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Sildenafil attenuates oxidative stress and endothelial dysfunction in lead-induced hypertension
(2023-01-01) Caetano, Ediléia Souza Paula [UNESP]; Mattioli, Sarah Viana [UNESP]; da Silva, Maria Luiza Santos [UNESP]; Martins, Laisla Zanetoni [UNESP]; Almeida, Alaor Aparecido [UNESP]; da Rocha, Ananda Lini Vieira [UNESP]; Nunes, Priscila Rezeck [UNESP]; Grandini, Núbia Alves [UNESP]; Correa, Camila Renata [UNESP]; Zochio, Gabriela Palma [UNESP]; Dias-Junior, Carlos Alan [UNESP]; Universidade Estadual Paulista (UNESP)
Lead (Pb) reduces NO bioavailability, impairs the antioxidant system, and increases the generation of reactive oxygen species (ROS). Pb-induced oxidative stress may be responsible for the associated endothelial dysfunction. Sildenafil has shown nitric oxide (NO)-independent action, including antioxidant effects. Therefore, we examined the effects of sildenafil on oxidative stress, reductions of NO and endothelial dysfunction in Pb-induced hypertension. Wistar rats were distributed into three groups: Pb, Pb + sildenafil and Sham. Blood pressure and endothelium-dependent vascular function were recorded. We also examined biochemical determinants of lipid peroxidation and antioxidant function. ROS levels, NO metabolites and NO levels in human umbilical vein endothelial cells (HUVECs) were also evaluated. Sildenafil prevents impairment of endothelium-dependent NO-mediated vasodilation and attenuates Pb-induced hypertension, reduces ROS formation, enhances superoxide dismutase (SOD) activity and antioxidant capacity in plasma and increases NO metabolites in plasma and HUVECs culture supernatants, while no changes were found on measurement of NO released from HUVECs incubated with plasma of the Pb and Pb + sildenafil groups compared with the sham group. In conclusion, sildenafil protects against ROS-mediated inactivation of NO, thus preventing endothelial dysfunction and attenuating Pb-induced hypertension, possibly through antioxidant effects.
Embryo-fetal safety evaluation of ondansetron in rats
(2023-04-01) Reis, Ana Carolina Casali [UNESP]; Jorge, Bárbara Campos [UNESP]; da Silva Moreira, Suyane [UNESP]; Stein, Júlia [UNESP]; Perdão, Carolina Barizan [UNESP]; de Matos Manoel, Beatriz; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (UNESP); Federal University of Grande Dourados
Background: Ondansetron is a 5HT3 receptor antagonist, used to mitigate the effects of nausea and vomiting after chemotherapy or surgery. Since nausea and vomiting are common experiences during the first trimester of pregnancy, this antiemetic has been the main drug used during this period. Methods: To evaluate the effects of ondansetron on the embryo-fetal development, which are still very contradictory, pregnant rats were exposed to therapeutic doses of ondansetron (1.7 or 2.5 mg/kg) daily, from gestational day (GD) 6 to 15. Results: No clinical signs of toxicity were observed in dams during the treatment. Although the hemato-biochemical parameters were similar among the groups, histological changes, as well as a reduction in the weight of kidney were found in the treated dams. After fetal examination, no visceral and skeletal abnormalities were observed in treated fetuses. Conclusion: In conclusion, therapeutic doses of ondansetron have low teratogenic potential in rats. These data provide important information about the drug safety during pregnancy.
Safety evaluation of ondansetron after gestational exposure on male reproductive parameters in rats
(2023-01-01) Reis, Ana Carolina Casali [UNESP]; Jorge, Bárbara Campos [UNESP]; Stein, Julia [UNESP]; Moreira, Suyane da Silva [UNESP]; Manoel, Beatriz de Matos [UNESP]; Aquino, Ariana Musa [UNESP]; Valente, Leticia Cardoso; Kassuya, Cândida Aparecida Leite; Scarano, Wellerson Rodrigo [UNESP]; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (UNESP); Federal University of Grande Dourados (UFGD)
Ondansetron is a 5HT3 receptor antagonist widely used to treat hyperemesis gravidarum, although its safety is still questionable. Since 5HT3 receptors, which are the target of this drug, can interfere with brain development through changes in neurotransmitter levels, this study evaluated whether the prenatal exposure to this drug could compromise reproductive and behavioral parameters in male offspring. Pregnant rats were treated with ondansetron (1.7 and 2.5 mg/kg/body weight; gavage), from gestational day 1–21. No exposure-related changes in clinical signs, body weight, food consumption, pregnancy length, and necropsy findings were observed in dams. Ondansetron exposure did not alter the anogenital distance or age of preputial separation in male offspring. Similarly, males exposed to therapeutic doses of ondansetron did not exhibit changes in play behavior. In adulthood, there were no changes in sperm parameters, as well as in testosterone level, sexual behavior and fertility. Furthermore, ondansetron did not interfere with testicular and epididymal histology, and with androgen receptor expression in hypothalamus. In conclusion, prenatal exposure to ondansetron did not cause maternal toxicity, as well as did not interfere with reproductive parameters of male offspring, indicating its safety after gestational exposure in rats.
Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre-eclampsia
(2023-05-01) Palei, Ana C.; Cruz, Juliana de O.; Chaguri, João Leandro [UNESP]; Peraçoli, José Carlos [UNESP]; Romão-Veiga, Mariana [UNESP]; Ribeiro-Vasques, Vanessa R. [UNESP]; Cavalli, Ricardo C.; Nunes, Priscila R. [UNESP]; Luizon, Marcelo R.; Sandrim, Valéria C. [UNESP]; University of Mississippi Medical Center; Universidade Federal de Minas Gerais (UFMG); Universidade Estadual Paulista (UNESP); Universidade de São Paulo (USP)
Objective: To assess and compare circulating tissue inhibitor of metalloproteinase 3 (TIMP-3) concentrations between women with pre-eclampsia and healthy pregnant women. We also aimed to determine the relationships between circulating TIMP-3 and matrix metalloproteinase 2 (MMP-2), MMP-9, TIMP-1, and TIMP-2 concentrations in pre-eclampsia. Methods: A primary case–control study included patients with pre-eclampsia (n = 219) and gestational hypertension (n = 118), healthy pregnant women (n = 214), and non-pregnant women (n = 66), and a replication case–control study included patients with pre-eclampsia (n = 177) and healthy pregnant women (n = 124), all from southeastern Brazil. Plasma TIMP-3, MMP-2, MMP-9, TIMP-1, and TIMP-2 concentrations were assessed using commercially available enzyme-linked immunosorbent assay kits, and the relationships between them were analyzed using Spearman's correlation. Results: In our primary study, patients with pre-eclampsia and gestational hypertension exhibited increased TIMP-3 concentrations compared with healthy pregnant women (both P < 0.0001) and non-pregnant women (both P < 0.001). These findings were confirmed in the replication study, showing elevated TIMP-3 concentrations in women with pre-eclampsia versus healthy pregnant women (P < 0.001). We found no difference in TIMP-3 concentrations between early-onset and late-onset pre-eclampsia. Moreover, TIMP-3 concentrations were significantly correlated with plasma concentrations of TIMP-1 (r = 0.2333; P = 0.0086) and MMP-2 (r = 0.2159; P = 0.0156) in pre-eclampsia. Conclusions: Circulating TIMP-3 concentration is increased in women with pre-eclampsia compared with healthy pregnant women, and it is positively correlated with plasma MMP-2 and TIMP-1 concentrations in pre-eclampsia.
Long-term reproductive effects of benzo(a)pyrene at environmentally relevant dose on juvenile female rats
(2022-01-01) Reis, Ana Carolina Casali [UNESP]; Jorge, Bárbara Campos [UNESP]; Paschoalini, Beatriz Rizzo [UNESP]; Bueno, Jéssica Nogueira [UNESP]; Stein, Julia [UNESP]; Moreira, Suyane da Silva [UNESP]; Manoel, Beatriz de Manoel [UNESP]; Fernandes, Glaura Scantamburlo Alves; Hisano, Hamilton; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (UNESP); Universidade Estadual de Londrina (UEL); Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA)
Since studies on the reproductive consequences after the exposure to environmentally relevant doses of Benzo(a)pyrene (BaP) during critical stages of development are scarce, this study evaluated female reproductive parameters of adult rats exposed to a low dose of BaP during the juvenile phase. Female rats (Post-natal 21) were treated with BaP (0 or 0.1 µg/kg/day; gavage) for 21 consecutive days. During the treatment, no clinical signs of toxicity were observed. Nevertheless, the ages of vaginal opening and first estrus were anticipated by the BaP-exposure. At the sexual maturity, the juvenile exposure compromised the sexual behavior, as well as the placental efficiency, follicle stimulating hormone levels, placenta histological analysis, and ovarian follicle count. A decrease in erythrocyte, platelet, and lymphocyte counts also was observed in the exposed-females. Moreover, the dose of BaP used in this study was not able to produce estrogenic activity in vivo. These data showed that juvenile BaP-exposure, at environmentally relevant dose, compromised the female reproductive system, possibly by an endocrine deregulation; however, this requires further investigation.
