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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), 2.10−5 g E2/kg/day (uterotrophic dose; UE2), 2.10−7 g E2/kg/day (nonuterotrophic dose; NUE2), 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 E2 groups, whereas PR and C3 mRNA were diminished by GBH0.5. GBH5-, GBH50-, and UE2-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 NUE2 group. These results indicate that, although the uterine weight was not affected, GBH modulates the expression of estrogen-sensitive genes. Fil: Varayoud, Jorgelina Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Durando, Milena de Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Ramos, Jorge Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Milesi, Maria Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Ingaramo, Paola Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Muñoz de Toro, Monica Milagros. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Luque, Enrique Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina

Studies regarding the effects of endocrine-disrupting chemicals (EDCs) on the reproductivefunctions of wild animals have raised increasing concern. Thus, here we evaluated theconsequences of in ovo exposure to endosulfan (END) and bisphenol A (BPA) in testes fromneonatal to juvenile (Juv) caimans (Caiman latirostris). Caiman eggs were collected from areaswith low to moderate anthropogenic intervention and incubated at male-producing temperature.At stage 20 of embryonic development (previous to gonad sex determination), eggs were exposedto either END (20 ppm) or BPA (1.4 ppm) and male gonad histomorphology examined in 10-day-old, 90-day-old, and Juv caimans. The relative seminiferous tubular area (RTA) was measuredin testes and the proliferation index and the expression of estrogen receptor alpha (ERa) werequantified in intratubular cells. Regardless of the treatment, all eggs resulted in male hatchlings.The testes of EDC-exposed caimans presented tortuous seminiferous tubules with empty tubularlumens. The RTA of 10-day-old caimans exposed to BPA was decreased. The percentage of cellsexpressing ERa was not different after in ovo treatment with EDCs (compared to the Controlgroup), although caimans exposed to END showed a different ERa distribution pattern. Theproliferation index was lower in 90-day-old caimans exposed to END, and higher in Juv caimansexposed to BPA. In ovo exposure to END or BPA modified sensitive parameters of C. latirostris malegonads. The alterations described here might compromise not only the sexual maturation but alsothe reproductive performance of adult caimans. Fil: Durando, Milena de Lourdes. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina Fil: Canessini Guillermina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina Fil: Cocito, Laura Leilén. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina Fil: Galoppo, Germán Hugo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina Fil: Zayas, Marcelo Alejandro. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina Fil: Luque, Enrique Hugo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina Fil: Muñoz de Toro, Monica Milagros. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina

Successful implantation is the result of complex molecular interactions between the hormonally primed uterus and a mature blastocyst. This very carefully synchronized interplay of hormonal signals and feedback loops is potentially vulnerable to chemicals such as endocrine disruptors that may disrupt endocrine signaling. Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide. This chapter describes the effects of brief postnatal exposure to BPA on female reproductive performance and specifically on the uterine adaptations during the preimplantation period. We propose that an early alteration in Hoxa10 gene expression affects the functional differentiation of the preimplantation uterus as part of an altered endocrine signal transduction pathway. These molecular alterations could explain, at least in part, the adverse effects of BPA on uterine implantation. Exposure to endocrine disruptors, such as BPA, could contribute to the impaired female fertility noted over the past decades. Fil: Varayoud, Jorgelina Guadalupe. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina Fil: Ramos, Jorge Guillermo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina Fil: Muñoz de Toro, Monica Milagros. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina Fil: Luque, Enrique Hugo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina

Hormonally controlled vascular changes play a key role in endometrial development and in the differentiation process necessary for implantation. Vascular endothelial growth factor (VEGF) has emerged as one of the central regulators of the uterine vasculature. Hormonal perturbations during neonatal development may alter sex steroid-dependent regulation of VEGF and may ultimately affect fertility later in life. The aim of this study was to determine whether neonatal exposure to the environmental estrogenic chemical bisphenol A (BPA) affects the adult rat uterine response to hormonal stimuli. Newborn female rats were given s.c. injections of vehicle, BPA (0.05 mg/kg per day or 20 mg/kg per day) or diethylstilbestrol (0.2 μg/kg per day) on Postnatal Days 1, 3, 5, and 7. To evaluate the long-term effects, rats were ovariectomized at Postnatal Day 80 and submitted to hormonal replacement. Rats neonatally exposed to xenoestrogens showed a decreased induction of uterine endothelial proliferation and a decreased Vegf mRNA expression in response to ovarian steroid treatment. Also, although the estrogen receptor alpha (ESR1) expression was lower in subepithelial cells than in controls, a higher expression of silencing mediator of retinoic acid and thyroid hormone receptor (NCOR1, also known as SMRT) corepressor was evidenced in the same compartment. The results indicate that disturbed Vegf expression in BPA rats could be the result of changes in endocrine pathways, such as an altered induction of ESR1 and/or NCOR1 expression. Because of the importance of VEGF in the implantation process, our data suggest that neonatal BPA exposure might have negative consequences on female fertility. Fil: Bosquiazzo, Veronica Lis. Universidad Nacional del Litoral; Argentina Fil: Varayoud, Jorgelina Guadalupe. Universidad Nacional del Litoral; Argentina Fil: Muñoz de Toro, Monica Milagros. Universidad Nacional del Litoral; Argentina Fil: Luque, Enrique Hugo. Universidad Nacional del Litoral; Argentina Fil: Ramos, Jorge Guillermo. Universidad Nacional del Litoral; Argentina

Estrogen receptor a (ERa) gene has been demonstrated to be under complex hormonal control and its activity could be regulated by mRNA alternative splicing. Here we investigated the regulation of transcription and translation of ERa in the rat uterus by ovarian steroids. We examined whether ERa mRNA splice isoforms expression is hormonally regulated. Adult ovariectomized (OVX) female rats were treated daily with 17-bestradiol (E2) (0.05 mg or 5 mg), progesterone (P4) (1 mg) or a combination of both hormones for 4 days. Animals were killed 24 h after the last injection and uterine horns were removed. The ERa protein and mRNA were evaluated by immunohistochemistry and RT-PCR analysis, respectively. In controls ERa mRNA and protein levels were high, demonstrating a constitutive expression of the ERa gene in the OVX rat uterus. When animals received P4 or the high dose of E2, the uterus showed a significant decrease of ERa mRNA and protein. However, when rats were treated with the low dose of E2 the ERa protein just showed a down regulation. In addition to the full length ERa mRNA, OVX control rat uterus expressed three shorter transcripts: S3, S4 and S3,4 (lacking exon 3, 4 and 3,4 respectively). Surprisingly, treatments with P4 and/or the low dose of E2 completed abolished the S3 isoform expression. In summary, our results suggest a dose dependent relationship between E2 and the level of control in the ERa transcription-translation cascade. Moreover, the alternative splicing of the ERa primary transcript is influenced by the hormonal milieu, suggesting that these events could affect the estrogen responsiveness of the rat uterus. Fil: Varayoud, Jorgelina Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Ramos, Jorge Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Monje, Lucas Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Bosquiazzo, Veronica Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Muñoz de Toro, Monica Milagros. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Luque, Enrique Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina