UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression

Bromati CR, Lellis-Santos C, Yamanaka TS, Nogueira TC, Leonelli M, Caperuto LC, Gorjao R, Leite AR, Anhe GF, Bordin S. UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression. Am J Physiol Regul Integr Comp Physiol 300: R92-R100, 2011. First published November 10, 2010; doi:10.1152/ajpregu.00169.2010.-Endocrine pancreas from pregnant rats undergoes several adaptations that comprise increase in beta-cell number, mass and insulin secretion, and reduction of apoptosis. Lactogens are the main hormones that account for these changes. Maternal pancreas, however, returns to a nonpregnant state just after the delivery. The precise mechanism by which this reversal occurs is not settled but, in spite of high lactogen levels, a transient increase in apoptosis was already reported as early as the 3rd day of lactation (L3). Our results revealed that maternal islets displayed a transient increase in DNA fragmentation at L3, in parallel with decreased RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation (pAKT), a known prosurvival kinase. Wortmannin completely abolished the prosurvival action of prolactin (PRL) in cultured islets. Decreased pAKT in L3-islets correlated with increased Tribble 3 (TRB3) expression, a pseudokinase inhibitor of AKT. PERK and eIF2 alpha phosphorylation transiently increased in islets from rats at the first day after delivery, followed by an increase in immunoglobulin heavy chain-binding protein (BiP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in islets from L3 rats. Chromatin immunoprecipitation (ChIP) and Re-ChIP experiments further confirmed increased binding of the heterodimer ATF4/CHOP to the TRB3 promoter in L3 islets. Treatment with PBA, a chemical chaperone that inhibits UPR, restored pAKT levels and inhibited the increase in apoptosis found in L3. Moreover, PBA reduced CHOP and TRB3 levels in beta-cell from L3 rats. Altogether, our study collects compelling evidence that UPR underlies the physiological and transient increase in beta-cell apoptosis after delivery. The UPR is likely to counteract prosurvival actions of PRL by reducing pAKT through ATF4/CHOP-induced TRB3 expression.

Semen parameters, fertility and testosterone levels in male rats exposed prenatally to betamethasone

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Adult partner preference and sexual behavior of male rats exposed prenatally to betamethasone

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Effects of Annona squamosa extract on early pregnancy in rats

Annona squamosa Linn., family Annonaceae, is said to show varied medicinal effects, including insecticide, antiovulatory and abortifacient. The purpose of present study was to investigate if A. squamosa seed aqueous extract, in doses higher than that popularly used to provoke abortion, interferes with reproductive performance, and to correlate the ingestion of this extract with possible alterations in rat embryonic implantation. Doses of 300 mg/kg (Treated Group I, n = 17) and 600 mg/kg (Treated Group II, n = 12) body wt. were administered by gavage, during days 1 to 5 of pregnancy (preimplantation period). The control group (n = 13) received water in the same manner, during the same period for comparison with experimental groups. The animals were euthanized on day 10 of pregnancy. Treatment of dams during the preimplantation period showed no signs of toxicity, and no alteration in the corpora lutea, implantations and embryo in terms of development numbers. The percentage of preimplantation and postimplantation losses in treated groups I and II did not differ from those of control. Treatment with aqueous extract of A. squamosa seeds caused no morphological change in the endometrium. The absence of morphological alterations in uterine epithelial cells in treated groups I and II permitted a viable embryonic implantation, as verified by the number of embryos in development at day 10 of pregnancy. Thus, A. squamosa seed aqueous extract did not interfere with the reproductive performance of pregnant rats.

