Alterações neuroendócrinas causadas por disruptores endócrinos: o exemplo do Bisfenol A

Los contaminantes ambientales, como los disruptores endocrinos,podrían provocar profundos cambios en los seres vivos. Aqui se analizan las alteraciones neuroendocrinas y reproductivas en mamíferos, incluyendo las descriptas en humanos, causadas por una molécula de origen industrial, el Bisfenol A.Exposure to endocrine disruptors may produce profound alterations in several species. As an example, the neuroendocrine and reproductive alterations due to Bisphenol A in mammals are summarized here.Os contaminantes ambientais, como os disruptores endócrinos, poderiam provocar profundas alterações nos seres vivos. Aqui são analisadas as alterações neuroendócrinas e reprodutivas em mamíferos, incluindo as descritas em humanos, causadas por uma molécula de origem industrial,o Bisfenol AFil: Bourguignon, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Fernández, Marina . Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Libertun, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Neonatal Exposure to Bisphenol A and Reproductive and Endocrine Alterations Resembling the Polycystic Ovarian Syndrome in Adult Rats

Bisphenol A (BPA), an endocrine disruptor, is a component of polycarbonate plastics, epoxy resins, and polystyrene. Several studies have reported potent in vivo effects, because BPA behaves as an estrogen agonist and/or antagonist and as an androgen and thyroid hormone antagonist. We investigated the effects of neonatal exposure to BPA on the reproductive axis in adult female Sprague-Dawley rats.Fil: Fernandez, Marina Olga. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Bourguignon, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Libertun, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Sodium arsenite, an endocrine disruptor that affects the reproductive axis and glucose homeostasis

La contaminación con As (As) en el agua de bebida se considera una amenaza para la salud en todo el mundo, ya que está asociado a un mayor riesgo de contraer enfermedades como cáncer de piel y pulmón, provocar efectos indeseables sobre el desarrollo, la reproducción las secreciones internas y alteraciones cardiovasculares. Debido a que el As puede actuar como un disruptor endócrino aquí investigamos el efecto de la exposición a As, durante períodos críticos del desarrollo neuroendócrino como es la gestación y las semanas postparto, sobre el eje reproductivo y el metabolismo de la glucosa, en las madres y sus crías. Se administraron 5 (A5) o 50 ppm (A50) de arsenito de sodio en el agua de bebida a ratas Sprague Dawley preñadas, desde el día 1 de gestación hasta el sacrificio (2 meses postparto). Al destete, se dividieron las crías en dos grupos: uno continuó recibiendo el mismo tratamiento que la madre y el otro recibió agua destilada hasta el día del sacrificio (4 meses). En las madres, la exposición a As produjo alteraciones en la homeostasis de la glucosa durante la preñez, probablemente alterando la funcionalidad de las células β, incrementando el riesgo de desarrollar diabetes gestacional. Además, alteró la fisiología reproductiva, sugiriendo el desarrollo de una falla ovárica prematura. Las crías expuestas a As durante el desarrollo presentaron alteraciones en la fisiología reproductiva, principalmente las hembras, mientras que el metabolismo de la glucosa no se vio afectado.Arsenic contamination in drinking water is considered a worldwide threat to health, that is associated with an increased risk of diseases such as skin and lung cancer, cause undesirable effects on development, internal reproduction secretions and cardiovascular disorders. Because As can act as an endocrine disruptor, here we investigated the effect of As exposure, during critical periods of neuroendocrine development as gestation and postnatal weeks, on the reproductive axis and metabolism of glucose in dams and their offspring. We administered 5 (A5) or 50 ppm (A50) of sodium arsenite in drinking water to Sprague Dawley rats from gestational day 1 until sacrifice (two months postpartum). At weaning the offspring were divided in two groups: one of each continued to receive the same treatment and the other one received distilled water until sacrifice (4 months of age). In dams, As exposure induces glucose homeostasis alterations during pregnancy, probably by altering β-cell function, increasing the risk of developing gestational diabetes. In addition, profoundly impaired reproductive physiology, suggesting premature ovarian failure due to arsenic exposure, may have developed. Offspring rats exposed to arsenic during development present altered reproductive physiology, mainly females, while metabolism is not affected.Fil:Bourguignon, Nadia Soledad. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