Lactational exposure to venlafaxine provokes late repercussions on reproductive parameters in male rat offspring
(Wiley-Blackwell, 2022-09-10) Moreira, Suyane da Silva [UNESP]; Manoel, Beatriz de Matos; Inacio, Joao Pedro Gaspar [UNESP]; Souza, Carolina Gabrielli de [UNESP]; Reis, Ana Carolina Casali [UNESP]; Jorge, Barbara Campos [UNESP]; Aquino, Ariana Musa de [UNESP]; Scarano, Wellerson Rodrigo [UNESP]; Cardoso, Claudia Lima Andrea; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (UNESP); Fed Univ Grande Dourados; Universidade Estadual de Mato Grosso do Sul (UEMS)
Exposure to selective serotonin reuptake inhibitors can affect hormone-dependent processes, such as the brain sexual differentiation. Because the use of these antidepressants cause concern during lactation, we evaluated the possible effects of venlafaxine on lactational exposure and its late repercussions on reproductive parameters in male rats. Lactating rats were exposed to venlafaxine (3.85, 7.7, or 15.4 mg/kg/body weight; gavage), from lactational day 1 to 20. Venlafaxine and O-desmethylvenlafaxine residues were found in all milk samples of dams treated, demonstrating the lactational transfer of this antidepressant to the offspring. Although the maternal behavior was normal, the dams presented an increase in urea and uric acid levels in the groups treated with 7.7 and 15.4, respectively, as well as a spleen weight increased in the 3.85 and 15.4 groups. The male offspring showed a decrease in play behavior parameters in the intermediate dose group. Sperm analysis indicated a reduction in sperm motility in all treated groups. The androgen receptor expression in the hypothalamus was decreased in the highest dose group, although the sexual behavior had not been affected. In conclusion, venlafaxine was transferred through breast milk and promoted changes in play behavior, sperm quality, and hypothalamic androgen receptor (AR) content, which may indicate an incomplete masculinization of the brain of male offspring.
Safety assessment of the ethanolic extract from Piper vicosanum yunck leaves in male rats
(2022-02-01) Jorge, Bárbara Campos [UNESP]; Júnior, Armando Jorge; Stein, Julia [UNESP]; Reis, Ana Carolina Casali [UNESP]; Moreira, Suyane da Silva [UNESP]; Manoel, Beatriz de Matos; Mota, Jonas da Silva; Kassuya, Cândida Aparecida Leite; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (UNESP); Federal University of Grande Dourados; Universidade Estadual de Mato Grosso do Sul (UEMS)
Background: Piper vicosanum (Piperaceae) is a species used in folk medicine mainly due to its anti-inflammatory and analgesic properties. However, the data available about its safety are still insufficient. Purpose: This study evaluated the toxicological profile and reproductive impacts in male rats treated with the ethanolic extract from Piper vicosanum leaves (EEPV) during a 28-day treatment. Methods: Male Wistar rats received ethanol extract of EEPV (0, 100, 200, or 300 mg/kg) by gavage for 28 consecutive days. Results: Males treated with EEPV did not exhibit clinical signs of toxicity during the treatment. Although hematological parameters were unaltered, a decrease in AST, total proteins, alkaline phosphatase and creatinine levels was observed in the treated animals. However, no evidence of histological changes was found in the liver and kidney. EEPV also induced an increase of abnormal sperm in males. Conclusion: The prolonged use of ethanolic extract of Piper vicosanum leaves affected biochemical and sperm parameters, showing that care should be taken when it is used for prolonged periods. Further studies, including a 90-day toxicity assay, should be performed.
Can maternal exposure to tamoxifen compromise sperm and behavioural parameters of male rat offspring?
