RESUMO
The Stockholm Convention is key to addressing the global threats of persistent organic pollutants (POPs) to humanity and the environment. It has been successful in identifying new POPs, but its national implementation remains challenging, particularly by low- and middle-income Parties. Concerted action is needed to assist Parties in implementing the Convention's obligations. This analysis aims to identify and recommend research and scientific support needed for timely implementation of the Convention. We aim this analysis at scientists and experts from a variety of natural and social sciences and from all sectors (academia, civil society, industry, and government institutions), as well as research funding agencies. Further, we provide practical guidance to scientists and experts to promote the visibility and accessibility of their work for the Convention's implementation, followed by recommendations for sustaining scientific support to the Convention. This study is the first of a series on analyzing policy needs for scientific evidence under global governance on chemicals and waste.
Assuntos
Poluentes Ambientais , Poluentes Ambientais/análise , PolíticasRESUMO
Paracetamol (PAR) is the analgesic and antipyretic of choice for pregnant and nursing women. PAR may reach the fetus and/or neonate through the placenta and/or milk and effect development. This study evaluated possible hepatic and renal effects in rat dams and their offspring exposed to PAR using a human-relevant route of administration and doses from Gestational Day 6 to Postnatal Day (PND) 21. Dams were gavaged daily with PAR (35 or 350mg kg-1) or water (CON). Dams and pups were killed on PND21 and 22 respectively, and blood was collected for biochemical analysis (aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine). The kidneys and liver were isolated and processed for histopathological assessment and evaluation of oxidative stress markers. Compared with the CON groups, pups exposed to 350mg kg-1 PAR had increased renal reduced glutathione (GSH), whereas dams exposed to both doses of PAR increased serum AST. PAR administration did not affect parameters of general toxicity or renal and hepatic oxidative stress. In conclusion, maternal exposure to human-relevant doses of PAR by gavage was not associated with hepatic or renal toxicity in the pups or dams, but PAR was not devoid of effects. Exposure to PAR increased renal GSH in pups, which could suggest an adaptive antioxidant response, and affected maternal serum AST activity.
Assuntos
Acetaminofen/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Animais , Animais Recém-Nascidos , Feminino , Rim/metabolismo , Rim/patologia , Lactação/efeitos dos fármacos , Lactação/fisiologia , Fígado/metabolismo , Fígado/patologia , Masculino , Exposição Materna/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos WistarRESUMO
Methylphenidate (MPH) is a central nervous system stimulant drug that increases concentration and energy level. The safety of MPH use during pregnancy is not well established. Considering the high rate of unplanned pregnancy among young women, potential for accidental exposure to MPH in early pregnancy is high. This study aimed to investigate if MPH administered during pregnancy would induce maternotoxicity, teratogenicity in mice, or both. Pregnant Swiss mice were treated with MPH (5 mg/kg, subcutaneously) or 0.9% saline (control group) from the 5th to the 17th day of pregnancy. In the MPH-treated group, a significant increase in the total number of resorptions with a consequent increase in post-implantation loss and a decrease in fetal viability were detected (all P < 0.05). A total of 91.43% of resorptions were classified as early resorptions. The group treated with MPH presented significant external (polydactyly P < 0.01), skeletal (incomplete ossification of the skull P < 0.01) and visceral (dilated ventricles P < 0.05) malformations. Behavioural effects (motor activity, memory of habituation and anxiety) were not observed in both male and female offspring evaluated at postnatal days 22, 35 and 75. The results suggest that MPH is an embryotoxic and teratogenic drug.
Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Metilfenidato/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Teratogênicos , Animais , Ansiedade , Comportamento Animal , Peso Corporal , Feminino , Idade Gestacional , Masculino , Exposição Materna , Memória/efeitos dos fármacos , Camundongos , Destreza Motora/efeitos dos fármacos , Gravidez , PrenhezRESUMO
This study aimed to better elucidate reproductive and possible hormonal effects of the fungicide carbendazim (CBZ) through a review of published toxicological studies as well as an evaluation of this fungicide in the Hershberger and uterotrophic assays, which are designed to detect in vivo effects of the sex hormones. The literature review indicates that CBZ induces reproductive and developmental toxicity through alteration of many key events which are important to spermatogenesis. The lower dose of CBZ (100mg/kg) evaluated in the Hershberger test increased prostate weight compared to control group but did not alter the weight of other testosterone-dependent tissues. In the uterotrophic assay, CBZ did not induce an estrogenic or an antiestrogenic effect. In the literature, it has been reported that CBZ may: (1) alter the levels of various hormones (testosterone, LH, FSH, GnRH); (2) negatively influence testicular steroidogenesis; (3) have androgenic effects acting directly in the androgenic receptors and/or increasing the expression of androgen receptors. Despite the contradictory results reported by the different studies that investigated a possible endocrine mode of action of CBZ, it seems that this fungicide may influence the hypothalamus-pituitary-gonad axis in addition to being a testicular toxicant.
Assuntos
Benzimidazóis/efeitos adversos , Carbamatos/efeitos adversos , Hormônios/metabolismo , Reprodução/efeitos dos fármacos , Antagonistas de Androgênios/efeitos adversos , Animais , Feminino , Fungicidas Industriais/efeitos adversos , Humanos , Masculino , Ratos , Ratos Wistar , Espermatogênese/efeitos dos fármacosRESUMO
Psychotropics are among the most prescribed medications. There are indications in the literature that fluoxetine (FLX; selective serotonin reuptake inhibitor [SSRI] antidepressant) and methylphenidate (MPH) could have a hormonal mode of action. This study was designed to evaluate the immature rat uterotrophic assay Substitute by (1) if sertraline (SER) and escitalopram (ESC) 2 other SSRI antidepressants would share the estrogenicity described for FLX and (2) MPH for estrogenicity and antiestrogenicity. The 18-day-old Wistar rats with were divided into olive oil, estradiol (0.3 mg/kg), estradiol + tamoxifen (10 mg/kg), SER (5, 15, or 45 mg/kg), ESC (2, 6, or 18 mg/kg), MPH (2.5 or 5 mg/kg), and estradiol + MPH groups. As expected, estradiol increased the weight of uterus, and this effect was counterbalanced by concomitant treatment with tamoxifen. The SER, ESC, and MPH had no effect on the uterus weight. The results suggest that ESC and SER do not share the estrogenicity described for FLX and that MPH does not disrupt estrogenic signaling.
Assuntos
Antidepressivos/farmacologia , Citalopram/farmacologia , Metilfenidato/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sertralina/farmacologia , Útero/efeitos dos fármacos , Animais , Feminino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Útero/crescimento & desenvolvimentoRESUMO
Paracetamol (PAR) is an over-the-counter analgesic/antipyretic used during pregnancy worldwide. Epidemiological studies have been associating gestational PAR exposure with neurobehavioral alterations in the progeny resembling autism spectrum disorders and attention-deficit hyperactivity disorder symptoms. The endocannabinoid (eCB) dysfunction was previously hypothesized as one of the modes of action by which PAR may harm the developing nervous system. We aimed to evaluate possible effects of gestational exposure to PAR on male and female rat's offspring behavior and if an acute injection of WIN 55,212-2 (WIN, 0.3 mg/kg), a non-specific cannabinoid agonist, prior to behavioral tests, would induce different effects in PAR exposed and non-exposed animals. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. Nest-seeking, open field, apomorphine-induced stereotypy, marble burying and three-chamber tests were conducted in 10-, 24-, 25- or 30-days-old rats, respectively. PAR exposure resulted in increased apomorphine-induced stereotyped behavior and time spent in the central area of the open field in exposed female pups. Additionally, it induced hyperactivity in the open field and increased marble burying behavior in both male and female pups. WIN injection modified the behavioral response only in the nest seeking test, and opposite effects were observed in control and PAR-exposed neonate females. Reported alterations are relevant for the neurodevelopmental disorders that have been associated with maternal PAR exposure and suggest that eCB dysfunction may play a role in the action by which PAR may harm the developing brain.
Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Ratos , Animais , Masculino , Feminino , Agonistas de Receptores de Canabinoides/efeitos adversos , Acetaminofen/toxicidade , Apomorfina , Ratos Wistar , Endocanabinoides , Transtorno do Espectro Autista/induzido quimicamente , Carbonato de Cálcio/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamenteRESUMO
BACKGROUND: Temporal lobe epilepsy (TLE) is the most common focal epilepsy subtype in adults and is frequently accompanied by depression, anxiety and psychosis. Aberrations in total paraoxonase 1 (PON1) status may occur in TLE and these psychiatric conditions. AIM: To examine PON1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in TLE. METHODS: We recruited 40 normal controls and 104 TLE patients, 27 without comorbidities and 77 with comorbidities including mood disorders (n = 25), anxiety disorders (n = 27) and psychosis (n = 25). RESULTS: Four-(chloromethyl)phenyl acetate hydrolysis (CMPAase) and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than those in normal controls. The areas under the receiver operating characteristic curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (± 0.037) for MTS. Partial least squares path analysis showed that there were specific indirect effects of PON1 genotype on TLE severity (P < 0.0001) and psychopathology (P < 0.0001), which were both mediated by lowered CMPAase activity, while arylesterase activity was not significant. The severity of TLE was significantly associated with psychopathology scores. Furthermore, PON1 CMPAase activity was inversely associated with Mini Mental State Examination score. CONCLUSION: The severity of TLE and comorbidities are to a large extent explained by reduced PON1 enzyme activities and by effects of the Q192R genotype, which are mediated by reduced CMPAase activity. Total PON1 status plays a key role in the pathophysiology of TLE, MTS and psychiatric comorbidities by increasing the risk of oxidative toxicity. PON1 enzyme activities are new drug targets in TLE to treat seizure frequency and psychiatric comorbidities.
RESUMO
Paracetamol (PAR) has been employed worldwide for pain and fever treatment during pregnancy and lactation. Epidemiologic studies have shown that exposure to PAR can increase the risk for developmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. This study aimed to investigate if gestational and lactational exposure to human-relevant doses of PAR could alter behavioural and brain oxidative stress parameters in the rat`s offspring. Wistar dams were gavaged daily with water or PAR (35 mg/kg/ or 350 mg/kg) during gestational day 6 to weaning (postnatal day 21). Behavioural assessments occurred at post-natal days 10 (nest seeking test), 27 (behavioural stereotypy) and 28 (three chamber sociability test and open field). Concentration of advanced oxidation protein products (AOPP), reduced glutathione (GSH), lipid hydroperoxides (LOOH) and activity of superoxide dismutase (SOD) were estimate in prefrontal cortex, hippocampus, striatum and cerebellum of 22-day-old rats. Compared to CON animals, males exposed to PAR during pregnancy and lactation augmented apomorphine-induced stereotyped behaviour (350 mg/kg) and ambulation in open-field test (35 mg/kg). Reduced exploratory behaviour in three chamber sociability test was observed in pups exposed to PAR at 350 mg/kg in both sexes. PAR treatment decreased hippocampal GSH level and striatal SOD activity in males exposed to 35 mg/kg, suggesting the vulnerability of these areas in PAR-induced developmental neurotoxicity. Findings suggest PAR use during pregnancy and lactation as a potential risk factor for neurodevelopmental disorders with males being more susceptible.
