Developmental exposure to bisphenol A alters the differentiation and functional response of the adult rat uterus to estrogen treatment

We assessed the long-term effect of perinatal exposure to bisphenol A (BPA) on the rat uterus and the uterine response to estrogen (E2) replacement therapy. BPA (0.5 or 50. μg/kg/day) was administered in the drinking water from gestational day 9 until weaning. We studied the uterus of female offspring on postnatal day (PND) 90 and 360, and the uterine E2 response on PND460 (PND460-E2). On PND90, BPA-exposed rats showed altered glandular proliferation and α-actin expression. On PND360, BPA exposure increased the incidence of abnormalities in the luminal and glandular epithelium. On PND460-E2, the multiplicity of glands with squamous metaplasia increased in BPA50 while the incidence of glands with daughter glands increased in BPA0.5. The expression of steroid receptors, p63 and IGF-I was modified in BPA-exposed rats on PND460-E2. The long-lasting effects of perinatal exposure to BPA included induction of abnormalities in uterine tissue and altered response to E2 replacement therapy.Fil: Vigezzi, Lucía. 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; ArgentinaFil: 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; ArgentinaFil: Kass, Laura. 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; ArgentinaFil: 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; ArgentinaFil: 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; ArgentinaFil: 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; Argentin

Neonatal exposure to xenoestrogens impairs the ovarian response to gonadotropin treatment in lambs

Bisphenol A (BPA) and diethylstilbestrol (DES) are xenoestrogens which have been associated with altered effects on reproduction. We hypothesized that neonatal xenoestrogen exposure affects the ovarian functionality in lambs. Thus, we evaluated the ovarian response to exogenous ovine Follicle Stimulating Hormone (oFSH) administered from postnatal day 30 (PND30) to PND32 in female lambs previously exposed to low doses of DES or BPA (BPA50: 50 μg/kg.day, BPA0.5: 0.5 μg/kg.day) from PND1 to PND14. We determined: a) follicular growth, b) circulating levels of E2, c) steroid receptors (ERA, ERB, AR) and atresia, d) mRNA expression levels of the ovarian bone morphogenetic protein (BMPs) system (BMP6, BMP15, BMP receptor type 1B, GDF9) and FSH receptor (FSHR). Lambs neonatally exposed to DES or BPA showed an impaired ovarian response to oFSH with a lower number of follicles ≥2 mm together with a lower number of atretic follicles and no increase in E2 serum levels in response to oFSH treatment. In addition, AR induction by oFSH was disrupted in granulosa and theca cells of lambs exposed to DES or BPA. An increase in GDF9 mRNA expression levels was observed in oFSH-primed lambs previously treated with DES or BPA50. In contrast, a decrease in BMPR1B was observed in BPA0.5-postnatally exposed lambs. The modifications in AR, GDF9 and BMPR1B may be associated with the altered ovarian function due to neonatal xenoestrogen exposure in response to an exogenous gonadotropin stimulus. These alterations may be the pathophysiological basis of subfertility syndrome in adulthood.Fil: Rivera, Oscar E.. Universidad Nacional de Lomas de Zamora. Facultad de Ciencias Agrarias; ArgentinaFil: 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; ArgentinaFil: Rodriguez, Horacio Adolfo. 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; ArgentinaFil: Santamaría, Clarisa Guillermina. 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; ArgentinaFil: 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; ArgentinaFil: Osti, Mario. 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; ArgentinaFil: Belmonte, Norberto Miguel. Universidad Nacional de Lomas de Zamora. Facultad de Ciencias Agrarias; ArgentinaFil: 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; ArgentinaFil: 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; Argentin

Postnatal exposure to a glyphosate-based herbicide modifies mammary gland growth and development in Wistar male rats