(2022-03-01) de Matos Manoel, Beatriz; da Silva Moreira, Suyane [UNESP]; Zampieri, Gabriela Morelli [UNESP]; Machado Pinheiro, Luísa [UNESP]; Jorge, Bárbara Campos [UNESP]; Casali Reis, Ana Carolina [UNESP]; Leite Kassuya, Cândida Aparecida; Arena, Arielle Cristina [UNESP]; Universidade Federal da Grande Dourados – UFGD; Universidade Estadual Paulista (UNESP)
Tamoxifen, a selective non-steroidal estrogen receptor modulator, is the standard adjuvant endocrine treatment for breast cancer. Since information on the risk of using tamoxifen during pregnancy is still scarce, this study evaluated whether the in utero and lactational treatment with this drug could compromise reproductive and behavioural parameters in male offspring. Pregnant Wistar rats were exposed to three doses of tamoxifen (0.12; 0.6; 3 μg/kg), by gavage, from gestational day 15 to lactational day 20. Tamoxifen exposure did not alter the anogenital distance in the male offspring; however, there was a significant increase in the body weight in the 0.12 μg/kg dose and a decrease in the 0.6 μg/kg dose. The male offspring treated with the highest dose exhibited a delay in the onset of puberty, evidenced by an increase in the age of preputial separation. Regarding sperm parameters, there was an increase in the sperm count in the cauda epididymis in the intermediate and highest dose groups, in addition to an increase in the number of static sperm and a decrease in the progressive sperm in the same groups. Moreover, an increase in the number of hyperplasia of the epithelial clear cells was observed in the epididymis. In conclusion, the present study demonstrated that maternal exposure to tamoxifen compromised the installation of puberty of the male offspring and the maturation of the epididymis, affecting sperm storage and motility in the adult life.
Preeclampsia and Gestational Hypertension: Biochemical and Antioxidant Features in Vitro Might Help Understand Different Outcomes
(2021-12-01) Galvão, Victoria Elizabeth [UNESP]; Cavalli, Ricardo Carvalho; Sandrim, Valeria Cristina [UNESP]; Universidade Estadual Paulista (UNESP); Universidade de São Paulo (USP)
Objective Gestational hypertension (GH) is characterized by increased blood pressure after the 20 thgestational week; the presence of proteinuria and/or signs of end-organ damage indicate preeclampsia (PE). Heme oxygenase-1 (HO-1) is an antioxidant enzyme with an important role in maintaining endothelial function, and induction of HO-1 by certain molecules shows potential in attenuating the condition's effects over endothelial tissue. HO-1 production can also be stimulated by potassium iodide (KI). Therefore, we evaluated the effects of KI over HO-1 expression in human umbilical vein endothelial cells (HUVECs) incubated with plasma from women diagnosed with GH or PE. Methods Human umbilical vein endothelial cells were incubated with a pool of plasma of healthy pregnant women (n = 12), pregnant women diagnosed with GH (n = 10) or preeclamptic women (n = 11) with or without the addition of KI for 24 hours to evaluate its effect on this enzyme expression. Analysis of variance was performed followed by Dunnet's test for multiple comparisons between groups only or between groups with addition of KI (p ≤ 0.05). Results KI solution (1,000 μM) reduced HO-1 in the gestational hypertension group (p = 0.0018) and cytotoxicity in the preeclamptic group (p = 0.0143); treatment with KI reduced plasma cytotoxicity but did not affect the preeclamptic group's HO-1 expression. Conclusion Our findings suggest that KI alleviates oxidative stress leading to decreased HO-1 expression; plasma from preeclamptic women did not induce the enzyme's expression in HUVECs, and we hypothesize that this is possibly due to inhibitory post-transcriptional mechanisms in response to overexpression of this enzyme during early pregnancy.
Lowland tapir exposure to pesticides and metals in the Brazilian Cerrado
(2020-01-01) Medici, Emília P.; Fernandes-Santos, Renata Carolina; Testa-José, Caroline; Godinho, Antonio Francisco [UNESP]; Brand, Anne-Fleur; Instituto de Pesquisas Ecológicas (IPÊ); IUCN SSC Tapir Specialist Group (TSG); Escola Superior de Conservação Ambiental e Sustentabilidade (ESCAS/IPÊ); Universidade Estadual Paulista (Unesp); Utrecht University
Context. The Cerrado is a Global Biodiversity Hotspot as well as Brazil's main frontier for large-scale agriculture and livestock production, making it one of the most threatened biomes in the country. Brazil is one of the biggest consumers of pesticides in the world and allows the use of chemicals that are banned in many other countries due to their adverse health effects in a wide range of species, including humans. Aims. This study aimed to assess pesticide and metal exposure of the lowland tapir - a threatened, large herbivorous mammal - to support future studies of the role of these chemicals in tapir health, survivorship, and population viability. Methods. Foot pad, proboscis, stomach contents, liver, bone, and nail samples were obtained from tapir carcasses found along highways (n ¼ 87). (i) Atomic absorption spectrophotometry (AAS) was used to detect metals in bone, nail and liver tissue; (ii) gas chromatography - nitrogen phosphorous detector (GC-NPD) to detect organophosphates in liver and skin; and (iii) high performance liquid chromatography - ultraviolet (HPLC-UV) to detect pyrethroids and carbamates in stomach contents. Key results. Two carbamates (aldicarb and carbaryl), three organophosphates (diazinon, malathion, and mevinphos), two pyrethroids (deltamethrin and permethrin), and two toxic metals (cadmium and lead) were detected in different tapir tissue samples, some at concentrations high enough to cause adverse health effects. In 90% of roadkill tapirs that were subjected to a full post-mortem examination (n ¼ 25), macroscopic alterations of liver and/or kidney tissue were observed. Conclusions. This study provides the first report to date of the detection of pesticides and metals in lowland tapirs. Implications. Some of the reported pesticide concentrations exceed environmental safety thresholds. Consequently, results from this study raise concerns over potential adverse health effects in tapirs that could lead to population level impacts, thus requiring further investigation.
