Exposure to a glyphosate-based herbicide affects the reproductive developmental programming with long-term consequences in a rat model.

LORENZ V; MILESI MM; GUERRERO SCHIMPF M; GASTIAZORO MP; PACINI G; CADAVIZ FERNÁNDEZ DB; LUQUE EH; VARAYOUD J

Simposio; International Federation of Placenta Associations 2019 (IFPA2019) - 8th Latin American Symposium on Maternal-Fetal Interaction and Placenta (VIII SLIMP).; 2019

Glyphosate-based herbicides (GBHs) could produce carcinogenic and endocrine disrupting effects on reproductive organs. We investigate whether postnatal exposure to GBH affects the reproductive developmental programming with long-term effects. We evaluate i) uterine sensitivity to estradiol (E2), ii) estrous cyclicity and steroid levels, and iii) carcinogenic effects in aged rats. Female pups were injected subcutaneously with saline solution (control) or GBH (2 mg of glyphosate/kg/day, secure dose according to EPA) during the first week of life. To evaluate the sensitivity to E2, rats were ovariectomized and exogenous treated with implants. Morphological and molecular uterine response to E2 was determined on postnatal day 60. Other animals were used to evaluate the estrous cycle and the steroid serum levels (E2) by RIA and progesterone (P4) by ELISA. Finally, a group of rats was maintained until 20 months of age. The uteri and vagina were processed for histopathology. GBH-treated rats showed a higher sensitivity to E2 evidenced by 1) increased luminal epithelial height, hyperplasia and stromal nuclei density, 2) increased cellular proliferation and induction of estrogenic genes. Also, GBH exposure altered estrous cyclicity in association with increased E2 and decreased P4 serum levels. Furthermore, GBH induced pre-neoplastic and neoplastic lesions, such as glands with daughter glands, uterine leiomyoma and vaginal rhabdomyosarcoma. In conclusion, early life exposure to GBH affected the reproductive developmental programming increasing pre-neoplastic and neoplastic lesions in the uterus and vagina of aged rats. The enhanced sensitivity to E2 and the increased E2/P4 serum levels could be possible mechanisms of induction of carcinogenic and endocrine disrupting effects of GBH.