Assuntos
Acetaminofen/farmacologia , Comportamento Animal/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Acetaminofen/administração & dosagem , Animais , Comportamento Animal/fisiologia , Aleitamento Materno , Fármacos do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/metabolismo , Masculino , Transtornos do Neurodesenvolvimento/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Fatores SexuaisRESUMO
BACKGROUND: Increased generation of reactive oxygen and nitrogen species in chronic kidney disease (CKD) patients leads to increased oxidative stress. The antioxidant capacity of folic acid has been shown to scavenge radicals efficiently. OBJECTIVE: The current study was carried out to examine the effects of folic acid treatment on biochemical and oxidative stress biomarkers in patients in different stages of CKD. METHODS: This was a randomized, non-blinded, clinical trial that assessed the effects of 3 months of treatment with 5 mg of folic acid daily or no treatment in 113 outpatients within CKD stages 3a and 3b. At the end of the intervention, we analyzed the data of 66 patients treated with folic acid and 47 in the control group. Serum homocysteine levels and biochemical and oxidative/nitrosative stress biomarkers were analyzed in all patients. RESULTS: In most patients, folic acid treatment normalized homocysteine levels and increased antioxidant enzyme activity (paraoxonase 1) and decreased sulfhydryl (SH) groups. In addition, oxidative biomarkers (products of nitric oxide and lipid hydroperoxide) were significantly lower post-treatment compared to baseline in the active intervention group. In the no active intervention group, no statistically significant effects were found on the oxidative and biochemical biomarkers. CONCLUSION: Folic acid treatment in stages 3a-4 CKD patients effectively ameliorated their hyperhomocysteinemia and increased the activity of antioxidant enzymes, as well as decreased the levels of pro-oxidant biomarkers in stage G3a and G3b CKD patients. Folic acid treatment attenuated oxidative/nitrosative stress and may be considered as a possible strategy to improve redox status and diminish the damages associated with oxidative/nitrosative stress in CKD patients. Further studies are needed to confirm these findings. Clinical Trials Registration No.: This study is registered in the Brazilian Record of Clinical Trials (ReBEC), under reference RBR-2bfthr.
Assuntos
Antioxidantes/administração & dosagem , Ácido Fólico/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Antioxidantes/farmacologia , Feminino , Ácido Fólico/farmacologia , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estresse Nitrosativo/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND: Hypertension, atherogenicity and insulin resistance are major risk factors of cardiovascular disorder (CVD), which shows a strong comorbidity with major depression (MDD) and bipolar disorder (BD). Activated oxidative and nitrosative stress (O&NS), inflammatory pathways, and increased atherogenicity are shared pathways underpinning CVD and mood disorders. METHODS: The current study examined the effects of lipid hydroperoxides (LOOH), superoxide dismutase (SOD), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), and malondialdehyde (MDA) on systolic (SBP) and diastolic (DBP) blood pressure in 96 mood disordered patients and 60 healthy controls. RESULTS: A large part of the variance in SBP (31.6%) was explained by the regression on a z unit-weighted composite score (based on LOOH, AOPP, SOD, NOx) reflecting nitro-oxidative stress toxicity (NOSTOX), coupled with highly sensitive C-reactive protein, body weight and use of antihypertensives. Increased DBP was best predicted (23.8%) by body mass index and NOSTOX. The most important O&NS biomarkers predicting an increased SBP were in descending order of significance: LOOH, AOPP and SOD. Higher levels of the atherogenic index of plasma, HOMA2 insulin resistance index and basal thyroid-stimulating hormone also contributed to increased SBP independently from NOSTOX. Although there were no significant changes in SBP/DBP in mood disorders, the associations between NOSTOX and blood pressure were significant in patients with mood disorders but not in healthy controls. CONCLUSIONS: Activated O&NS pathways including increased lipid peroxidation and protein oxidation, which indicates hypochlorous stress, are the most important predictors of an increased BP, especially in patients with mood disorders.
Assuntos
Hipertensão , Transtornos do Humor , Produtos da Oxidação Avançada de Proteínas/metabolismo , Biomarcadores/metabolismo , Pressão Sanguínea , Humanos , Estresse OxidativoRESUMO
Paracetamol is a widely used medication during gestation and lactation periods for the treatment of pain and fever. Several studies have shown that exposure to paracetamol can increase the incidence of cryptorchidism and decrease testosterone production. Therefore, the present study aimed to evaluate if maternal treatment with paracetamol during gestation and gestation/lactation periods can alter reproductive and behavioral parameters in male offspring. Female Wistar rats were treated daily by gavage with water or paracetamol (350 mg/kg/day) during gestation (CTRG and PARG) or gestation/lactation periods (CTRGL and PARGL). There were significant differences in histomorphometry (increased volume and total length of the seminiferous tubules) and weight of testes (PARG group) and copulatory behavior and testosterone levels (PARG and PARGL groups) at PND 120. Therefore, the present study showed that maternal exposure to paracetamol has an impact on the reproductive system and sexual behavior of male adult offspring suggesting an impaired in sexual hypothalamic differentiation at the beginning of the development of the brain.
Assuntos
Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Reprodução/efeitos dos fármacos , Animais , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Masculino , Troca Materno-Fetal , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos Wistar , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/crescimento & desenvolvimento , Comportamento Sexual Animal/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testosterona/sangueRESUMO
Paracetamol (PAR) is an over-the-counter medicine used as analgesic or antipyretic by 40-50% of the pregnant women in different countries. Epidemiologic studies have been associating maternal use of PAR with neurodevelopmental disruption and special attention has been given to its potential to increase the odds for neurodevelopmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. Population-based research do not allow the establishment of causal relationships because variable control is weak. We aimed to evaluate the potential of PAR to induce developmental neurotoxicity in rats. Pregnant Wistar rats were gavaged with PAR (350â¯mg/kg/day) or water from gestational day 6 until delivery. General toxicity endpoints included dams' body weight and food intake as well as pups' body weight until weaning. Behavioral evaluation occurred at post-natal days 10 (nest seeking test), 27 (behavioral stereotypy), 28 (three chamber sociability test and open field) and 29 (hot plate and elevated plus-maze). Moreover, lipid hidroperoxide (LOOH), reduced glutathione (GSH) and brain derived neurotrophic factor (BDNF) levels were quantified in prefrontal cortex and hippocampus of 22-days-old rats. Gestational exposure to PAR impaired nest seeking behavior, augmented apomorphine-induced behavioral stereotypy and decreased rostral grooming in the elevated plus maze. Exposed female pups presented elevated vertical exploration in the open field test. No alterations were observed in LOOH, GSH or BDNF levels in the prefrontal cortex or hippocampus. Exposure regimen did not affect general toxicity parameters or pups' behavior in the hot plate and sociability tests. These data suggest PAR as a developmental neurotoxicant. Observed alterations may be relevant for neurodevelopmental disorders.
Assuntos
Acetaminofen/efeitos adversos , Apomorfina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Asseio Animal/efeitos dos fármacos , Comportamento de Nidação/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/psicologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sinergismo Farmacológico , Feminino , Glutationa/metabolismo , Hipocampo/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , RatosRESUMO
Oxidative stress toxicity (OSTOX), as well as lowered antioxidant defenses (ANTIOX), plays a role in temporal lobe epilepsy (TLE). Nevertheless, the associations between OSTOX/ANTIOX and psychiatric comorbidities in TLE are largely unknown. Thus, this study examines plasma malondialdehyde (MDA), lipid hydroperoxides (LOOH), advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), and sulfhydryl (-SH) groups in depression due to TLE (n = 25); anxiety disorders due to TLE (n = 27); psychotic disorder due to TLE (n = 25); "pure TLE" (n = 27); and healthy controls (n = 40). TLE and mesial temporal sclerosis (MTS) were characterized by significant increases in OSTOX (MDA, AOPP, LOOH) and lowered ANTIOX (-SH groups, TRAP). The discrimination of pure TLE from controls yielded a significant area under the ROC curve for MDA (0.999), AOPP (0.851), -SH groups (0.899), and the OSTOX/ANTIOX ratio (0.996). Seizure frequency is significantly associated with increased MDA and lowered LOOH and NOx levels. Increased MDA was associated with the severity of depressive and physiosomatic symptoms, while increased AOPP levels predicted suicidal ideation. Depression and anxiety disorders co-occurring with TLE showed significantly lower MDA levels than TLE without any comorbidities. The psychotic and negative symptoms of TLE are associated with increased MDA levels and excitation with increased LOOH and lowered TRAP levels. These results indicate that oxidative stress toxicity especially protein oxidation and aldehyde formation coupled with lowered -SH groups plays a key role in the pathophysiology of TLE/MTS. Increased aldehyde formation also impacts psychopathology and psychosis, as well as negative and depressive symptoms.