Parental exposure to benzo(a)pyrene in the peripubertal period impacts reproductive aspects of the F1 generation in rats
(2021-03-01) Jorge, Bárbara Campos [UNESP]; Reis, Ana Carolina Casali [UNESP]; Stein, Julia [UNESP]; Balin, Paola da Silva [UNESP]; Sterde, Érika Tissiana [UNESP]; Barbosa, Mariana Gazoli [UNESP]; de Aquino, Ariana Musa [UNESP]; Kassuya, Cândida Aparecida Leite; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (Unesp); Federal University of Grande Dourados
Benzo(a)pyrene (BaP) is an ubiquitous environmental pollutant which can lead to adverse effects on male reproduction. However, the persistence of these changes on a multigenerational scale has not been sufficiently explored. This study evaluated if peripubertal exposure to BaP in male rats can induce reproductive impairment in offspring. Male rats received BaP at environmentally relevant doses (0, 0.1, 1, or 10 μg/kg/day) orally from post-natal (PND) 23–53. On PND 90, treated males were mated with non-treated females for obtaining the next generation (F1). The paternal exposure to BaP decreased the body weight of offspring on PND 1, 13 and 22, as well as it provoked a reduction in the relative anogenital distance of the males. This exposure also brought forward the onset of puberty, evidenced by an earlier vaginal opening and first estrous in females of the lowest dose group and by a delay in the testicular descent and preputial separation ages in males. The males presented a decrease in the daily sperm production and a disrupted sperm morphology. Furthermore, the testicular histology was altered, evidenced by a reduction in the Leydig cell numbers and in the seminiferous tubules diameter, as well as a disrupted seminiferous tubules staging. The estrous cyclicity and some fertility parameters were changed in the females, as well as alterations in the ovary and uterus histology were observed. BaP compromised several reproductive parameters of the F1 generation, suggesting that peripubertal exposure to this compound provokes permanent modifications in male germ line of F0 generation.
Effects of benzo(a)pyrene at environmentally relevant doses on embryo-fetal development in rats
(2021-05-01) da Silva Moreira, Suyane [UNESP]; de Lima Inocêncio, Leonardo Cesar [UNESP]; Jorge, Bárbara Campos [UNESP]; Reis, Ana Carolina Casali [UNESP]; Hisano, Hamilton; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (Unesp); Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA)
Studies have demonstrated that Benzo(a)Pyrene (BaP), a polycyclic aromatic hydrocarbon ubiquituous in the environment, can cause teratogenic effects. Since the majority of studies used in vitro models or high doses of BaP, this study evaluated the teratogenicity, reproductive and developmental performance of low doses of BaP through maternal and fetus examination after daily oral administration of BaP (0; 0.1; 1.0 or 10 μg/kg) to pregnant Wistar rats from Gestational day (GD) 6 to GD 15 (the organogenesis period). Pregnant rats did not exhibit clinical signs of toxicity during the exposure period. However, dams exposed to the lowest dose of BaP showed a reduction in the erythrocytes number and in the creatinine levels. The groups exposed to 0.1 and 1.0 μg/kg presented a decrease in placental efficiency, as well as an increase in placental weight. After fetal examination, the treated group with the lowest dose showed a reduced relative anogenital distance, while the curve of normal distribution of weight was changed in the highest dose group. In addition, anomalies evidenced by changes in the renal size and degree of fetal ossification were observed in treated-fetus. In conclusion, treatment with BaP during organogenesis at this dose level is detrimental to the normal development of fetuses.