Our aim was to evaluate whether postnatal exposure to a glyphosate-based herbicide (GBH) modifies mammary gland development in pre- and post-pubertal male rats. From postnatal day 1 (PND1) to PND7, male rats were injected subcutaneously every 48 h with either saline solution (vehicle) or 2 mg GBH/kg·bw. On PND21 and PND60, mammary gland and blood samples were collected. Estradiol (E2) and testosterone (T) serum levels, mammary gland histology, collagen fiber organization, mast cell infiltration, proliferation index, and estrogen (ESR1) and androgen receptor (AR) expression levels were evaluated. At PND21, GBH-exposed male rats exhibited greater development of the mammary gland with increased stromal collagen organization and terminal end buds (TEBs) compared to control rats. At PND60, the number of TEBs remained high and was accompanied by an increase in mast cell infiltration, proliferation and ESR1 expression in GBH-exposed male rats. In contrast, no effects were observed in E2 and T serum levels and AR expression in both days studied. Our results showed that a postnatal subacute treatment with GBH induces endocrine-disrupting effects in the male mammary gland in vivo, altering its normal development.Fil: Altamirano, Gabriela Anahí. Universidad Nacional del Litoral; ArgentinaFil: Delconte, Melisa. Universidad Nacional del Litoral; ArgentinaFil: Gomez, Ayelen Luciana. 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; ArgentinaFil: Ingaramo, Paola Inés. Universidad Nacional del Litoral; ArgentinaFil: 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; ArgentinaFil: 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; ArgentinaFil: Muñoz de Toro, Monica Milagros. Universidad Nacional del Litoral; ArgentinaFil: Kass, Laura. 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; Argentin

Polycystic ovary syndrome: Importance of inositols in its therapeutics

El síndrome de ovario poliquístico (SOP) es una patología endocrina, de sintomatología variable, con alta prevalencia en mujeres en edad reproductiva. Las mujeres con SOP pueden presentar un amplio espectro de síntomas que incluyen disfunciones metabólicas (resistencia a la insulina, hiperinsulinemia, dislipemia), reproductivas (oligo/anovulación, amenorrea) y endocrinas (hiperandrogenismo, hirsutismo, acné). Las complicaciones metabólicas pueden llevar a que las pacientes desarrollen diabetes mellitus tipo 2, síndrome metabólico y patologías cardiovasculares. Si a esto se suma la ausencia de ciclicidad ovárica y un exceso de los niveles circulantes de andrógenos, las predispone a subfertilidad/infertilidad e incluso a un mayor riesgo de neoplasias uterinas. El uso de modelos animales de SOP, como los desarrollados por nuestro grupo de trabajo, constituye una herramienta imprescindible para estudiar aspectos básicos y moleculares del síndrome que contribuyen con la búsqueda de nuevos blancos terapéuticos. Los inositoles son sensibilizadores de insulina cuyo uso está en investigación para atenuar las complicaciones asociadas al SOP. Su administración oral es bien tolerada por las pacientes. Diferentes estudios se han llevado a cabo evaluando el efecto de las dos principales isoformas: el mioinositol (MIO) y el D-chiro-inositol (DCI). Las investigaciones se realizaron estudiando las isoformas juntas, separadas y/o coadministradas con otras drogas ampliamente utilizadas en estas pacientes (metformina, citrato de clomifeno). El objetivo de la presente revisión es resumir las evidencias obtenidas hasta la fecha sobre los tratamientos, las dosis empleadas, los beneficios y las recomendaciones en el uso de inositoles para el tratamiento de las complicaciones frecuentes en las mujeres que sufren SOP.Polycystic ovary syndrome (PCOS) is an endocrine disease with variable symptoms and a high prevalence in women of reproductive age. Women with PCOS may present a wide spectrum of symptoms, including metabolic (insulin resistance, hyperinsulinemia, dyslipidemia), reproductive (oligo/anovulation, amenorrhea), and endocrine (hyperandrogenism, hirsutism, acne) disorders. Metabolic complications can lead to diabetes mellitus type 2, metabolic syndrome, and cardiovascular diseases. In addition to these complications, if there is an absence of ovarian cyclicity as well as an excess of the circulating levels of androgens, women are predisposed to subfertility / infertility and even a higher risk of uterine neoplasms. The use of animal models of PCOS, such as those developed by our work group, is an essential tool to study basic and molecular aspects of the syndrome that contribute to the search for new therapeutic targets. Inositols are insulin sensitizers whose use is being investigated to reduce complications associated with PCOS. Its oral administration is well tolerated by patients. Different studies have been carried out to evaluate the effect of the two main isoforms, myo-inositol (MIO) and D-chiro-inositol (DCI). During the investigations the isoforms were studied together, separated and/or co-administered with other drugs widely used in these patients (metformin, clomiphene citrate). The aim of this review is to summarize the evidence obtained up to date on the treatments, doses, benefits and recommendations about the use of inositols for the treatment of prevalent complications in women with PCOS.Fil: Bracho, Gisela Soledad. 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; ArgentinaFil: Acosta, María Virginia. 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; ArgentinaFil: 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; ArgentinaFil: 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; Argentin