DUAL MODULATION OF NK2 TACHYKININ RECEPTOR SIGNALLING PATHWAYS BY AN ALLOSTERIC COMPOUND.Running Title: Dual allosteric modulation of NK2R

International audienceWhen stimulated by its natural agonist, neurokinin A, the tachykinin NK2 receptor undergoes stabilization in two active states that mediate distinct intracellular responses, a phospholipase C-mediated calcium response and an adenylyl cyclase-mediated cAMP production. Here, we show that the new compound LPI 805 modulates not only binding of agonists, but also differentially affects calcium and cAMP responses in opposite ways. LPI 805 has no biological activity by itself. It accelerates dissociation kinetics of bound neurokinin A by altering the equilibrium between the two active states of the NK2 receptor. In co-application with agonists, LPI 805 potentiates calcium responses and simultaneously decreases, or even abolishes, cAMP-dependent responses of NK2 receptors. LPI 805 thus behaves as an allosteric modulator that exhibits dual positive/negative response regulation of the NK2 tachykinin receptor. These data not only strengthen to the notion of multiple active, and interconvertible conformations of G protein-coupled receptors, but also opens new ways to design pharmacological agents able to selectively modulate a subset of intracellular responses linked to members of this important receptor family

Neonatal exposure to bisphenol A alters the hypothalamic-pituitary-thyroid axis in female rats

Bisphenol A (BPA) is a component of polycarbonate plastics, epoxy resins and polystyrene found in many common products. Several reports revealed potent in vivo and in vitro effects. In this study we analyzed the effects of the exposure to BPA in the hypothalamic-pituitary-thyroid axis in female rats, both in vivo and in vitro. Female Sprague-Dawley rats were injected sc from postnatal day 1 (PND1) to PND10 with BPA: 500 μg 50 μl−1 oil (B500), or 50 μg 50 μl−1 (B50), or 5 μg 50 μl−1 (B5). Controls were injected with 50 μl vehicle during the same period. Neonatal exposure to BPA did not modify TSH levels in PND13 females, but it increased them in adults in estrus. Serum T4 was lower in B5 and B500 with regards to Control, whereas no difference was seen in T3. No significant differences were observed in TRH, TSHβ and TRH receptor expression between groups. TSH release from PPC obtained from adults in estrus was also higher in B50 with regard to Control. In vitro 24 h pre-treatment with BPA or E2 increased basal TSH as well as prolactin release. On the other hand, both BPA and E2 lowered the response to TRH. The results presented here show that the neonatal exposure to BPA alters the hypothalamic pituitary-thyroid axis in adult rats in estrus, possibly with effects on the pituitary and thyroid. They also show that BPA alters TSH release from rat PPC through direct actions on the pituitary.Fil: Fernandez, Marina Olga. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bourguignon, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Arocena, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rosas, Nicolás Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Libertun, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Non-invasive endocrine monitoring of ovarian and adrenal activity in chinchilla (Chinchilla lanigera) females during pregnancy, parturition and early post-partum period