Ibuprofen compromises sexual behavior and fertility in female rats exposed during the perinatal period
(2020-10-20) Jorge, Bárbara Campos [UNESP]; Balin, Paola da Silva [UNESP]; Carneiro, Giovanna de Brito [UNESP]; Belleti, Rafael [UNESP]; Reis, Ana Carolina Casali [UNESP]; Stein, Julia [UNESP]; de Barros, Aline Lima; Kassuya, Cândida Aparecida Leite; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (Unesp); Universidade Estadual de Mato Grosso do Sul (UEMS); Federal University of Grande Dourados
The influence of ibuprofen exposure during the perinatal period, when the brain sexual differentiation process occurs, on the sexual behavior and fertility of female offspring Wistar rats has been evaluated. Ibuprofen was orally administered to the dams at doses of 0, 10, 30 or 60 mg/kg during the gestational (from day 15 to delivery) and lactational period. Females exposed to ibuprofen showed no signs of maternal toxicity. However, ibuprofen provoked a reduction in intrauterine and postnatal growth in female offspring. The treated offspring also showed a decrease in the anogenital distance at birth, while no difference was observed in external signs of the onset of puberty. At adulthood, although the ibuprofen did not interfere with the estrous cyclicity, the lordosis quotient of treated females was reduced. Furthermore, these females presented reduced fertility and low fetal and placenta weights. The females also presented an increase in the percentage of small fetuses and a reduction in the large fetuses for their gestational ages. Perinatal exposure to ibuprofen may interfere with the sexual differentiation of the brain of female offspring of Wistar rats, causing a long-term impact in the sexual behavior and fertility of these females.
Exposure to benzo(a)pyrene from juvenile period to peripubertal impairs male reproductive parameters in adult rats
(2021-01-01) Jorge, Bárbara Campos [UNESP]; Reis, Ana Carolina Casali [UNESP]; Sterde, Érika Tissiana [UNESP]; Balin, Paola da Silva [UNESP]; Scarano, Wellerson Rodrigo [UNESP]; Hisano, Hamilton; Arena, Arielle Cristina [UNESP]; Universidade Estadual Paulista (Unesp); Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA)
Benzo(a)pyrene (BaP) is a persistent organic pollutant and endocrine disruptor that can compromise the steroidogenesis process by interacting with the StAR protein, causing adverse effects on male reproduction. However, consequences of prepubertal BaP exposure and its impacts on adult life are yet unknown. This study investigated the effects of BaP exposure from the juvenile period to peripubertal on reproductive parameters in adult male rats. Males were exposed to 0; 0.1; 1 or 10 μg/kg/day of BaP from post-natal (PND) 23 to PND 53 (by gavage). The lowest dose of BaP was able to compromise the male copulatory behavior, as evidenced by the delay in the first mount, intromission and ejaculation. Furthermore, BaP-treated groups showed lower sperm quality (disrupted motility and morphology) and quantity, reduced relative weights of the thyroid and seminal gland. Serum testosterone levels and the Leydig cells nuclei volume were decreased by BaP exposure whereas the StAR expression was increased. Histopathological changes in the testis also were detected in the males exposed to BaP. These results showed that prepubertal BaP-exposure adversely influenced the male reproductive system in the adult life, indicating that a comprehensive risk assessment of BaP-exposure on prepubertal period is necessary. Prepubertal BaP-exposure compromised reproductive parameters in male rats, causing permanent changes in StAR protein expression in testis.
Characterization of leachate produced by a landfill and its influence on a sewage treatment plant
(2020-01-01) Destro, Guilherme E. [UNESP]; Junior, Sergio S. Braga [UNESP]; Tadayozzi, Yasmin S. [UNESP]; Almeida, Alaor A. [UNESP]; Chaves, Andrea R.; Forti, Juliane C. [UNESP]; Universidade Estadual Paulista (Unesp); Chemistry Institute
Although landfills are generally an environmentally safe option for the disposal of solid waste, the treatment and management of landfill leachate are still critical. The aim of this work was to study through physical-chemical analyses the effects of leachate on the effluent of the sewage treatment plant to which it is disposed on both study sites. The results were compared with those of existing studies, current legislation, municipal waste management practices, and landfill operations. Ethinylestradiol analyses were also performed on the influent and effluent from the sewage treatment plant. The results showed that the landfill leachate has a polluting potential, being found parameters above the allowed value, such as chemical oxygen demand (3,510.33 mg L−1), chloride (3,631.78 mg L−1), and manganese (21.61 mg L−1). The properties of the leachate indicated that the landfill was still in the acid formation phase and did not influence the influent that reached the sewage treatment plant in any way. Ultimately, the quality of the discharged wastewater met all of the predischarge regulatory criteria for materials being sent to a receiving water body, except for the chloride parameter that is not being treated at all.