Perinatal exposure to diethylstilbestrol alters the functional differentiation of the adult rat uterus

The exposure to endocrine disrupters and female reproductive tract disorders has not been totally clarified. The present study assessed the long-term effect of perinatal (gestation + lactation) exposure to diethylstilbestrol (DES) on the rat uterus and the effect of estrogen replacement therapy. DES (5 g/kg bw/day) was administered in the drinking water from gestational day 9 until weaning and we studied the uterus of young adult (PND90) and adult (PND360) females. To investigate whether perinatal exposure to DES modified the uterine response to a long-lasting estrogen treatment, 12-month-old rats exposed to DES were ovariectomized and treated with 17-estradiol for 3 months (PND460). In young adult rats (PND90), the DES treatment decreased both the proliferation of glandular epithelial cells and the percentage of glandular perimeter occupied by -smooth muscle actin-positive cells. The other tissue compartments remained unchanged. Cell apoptosis was not altered in DES-exposed females. In control adult rats (PND360), there were some morphologically abnormal uterine glands. In adult rats exposed to DES, the incidence of glands with cellular anomalies increased. In response to estrogens (PND460), the incidence of cystic glands increased in the DES group. We observed glands with daughter glands and conglomerates of glands only on PND460 and in response to estrogen replacement therapy, independently of DES exposure. The p63 isoforms were expressed without changes on PND460. Estrogen receptors and showed no changes, while the progesterone receptor decreased in the subepithelial stroma of DESexposed animals with estrogen treatment. The long-lasting effects of perinatal exposure to DES included the induction of abnormalities in uterine tissues of aged female rats and an altered response of the adult uterus to estradiol.Fil: Bosquiazzo, Veronica Lis. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Departamento de Fisiologia. Laboratorio de Endocrinologia y Tumores Hormonodependientes; ArgentinaFil: Vigezzi, Lucía. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Departamento de Fisiologia. Laboratorio de Endocrinologia y Tumores Hormonodependientes; ArgentinaFil: Muñoz de Toro, Mónica. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Departamento de Fisiologia. Laboratorio de Endocrinologia y Tumores Hormonodependientes; ArgentinaFil: Luque, Enrique Hugo. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Departamento de Fisiologia. Laboratorio de Endocrinologia y Tumores Hormonodependientes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe; Argentin