Hepatoprotective and anti-inflammatory effects of silibinin on experimental preeclampsia induced by 1-NAME in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effect of Bauhinia forficata aqueous extract on the maternal-fetal outcome and oxidative stress biomarkers of streptozotocin-induced diabetic rats

Ethnopharmacological relevance: Bauhinia forficata Link, commonly known as paw-of-cow, is widely used in Brazilian folk medicine for the treatment of diabetes.Aim of this study: To evaluate the effect of Bauhinia forficata treatment on maternal-fetal outcome and antioxidant systems of streptozotocin-induced diabetic rats.Materials and methods: Virgin female Wistar rats were injected with 40 mg/kg streptozotocin before mating. Oral administration of an aqueous extract of Bauhinia forficata leaves was given to non-diabetic and diabetic pregnant rats at increasing doses: 500 mg/kg from 0 to 4th day of pregnancy, 600 mg/kg from 5th to 14th day and 1000 mg/kg from 15th to 20th day. At day 21 of pregnancy the rats were anaesthetized with ether and a maternal blood sample was collected for the determination superoxide dismutase (SOD) and reduced glutathione (GSH). The gravid uterus was weighed with its contents and fetuses were analyzed.Results and conclusion: The data showed that the diabetic dams presented an increased glycemic level, resorption, placental weight, placental index, and fetal anomalies, and reduced GSH and SOD determinations, live fetuses, maternal weight gain, gravid uterine weight, and fetal weight. It was also verified that Bauhinia forficata treatment had no hypoglycemic effect, did not improve maternal outcomes in diabetic rats, but it contributed to maintain GSH concentration similarly to non-diabetic groups, suggesting relation with the decreased incidence of visceral anomalies. (C) 2007 Elsevier B.V. All rights reserved.

Sexual behavior, neuroendocrine, and neurochemical aspects in male rats exposed prenatally to stress

The present study was designed to examine some short- and long-term effects of maternal restraint stress-during the period of sexual brain differentiation-on reproductive and endocrine systems, sexual behavior, and brain neurotransmitters in male rat descendants. Pregnant rats were exposed to restraint stress for 1 h/day from gestational days (GDs) 18 to 22. Prenatal stress did not influence the wet weight of sexual organs and the quantity of germ cells in adult male pups; however, these animals showed reduced testosterone levels, delayed latency to the first mount and first intromission, and also decreased number of ejaculations. Additionally, there was an increase in the dopamine and serotonin levels in the striatum. Our results indicate that prenatal stress had a long-term effect on neurotransmitter levels and sexual behavior. In this sense, reproductive problems caused by injuries during the fetal period can compromise the later success of mating as well as the capacity to generate descendants. (C) 2004 Elsevier B.V. All rights reserved.

Could neonatal testosterone replacement prevent alterations induced by prenatal stress in male rats?

The present study was designed to examine whether testosterone replacement is able to prevent some effects of maternal restraint stress during the period of brain sexual differentiation - on endocrine system and sexual behavior in male rat descendants. Pregnant rats were exposed to restraint stress for 1 h/day from gestational days 18 to 22. At birth, some male pups from these stressed rats received testosterone propionate. The neonatal testosterone replacement was able to prevent the reduction in anogenital distance at 22 days of age observed in pups from stressed pregnant rats as well as prevents the decrease in testosterone levels during the adulthood of these animals. Testosterone replacement in these males also presented an improvement in sexual performance. In this way, testosterone replacement probably through increasing neonatal level of this hormone was able to prevent the later alterations caused by the prenatal stress during the period of brain sexual differentiation. (c) 2005 Published by Elsevier B.V.

Effects of prenatal hydrocortisone acetate exposure on fertility and sexual behavior in male rats

The aim of the present study was to investigate the effects of hydrocortisone during the prenatal period and its later repercussions on the fertility and sexual behavior of male rats. Pregnant rats were treated (s.c.) with hydrocortisone acetate, at 1.5 mg/day on the 17th, 18th, and 19th days of gestation. Decreased body weight and no alteration in anogenital distance were observed in male offspring. Adulthood, presented reductions of body weight, plasma testosterone levels, and seminal-vesicle wet weight without secretion as well as no alteration in the wet weights of the testes, epididymis, and seminal vesicle with secretion in the treated group. Males exposed to hydrocortisone during the prenatal period were able to mate with normal females, which became pregnant but exhibited an increased number of post-implantation losses. In spite of this, these treated males exhibited decreased male sexual behavior and the appearance of female sexual behavior after these male rats were castrated and pretreated with exogenous estrogen. These results indicate that exposure to hydrocortisone in the later stages of pregnancy may have a long-term effect on the fertility and sexual behavior of mate rats, suggesting an incomplete masculinization and defeminization of the central nervous system. (C) 2003 Elsevier B.V. (USA). All rights reserved.