Circulating heme oxygenase-1: Not a predictor of preeclampsia but highly expressed in pregnant women who subsequently develop severe preeclampsia
(2018-01-01) Sandrim, Valéria C. [UNESP]; Caldeira-Dias, Mayara [UNESP]; Bettiol, Heloisa; Barbieri, Marco Antonio; Cardoso, Viviane Cunha; Cavalli, Ricardo Carvalho; Universidade Estadual Paulista (Unesp); Universidade de São Paulo (USP)
Preeclampsia is the major cause of maternal and fetal deaths worldwide. Circulating biomarker concentrations to predict preeclampsia must be determined. Therefore, the objective was to evaluate heme oxygenase-1 (HO-1) concentration in both plasma and urine samples from pregnant women before the development of preeclampsia and to identify a potential biomarker for preeclampsia development. We performed a case-control study nested in a prospective study cohort at University Hospital of the Ribeirao Preto Medical School, University of São Paulo (HCFMRP-USP), Ribeirao Preto, Brazil. Of 1400 pregnant women evaluated at 20-25 weeks of gestation, 460 delivered in hospitals outside our institution. Of 940 pregnant women who completed the protocol, 30 developed preeclampsia (cases, 14 cases of severe preeclampsia and 16 cases of mild preeclampsia). Healthy pregnant women (controls, n = 90) were randomly selected from the remaining 910 participants. HO-1 concentration was evaluated in plasma/urine samples by using a commercial enzyme-linked immunosorbent assay kit. We found similar HO-1 levels in the plasma and urine for case and control groups. In the subgrouped preeclampsia, lower plasma HO-1 levels were found in mild compared with severe preeclampsia. We conclude that plasma HO-1 levels were not altered at 20-25 weeks of gestation before the manifestation of preeclampsia symptoms. Pregnant women who subsequently develop severe preeclampsia show higher expression of HO-1. This may be indicative of important underlying pathophysiologic mechanisms that differentiate between mild and severe preeclampsia and may possibly be related to a higher prooxidative status even before the development of clinical symptoms.
Tobacco influence in heavy metals levels in head and neck cancer cases
(2018-09-01) Bandeira, Celso Muller [UNESP]; de Almeida, Adriana Ávila [UNESP]; Carta, Celina Faig Lima; Almeida, Alaor Aparecido [UNESP]; de Figueiredo, Fellipe Augusto Tocchini [UNESP]; Sandrim, Valeria Cristina [UNESP]; Gonçalves, Antonio José; Almeida, Janete Dias [UNESP]; Universidade Estadual Paulista (Unesp); University Braz Cubas; Irmandade daSanta Casa de Misericordia de Sao Paulo (ISCMSP)
Heavy metals intoxication is known to be risk factors for various diseases, including cancer. These metals may be presented in food and soil as well as in leaf and tobacco smoke. The aim of this study was to correlate the exposure to heavy metals stemming from tobacco and head and neck squamous cell carcinoma carcinogenesis. Analysis of lead, copper, manganese, arsenic, chromium, and cadmium by atomic absorption spectrophotometry was performed in whole blood samples from 91 patients: 68 smokers with oral cavity, pharynx, or laryngeal cancer; 8 non-smokers with oral or larynx cancer; and 15 non-cancer smokers with tobacco-related diseases (control group). No differences were found in metals quantifications, except a significant difference was observed (p = 0.0223) with higher mean in copper levels for non-smokers with cancer. The present study concluded, for the groups evaluated, it was not possible to prove the relationship between the studied metals in the development of the neoplasm. On the other hand, the results of copper demonstrated a correlation with smokers with cancer and lower levels of circulating copper.
Insecticidal activity of an essential oil of Tagetes patula L. (Asteraceae) on common bed bug Cimex lectularius L. and molecular docking of major compounds at the catalytic site of ClAChE1
(2017-01-01) Politi, Flávio Augusto Sanches [UNESP]; Nascimento, Juliana Damieli [UNESP]; da Silva, Alexander Alves [UNESP]; Moro, Isabela Jacob [UNESP]; Garcia, Mariana Lopes; Guido, Rafael Victório Carvalho; Pietro, Rosemeire Cristina Linhari Rodrigues [UNESP]; Godinho, Antônio Francisco [UNESP]; Furlan, Maysa [UNESP]; Universidade Estadual Paulista (Unesp); Universidade de São Paulo (USP)
Emerging resistance to insecticides has influenced pharmaceutical research and the search for alternatives to control the common bed bug Cimex lectularius. In this sense, natural products can play a major role. Tagetes patula, popularly known as dwarf marigold, is a plant native to North America with biocide potential. The aim of this work was to evaluate the biological activity of T. patula essential oil (EO) against adult common bed bugs via exposure to dry residues by the Impregnated Paper Disk Test (IPDT) using cypermethrin as a positive control. We selected the enzyme acetylcholinesterase as a target for modeling studies, with the intent of investigating the molecular basis of any biological activity of the EO. Chemical analysis of the EO was performed using gas chromatography coupled to mass spectrometry (GC-MS). Additionally, oral and dermal acute toxicity tests were performed according to Organization for Economic Cooperation and Development (OECD) guidelines. The sulforhodamine B assay (SRB) was performed to verify the cytotoxicity of EO to HaCaT cells. The EO eliminated 100 % of the bed bugs at 100 mg mL−1 with an LC50 value of 15.85 mg mL−1. GC-MS analysis identified α-terpinolene, limonene, piperitenone, and piperitone as major components of the mixture. Molecular modeling studies of these major compounds suggested that they are acetylcholinesterase inhibitors with good steric and electronic complementarity. The in vitro cytotoxicity evaluation revealed a LC50 = 37.06 μg mL−1 and in vivo acute toxicity showed an LC50 >4000 mg kg−1, indicating that the EO presents low risk of toxic side effects in humans. The T. patula essential oil components provide a promising strategy for controlling bed bug populations with low mammalian toxicity. These findings pave the way for further in vivo studies aimed at developing a safe and effective insecticide.