Assuntos
Antioxidantes/metabolismo , Transtorno Depressivo Maior/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Estresse Oxidativo/fisiologia , Transtornos Psicóticos/metabolismo , Adulto , Antioxidantes/farmacologia , Transtorno Depressivo Maior/patologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estresse Nitrosativo/fisiologia , Transtornos Psicóticos/complicaçõesRESUMO
BACKGROUND: Nitro-oxidative stress (NOS) has been implicated in the pathophysiology of psychiatric disorders. The activity of the polymorphic antioxidant enzyme paraoxonase 1 (PON1) is altered in diseases where NOS is involved. PON1 activity may be estimated using different substrates some of which are influenced by PON1 polymorphisms. OBJECTIVES: 1) to review the association between PON1 activities and psychiatric diseases using a standardized PON1 substrate terminology in order to offer a state-of-the-art review; and 2) to review the efficacy of different strategies (nutrition, drugs, lifestyle) to enhance PON1 activities. METHODS: The PubMed database was searched using the terms paraoxonase 1 and psychiatric diseases. Moreover, the database was also searched for clinical trials investigating strategies to enhance PON1 activity. RESULTS: The studies support decreased PON1 activity as determined using phenylacetate (i.e., arylesterase or AREase) as a substrate, in depression, bipolar disorder, generalized anxiety disorder (GAD) and schizophrenia, especially in antipsychotic-free patients. PON1 activity as determined with paraoxon (i.e., POase activity) yields more controversial results, which can be explained by the lack of adjustment for the Q192R polymorphism. The few clinical trials investigating the influence of nutritional, lifestyle and drugs on PON1 activities in the general population suggest that some polyphenols, oleic acid, Mediterranean diet, no smoking, being physically active and statins may be effective strategies that increase PON1 activity. CONCLUSION: Lowered PON1 activities appear to be a key component in the ongoing NOS processes that accompany affective disorders, GAD and schizophrenia. Treatments increasing attenuated PON1 activity could possibly be new drug targets for treating these disorders.
Assuntos
Arildialquilfosfatase/metabolismo , Transtornos Mentais/enzimologia , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Arildialquilfosfatase/análise , Humanos , Neurologistas , PsiquiatriaRESUMO
Objectives: Mood disorders (MDs) frequently co-exist with cardiovascular disease (CVD) and immune-inflammatory and oxidative stress are important shared pathophysiological pathways. Even though there has been an extensive investigation of the enzyme paraoxonase 1 (PON1) as a biomarker of susceptibility for CVD, there are few reports studying PON1 in MDs. The aim of this study was to determine the association between PON1 activities as well as functional genotypes and MD diagnosis, clinical characteristics and outcomes. Methods: PON1 activities and functional genotypes were assayed in 58 bipolar disorder (BD) and 32 major depressed patients (MDD) and compared with 59 controls. Results: Our findings show significantly lower PON1 total and CMPAase activities in MDs, which are partly related to the number of previous depressive and manic episodes. Lowered CMPAase activity is associated with a worse outcome of MDs as indicated by lowered quality of life (WHOQoL-BREF scale) and increased disability in the Sheeham scale. Conclusions: We hypothesise that lowered PON1 total and CMPAase activities may play a role in the pathophysiology of MDs by lowering antioxidant defences thereby increasing the risk of lipid peroxidation and inflammation; lowered inhibition of quorum-sensing lactones thereby increasing bacterial proliferation; and attenuated homocysteine thiolactone catabolism which may trigger immune-inflammatory response and/or induce neurotoxicity.