Copulatory efficiency and fertility in male rats exposed perinatally to flutamide

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Reproductive development and function of female rats exposed to di-eta-butyl-phthalate (DBP) in utero and during lactation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Maternal exposure to aqueous extract of Jacaranda decurrens: Effects on reproductive system in male rats

Context: Jacaranda decurrens subsp. symmetrifoliolata Farias & Proenca (Bignoniaceae) is a species widely used for their medicinal properties. At least to our known, no study has been conducted concerning its toxicological profile after gestational and lactational exposure.Objective: The present study was carried out to evaluate the effects of J. decurrens on development of the reproductive system in male rats.Materials and methods: Pregnant rats were treated daily (gavage) with 250 or 500 mg/kg/day of aqueous extract of J. decurrens or vehicle, from day 12 of pregnancy to day 21 of lactation.Results and Discussion: Both doses of J. decurrens significantly anticipated (p < 0.05) the age of testicular descent to the scrotum, a parameter indicative of puberty initiation. Furthermore, at puberty, there was a significant reduction (p < 0.05) in testicular and epididymis weights in the offspring exposed to the higher dose of extract, without effect on sperm production and the histology of reproductive organs. on the other hand, at adulthood, the reproductive parameters analyzed did not differ among groups.Conclusions: J. decurrens, in this experimental model, interfered with the initial development of the reproductive system, but without lasting effects on sperm production in adulthood.

SPERM QUALITY IN ADULT MALE RATS EXPOSED TO CADMIUM IN UTERO and LACTATION

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effects of Gestational and Lactational Fenvalerate Exposure on Immune and Reproductive Systems of Male Rats

The aim of this study was to determine the consequent reproductive developmental and immunotoxic effects due to exposure to fenvalerate during pregnancy and lactation in male offspring of maternal-treated rats. Pregnant rats were treated daily by oral gavage with 40 or 80 mg/kg of fenvalerate or corn oil (vehicle, control), from d 12 of pregnancy to d 21 of lactation. Immune and reproductive developmental effects were assessed in male offspring at postnatal days (PND) 40 (peripuberty), 60 (postpuberty), and 90 (sexual maturity). Treatment with the higher dose (80 mg/kg) resulted in convulsive behavior, hyperexcitability, and mortality in 45% of the dams. Fenvalerate was detected in the fetus due to placental transfer, as well as in pups due to breast-milk ingestion, persisting in male offspring until PND 40 even though pesticide treatment was terminated on PND 20. However, fenvalerate did not produce marked alterations in age of testicular descent to the scrotum and prepucial separation, parameters indicative of puberty initiation. In contrast, at puberty, there was a reduction in testicular weight and sperm production in male offspring of maternal-treated rats. At adulthood, the sperm counts and fertility did not differ between control and treated groups. Testosterone levels were not changed at any time during reproductive development. Similarly, no apparent exposure-related effects were detected in the histological structures of the lymphohematopoietic system. Data indicate that fenvalerate, in this experimental model, interfered with initial development of the male reproductive system, but that these effects on sperm production or fertility did not persist into adulthood. There was no apparent evidence that fenvalerate altered testosterone levels or produced a disruption in male endocrine functions.

Assessment of Female Reproductive Endpoints in Sprague-Dawley Rats Developmentally Exposed to Diuron: Potential Ovary Toxicity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)