The chinchilla is a rodent that bears one of the finest and most valuable pelts in the world. The wild counterpart is, however, almost extinct because of a drastic past and ongoing population decline. The present work was developed to increase our knowledge of the reproductive physiology of pregnancy and post-partum estrus in the chinchilla, characterizing the endocrine patterns of urinary progesterone, estradiol, LH and cortisol metabolites throughout gestation and post-partum estrus and estimating the ovulation timing at post-partum estrus.Longitudinal urine samples were collected once per week throughout pregnancy and analyzed for creatinine, cortisol, LH, estrogen and progesterone metabolite concentrations. To indirectly determine the ovulation timing at post-partum estrus, a second experiment was performed using pregnant females subjected to a post-partum in vivo fertilization scheme. Urinary progestagen metabolites increased above baseline levels in early pregnancy between weeks-8 and -11 respectively to parturition, and slightly declined at parturition time. Urinary estrogens showed rising levels throughout mid- and late pregnancy (weeks-9 to -6 and a further increase at week-5 to parturition) and decreased in a stepwise manner after parturition, returning to baseline levels two weeks thereafter. Cortisol metabolite levels were relatively constant throughout pregnancy with a tendency for higher levels in the last third of gestation and after the pups´ birth. Parturition was associated with dramatic reductions in urinary concentrations of sex steroids (especially progestagens). Observations in breeding farms indicated that the females that resulted in a second pregnancy after mating, did so on the second day after parturition. These data were in agreement with an LH peak detected 24. h after parturition. Urinary steroid hormone patterns of estrogen and progestagen metabolites provided valuable information on endocrine events during pregnancy and after parturition in the chinchilla. Results presented in this study enhance our understanding of natural reproductive dynamics in the chinchilla and support empirical observations of breeders that post-partum ovulation occurs ~48. h after parturition.Fil: Mastromonaco, Gabriela F.. Toronto Zoo. Reproductive Physiology; CanadáFil: Cantarelli, Verónica Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Galeano, Maria Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Bourguignon, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gilman, Christine. Toronto Zoo. Reproductive Physiology; CanadáFil: Ponzio, Marina Flavia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentin

Evaluation of sodium arsenite exposure on reproductive competence in pregnant and postlactational dams and their offspring

We investigated arsenite exposure on the reproductive axis of dams (during pregnancy and at cyclicity resumption) and their offspring. Pregnant rats were exposed to 5 (A5) or 50 ppm (A50) of sodium arsenite in drinking water from gestational day 1 (GD1) until sacrifice at GD18 or two months postpartum. Offspring were exposed to the same treatment as their mothers from weaning to adulthood. A50-pregnant rats gained less weight, showed increased testosterone and estradiol but pregnancy was unaffected. After lactation, arsenic-exposed dams presented compromised cyclicity, decreased estradiol, increased follicle-stimulating hormone (FSH), less preovulatory follicles and presence of ovarian cysts, suggesting impaired reproduction. A50-offspring presented lower body weight; A50-female-offspring showed elevated gonadotropin releasing hormone (GnRH), FSH and testosterone, while A50-males showed diminished GnRH/FSH, but normal testosterone. We conclude that arsenite at the present exposure levels did not compromise pregnancy outcome while it negatively affected reproductive physiology in postpartum dams and their offspring.Fil: Bourguignon, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bonaventura, Maria Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rodríguez, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bizzozzero Hiriart, Marianne. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ventura, Clara. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Nuñez, Mariel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Libertun, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Abundance and size of hyaluronan in naked mole-rat tissues and plasma

Large amounts of ultra-high molecular weight hyaluronan (HA) have been described as the main cause of cancer resistance in naked mole-rats (Heterocephalus glaber, NMR). Our work examined HA metabolism in these rodents more closely. HA was localized and quantified using HA binding proteins. Its molecular weight was determined using size exclusion chromatography and gel electrophoresis, HA family gene expression using RNAseq analysis, and hyaluronidase activity using zymography. Guinea pigs (Cavia porcellus) and mice (Mus musculus) were used as controls for some experiments. We found that HA localization was similar in NMR, guinea pig, and mouse tissues but NMR had larger amounts and higher molecular weight (maximum, around 2.5 MDa) of HA in serum and almost all tissues tested. We could not find ultra-high molecular weight HA (≥ 4 MDa) in NMR samples, in contrast to previous descriptions. Hyaluronidase-1 had lower expression and activity in NMR than mouse lymph nodes. RNAseq results showed that, among HA family genes, Tnfaip6 and hyaluronidase-3 (Hyal3) were systematically overexpressed in NMR tissues. In conclusion, NMR samples, contrary to expectations, do not harbor ultra-high molecular weight HA, although its amount and average molecular weight are higher in NMR than in guinea pig tissues and serum. Although hyaluronidase expression and activity are lower in NMR than mouse lymph nodes, this not sufficient to explain the presence of high molecular weight HA. A different activity of the NMR HA synthases remains possible. These characteristics, together with extremely high Hyal3 and Tnfaip6 expression, may provide the NMR with a bespoke, and perhaps protective, HA metabolism