Hyperandrogenism Induces Histo-Architectural Changes in the Rat Uterus

The effects of androgens on the uterus have been poorly studied and they need to be clarified to understand why androgen excess, such as observed in women with polycystic ovary syndrome (PCOS), is a risk factor for the development of endometrial hyperplasia, cancer, and infertility. Thus, uterine histomorphology in a PCOS experimental model was evaluated. Beginning at weaning, female rats were injected daily with dehydroepiandrosterone (DHEA, 6 mg/100 g body weight) or vehicle (sesame oil) for 20 consecutive days. On postnatal day 41 (PND41), DHEA-treated animals showed high serum testosterone levels. In addition, uterine histological analysis showed a significant increase in luminal epithelial height and glandular density without changes in cell proliferation. The thickness of the subepithelial stroma and myometrium also increased in these animals. The effect of DHEA on uterine thickness was accompanied by a significant reduction in cell density in both tissue compartments (subepithelial stroma and myometrium). Cell proliferation was not altered in the myometrium, whereas a decrease in the proliferative activity was seen at PND41 in the subepithelial stroma of DHEA animals. The analysis of the extracellular space showed that the changes in the thickness of the subepithelial stroma and myometrium were related to an increase in the organization of collagen fibers and water imbibition. The latter was associated with higher aquaporin 3 and 8 expression. This study provides evidence to further the understanding of PCOS-associated hyperandrogenism effects on uterine architecture. This could have implications for the regulation of uterine function and the development of uterine lesions.Fil: Bracho, Gisela Soledad. 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; ArgentinaFil: Altamirano, Gabriela Anahí. 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; ArgentinaFil: Kass, Laura. 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; ArgentinaFil: 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; ArgentinaFil: 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; Argentin

The estrogen receptor α Σ3 mRNA splicing variant is differentially regulated by estrogen and progesterone in the rat uterus

The gene for estrogen receptor a (ERa) has been shown to be under complex hormonal control and its activity can be regulated by mRNA alternative splicing. Here we examined the regulation of ERa transcription and translation in the rat uterus by ovarian steroid hormones. We examined whether expression of ERa mRNA splic isoforms is hormonally regulated in ovariectomized (OVX) and cycling rats. Adult OVX female rats were treated daily with 17-estradiol (E2) (0·05 μg/rat or 5 μg/rat), progesterone (P4) (1 mg/rat) or a combination of both hormones for 4 days. Animals were killed 24 h after the last injection and uterine horns were removed. In order to determine whether ERa mRNA isoforms are differentially expressed under various physiological conditions, animals were evaluated at proestrus, estrus and diestrus. The ERa protein and mRNA were detected by immunohistochemistry and comparative RT-PCR analysis respectively. The presence of ERa mRNA isoforms was evaluated using a nested RT-PCR assay. In OVX control rats, ERa mRNA and protein levels were high, demonstrating a constitutive expression of the ERa gene in the uterus. When animals received P4 or the high dose of E2,a significant decrease in both ERa mRNA and protein was observed in the uterus. However, when rats were treated with the low dose of E2, only the ERa protein was down-regulated; no changes were observed in ERa mRNA expression. In addition to the full-length ERa mRNA, OVX control rat uteri expressed three shorter transcripts: a3, a4 and a3,4 (lacking exon 3, exon 4, or both 3 and 4 respectively). Surprisingly, when OVX animals were treated with P4, the low dose of E2 or a combination of both steroids, expression of the a3 isoform was completely abolished. During the estrous cycle, all ERa mRNA splicing variants were detected at proestrus and estrus. However, in diestrus, significant low levels of the a3 isoform were observed. In summary, our results suggest a dose-dependent relationship between E2 concentrations and the level of control in the ERa transcription–translation cascade. Moreover, the alternative splicing of the ERa imary transcript is influenced by the hormonal milieu, suggesting that these events could affect the estrogen responsiveness of the rat uterus during the estrous cycle.Fil: Varayoud Jorgelina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; ArgentinaFil: Ramos J Guillermo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; ArgentinaFil: Monje, Lucas Daniel. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; ArgentinaFil: Bosquiazzo, Veronica Lis. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; ArgentinaFil: Muñoz de Toro, Monica Milagros. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; ArgentinaFil: Luque, Enrique Hugo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Fisiología. Laboratorio de Endocrinología y Tumores Hormonodependientes; Argentin

Epigenetic regulation of steroidogenic enzymes expressed in peripheral blood mononuclear cells from healthy individuals and from patients with chronic lymphocytic leukemia

