Neonatal glyphosate based herbicide exposure enhances the sensitivity of the rat uterus to estradiol

GUERRERO SCHIMPF M; MILESI MM; LUQUE EH; VARAYOUD J

Buenos Aires

Congreso; LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2017

Sociedad Argentina de Investigación Clínica (SAIC)

Endometrial adenocarcinoma is considered to be relatedwith a hyperestrogenic state, often associated with endometrial hyperplasia. Ina previous work, we demonstrated that neonatal exposure to a glyphosate basedherbicide (GBH) alters uterine development in prepubertal rats causingendometrial hyperplasia together with increased cell proliferation. Our goal inthe present study was to determine whether exposure to low-dose of a GBH duringpostnatal development might enhance the sensitivity of the uterus to anestrogenic treatment. Female Wistar pups were injected subcutaneously with salinesolution (control, C) or GBH using the reference dose (2 mg/kg/day, EPA) on postnataldays (PND) 1, 3, 5, and 7. At weaning (PND21), female rats were bilaterallyovariectomized and treated with silastic capsules filled with 17â-estradiol (E2, 1mg/ml) until they were two months of age. On PND60, uterinesamples were removed and processed for histology and for mRNA extraction toevaluate: i) morphological changes, ii) cell proliferation by Ki67immunostaining and, iii) the expression of the estrogen receptors alpha (ESR1)and beta (ESR2) using immunohistochemistry and real time PCR. GBH treatment eliciteduterine histological abnormalities after E2 stimulation. The luminal andglandular epithelium in three out of seven GBH-exposed animals were markedlyhyperplastic. Moreover, the luminal epithelial cells of the GBH group showed adramatically increase in cell proliferation (C: 16.36 ± 1.10%; GBH: 29.07 ±3.89%, p<0.05) in association with a strong induction of ESR1 (C: 2.03 ±0.36; GBH: 4.05 ± 0.30, p<0.05). In animals treated with GBH, ESR2expression was upregulated at transcriptional and translational levels, whereasrelative expression of ESR1 mRNA was downregulated when compared to controlanimals. These results suggest that early postnatal exposure to a GBH enhances the sensitivityof the rat uterus to estradiol and these changes could predispose to the developmentof endometrial cancer. Key words: glyphosate based herbicide; uterus; estradiol; proliferation; estrogenreceptors