pathways of estrogen metabolism, hops extract as a whole only modulated the genotoxic pathway by an up-regulation of CYP1B1 mRNA expression. These data demonstrate the relevant role of 6-PN contained in the hops extract as potential modulator of estrogen metabolism due to its ERα and AHR agonist activity.