Sex hormone synthesis occurs in various organs and tissues besides the gonads, such as adrenal glands, brain, intestines, skin, fat, bone, and cells of the immune system. Regarding the latter, it is still not clear which pathways are active, and if they are modified in case of illness of the immune system. Our goal in this study was to determine mRNA expression of different steroidogenic enzymes in peripheral blood mononuclear cells (PBMCs) from healthy individuals of both sexes and of different ages, and then to compare their expression between healthy individuals and patients with Chronic Lymphocytic Leukemia (CLL). Furthermore, to elucidate possible mechanisms that regulate enzyme expression, we analyzed epigenetic events like promoter methylation. We determined that normal cells of the immune system, regardless of sex and age, expressed P450 side chain cleavage (P450scc), cytochrome P450 17α-hydroxylase/c17,20-lyase (P45017α), 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3β-HSD), steroid 5 α reductase (5α-R) types 1, 2 and 3, 3α-hydroxysteroid dehydrogenase (3α-HSD) type 3, and 17β-hydroxysteroid dehydrogenase (17β-HSD) types 1, 3 and 5. We also established that 5α-R 1, 5α-R 3, 3α-HSD 3, 17β-HSD 1 and 17β-HSD 5 expression was altered in CLL patients, and that promoter regions of 5α-R 1, 17β-HSD 1 and 17β-HSD 5 were diferentially methylated. These results suggest that steroidogenic pathways may be affected in CLL cells, and this could be related to disease pathogenesis.Fil: Gaydou, Luisa. 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; ArgentinaFil: Rossetti, María Florencia. 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; ArgentinaFil: Tschopp, María Virginia. 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; ArgentinaFil: Stoker, Cora. 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; ArgentinaFil: 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; ArgentinaFil: 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; Argentin

Effects of neonatal exposure to bisphenol A on steroid regulation of vascular endothelial growth factor expression and endothelial cell proliferation in the adult rat uterus

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; ArgentinaFil: Varayoud, Jorgelina Guadalupe. Universidad Nacional del Litoral; ArgentinaFil: Muñoz de Toro, Monica Milagros. Universidad Nacional del Litoral; ArgentinaFil: Luque, Enrique Hugo. Universidad Nacional del Litoral; ArgentinaFil: Ramos, Jorge Guillermo. Universidad Nacional del Litoral; Argentin

Neonatal exposure to low doses of endosulfan disrupts the expression of proteins regulating uterine development and differentiation.

This study investigates the effects of neonatal exposure to low doses of endosulfan on the expression of proteins regulating uterine development and differentiation. Female pups received vehicle, endosulfan (Endo6: 6μg/kg, Endo600: 600μg/kg) or diethylstilbestrol (DES: 0.2μg/kg) from postnatal day 1 (PND1) to PND7. The uterine expression of estrogen receptor alpha (ERα), progesterone receptor (PR), Hoxa10 and alpha smooth muscle actin (α-SMA) was detected by immunohistochemistry on PND8 (neonatal period) and PND21 (prepubertal period), to evaluate acute and short-term responses. ERα, Hoxa10 and α-SMA were induced in the Endo600 group in both ages, while a striking decrease in PR expression was detected in the prepubertal rats following each dose of endosulfan. DES treatment deregulated ERα and Hoxa10 uterine expression at each age. Studies are currently underway to investigate whether the dysregulation of steroid receptors, Hoxa10 and α-SMA observed following neonatal exposure to endosulfan affect uterine functions in adulthood.Fil: Milesi, Maria Mercedes. Universidad Nacional del Litoral; ArgentinaFil: Varayoud, Jorgelina Guadalupe. Universidad Nacional del Litoral; ArgentinaFil: Bosquiazzo, Veronica Lis. Universidad Nacional del Litoral; ArgentinaFil: Muñoz de Toro, Monica Milagros. Universidad Nacional del Litoral; ArgentinaFil: Luque, Enrique Hugo. Universidad Nacional del Litoral; Argentin