DEVELOPMENTAL EXPOSURE TO A GLYPHOSATE-BASED HERBICIDE INCREASES THE RISK OF NEOPLASTIC LESIONS IN UTERUS AND VAGINA OF AGED RATS

GUERRERO SCHIMPF ML; MILESI MM; GASTIAZORO MP; LUQUE EH; VARAYOUD, JORGELINA

Congreso; II latin american congress of clinical and laboratorial toxicology. Modern toxicology for health and prevention; 2018

Introduction: Glyphosate-based herbicides (GBHs) have been one of the most intensive herbicideused over the last two decades. In the last years, it has been controversy regarding itscarcinogenic potential. While the European Food Safety Authority concluded ?no evidence ofcarcinogenicity was confirmed in either rats or mice?, the International Agency for Research onCancer found there is ?sufficient evidence of carcinogenicity in animals?. Thus, the carcinogenicpotential of glyphosate and GBHs in laboratory animals remains uncertain. Estrogens have beenimplicated as important etiologic agents of cancer in the female reproductive system. Increasedserum 17β-estradiol (E2)/progesterone (P4) ratio has been demonstrated to be a mechanism ofcarcinogenesis in estrogen-dependent tissues.Objectives: Investigate whether a brief postnatal exposure to GBH disrupts estrous cyclicity andhormone steroid levels, and causes gynecologic neoplastic lesions in aged rats.Methodology: All procedures used in this study were approved by the Institutional EthicsCommittee of the School of Biochemistry and Biological Sciences (UNL). Female Wistar pups wereinjected subcutaneously with saline solution (control, C) or GBH at a dose of 2 mg/kg/day(reference dose, EPA) on postnatal days (PND) 1, 3, 5, and 7. Animals were kept with feed andwater ad libitum without further treatment until adulthood. From PND120 the estrous cycle wasdaily monitored by vaginal smears. In addition, blood from the tail was obtained at the estrousstage to determine E2 and P4 serum levels by RIA and ELISA, respectively. Finally, the animalswere sacrificed at 20 months of age, and the uteri and vagina were dissected and processed forhistopathology.Results/Discussion: GBH-exposed rats showed alterations in estrous cyclicity associated withchanges in E2 and P4 serum levels. An increased level of E2 (C: 28.94±1.36 vs. GBH: 33.46±1.03pg/ml, p<0.05) and decreased level of P4 (C: 10.91±0.19 vs. GBH: 7.39±0.65 ng/ml, p<0.001) wasdetected in GBH-exposed rats. Control aged rats showed uterine glandular abnormalities (pre-neoplastic lesions) associated with aging, such as glands with squamous metaplasia and glandswith daughter glands (GDG). GBH-exposed rats showed an increased incidence of GDG (C: 2/11vs. GBH: 5/10). Furthermore, GBH exposure elicited the development of neoplastic lesions.Uterine leiomyoma (10% of rats) and vaginal rhabdomyosarcoma (20% of rats) were detected inGBH-exposed rats.Conclusions: Developmental exposure to GBH increases the risk to develop pre-neoplastic andneoplastic lesions in the uterus and vagina of aged rats. A possible mechanistic explanation ofthese effects could be associated with increased E2/P4 serum levels and abnormal estrouscyclicity.