Memory impairment due to fipronil pesticide exposure occurs at the GABAA receptor level, in rats
(2016-10-15) Godinho, Antonio Francisco [UNESP]; Chagas, Ana Carolina Souza [UNESP]; Carvalho, Caio Cristóvão [UNESP]; Horta, Daniel França [UNESP]; De Fraia, Daniel [UNESP]; Anselmo, Fabio [UNESP]; Chaguri, João Leandro [UNESP]; Faria, Caique Aparecido [UNESP]; Universidade Estadual Paulista (Unesp)
Fipronil (F) a pesticide considered of second generation cause various toxic effects in target and non-target organisms including humans in which provoke neurotoxicity, having the antagonism of gamma-amino butyric acid (GABA) as their main mechanism for toxic action. GABAergic system has been involved in processes related to the memory formation and consolidation. The present work studied the importance of GABA to the mechanisms involved in the very early development of fipronil-induced memory impairment in rats. Memory behavior was assessed using new object recognition task (ORT) and eight radial arm maze task (8-RAM) to study effects on cognitive and spatial memory. Locomotor behavior was assessed using open field task (OF). The dose of fipronil utilized was studied through a pilot experiment. The GABA antagonist picrotoxin (P) was used to enhance fipronil effects on GABAergic system. Fipronil or picrotoxin decrease memory studied in ORT and 8-RAM tasks. Additionally, F and P co-exposure enhanced effects on memory compared to controls, F, and P, suggesting strongly a GABAergic effect. Weight gain modulation and fipronil in blood were utilized as animal's intoxication indicators. In conclusion, here we report that second-generation pesticides, such as fipronil, can have toxic interactions with the CNS of mammals and lead to memory impairment by modulating the GABAergic system.
Exposure to fipronil elevates systolic blood pressure and disturbs related biomarkers in plasma of rats
(2016-03-01) Chaguri, Joao Leandro [UNESP]; Godinho, Antonio Francisco [UNESP]; Horta, Daniel França [UNESP]; Gonçalves-Rizzi, Victor Hugo [UNESP]; Possomato-Vieira, Jose Sergio [UNESP]; Nascimento, Regina Aparecida [UNESP]; Dias-Junior, Carlos Alan [UNESP]; Universidade Estadual Paulista (Unesp)
Recent reports show that fipronil affects non-target organisms, including environmental species populations and potentially humans. We aimed to examine if fipronil exposure affects the systolic blood pressure and related biomarkers. Thus, fipronil was orally administered to rats (30 mg/kg/day) during 15 days (Fipronil group) or physiological solution (Control group). While fipronil increased significantly the systolic blood pressure (158 ± 13 mmHg), no significant changes were observed in Control group (127 ± 3 mmHg). Significantly, higher levels of fipronil in plasma were observed in Fipronil group (0.46 ± 0.09 μg/mL versus 0.17 ± 0.11 μg/mL in Control group). Fipronil group showed lower weight gain compared with Control group. While fipronil resulted in higher concentrations of endothelin-1, reduced antioxidant capacity and lower levels of circulating matrix metalloproteinase 2 (MMP-2) and nitric oxide (NO) metabolites compared to Control group, no alteration was observed in serum biomarkers of renal and hepatic/biliary functional abilities. Therefore, this study suggests that fipronil causes hypertension and endothelin-1 plays a key role. Also, these findings suggest that reductions of both MMP-2 and NO may contribute with the elevation of systolic blood pressure observed with fipronil.

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