Assuntos
Arildialquilfosfatase/metabolismo , Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Adulto , Arildialquilfosfatase/genética , Biomarcadores/metabolismo , Estudos de Casos e Controles , Avaliação da Deficiência , Feminino , Genótipo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Qualidade de Vida , RecidivaRESUMO
Depressive disorders have a worldwide high prevalence. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) antidepressant, has been widely prescribed for depression during pregnancy and/or lactation. Since serotonin is a neurotrophic factor, the use of FLX by mothers could disrupt brain development resulting in behavioral alterations in their progeny. The aim of the present study was to evaluate the effects of developmental FLX exposure on sexual behavior, as well as on endocrine parameters, of male mice. Swiss dams were treated daily, by gavage, with 7.5 mg/kg of FLX during pregnancy and lactation. Male pups were tested for copulatory behavior and sexual incentive motivation. Male pups also had their anogenital distance, plasmatic testosterone concentration and testis, epididymis, seminal vesicle and pituitary wet weights assessed. Copulatory behavior, anogenital distance, plasmatic testosterone concentration and organs wet weights were not affected by FLX exposure. However, this exposure eliminated preference for a sexual incentive on the sexual incentive motivation test, which indicates reduced sexual motivation, a classic side effect of SSRIs in humans who take these antidepressants.
Assuntos
Fluoxetina/efeitos adversos , Motivação , Efeitos Tardios da Exposição Pré-Natal , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Copulação/efeitos dos fármacos , Feminino , Genitália Masculina/anatomia & histologia , Genitália Masculina/efeitos dos fármacos , Lactação/fisiologia , Masculino , Camundongos , Hipófise/efeitos dos fármacos , Hipófise/crescimento & desenvolvimento , Gravidez , Testosterona/sangueRESUMO
Accumulating evidence shows that nitro-oxidative pathways play an important role in the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD) and maybe anxiety disorders. The current study aims to examine superoxide dismutase (SOD1), catalase, lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), malondialdehyde (MDA), glutathione (GSH), paraoxonase 1 (PON1), high-density lipoprotein cholesterol (HDL), and uric acid (UA) in participants with and without generalized anxiety disorder (GAD) co-occurring or not with BD, MDD, or tobacco use disorder. Z unit-weighted composite scores were computed as indices of nitro-oxidative stress driving lipid and protein oxidation. SOD1, LOOH, NOx, and uric acid were significantly higher and HDL and PON1 significantly lower in participants with GAD than in those without GAD. GAD was more adequately predicted by increased SOD + LOOH + NOx and lowered HDL + PON1 composite scores. Composite scores of nitro-oxidative stress coupled with aldehyde and AOPP production were significantly increased in participants with comorbid GAD + MDD as compared with all other study groups, namely MDD, GAD + BD, BD, GAD, and healthy controls. In conclusion, GAD is characterized by increased nitro-oxidative stress and lipid peroxidation and lowered lipid-associated antioxidant defenses, while increased uric acid levels in GAD may protect against aldehyde production and protein oxidation. This study suggests that increased nitro-oxidative stress and especially increased SOD1 activity, NO production, and lipid peroxidation as well as lowered HDL-cholesterol and PON1 activity could be novel drug targets for GAD especially when comorbid with MDD.
Assuntos
Transtornos de Ansiedade/complicações , Transtorno Depressivo Maior/complicações , Peroxidação de Lipídeos/fisiologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Adulto , Produtos da Oxidação Avançada de Proteínas/metabolismo , Análise de Variância , Transtornos de Ansiedade/epidemiologia , Arildialquilfosfatase/metabolismo , Índice de Massa Corporal , Transtorno Depressivo Maior/epidemiologia , Feminino , Humanos , Lipoproteínas HDL/metabolismo , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Ácido Úrico/metabolismo , Adulto JovemRESUMO
Several studies have suggested that propiconazole (PROP) may be an endocrine disruptor; possibly altering the activity of the CYP51 enzyme, which is part of the cholesterol biosynthesis pathway required for the production of sexual steroid hormones. Another PROP effect is inhibition of the aromatase enzyme that converts androgens into estrogens, which could lead to negative effects on reproductive parameters. Therefore, the present study evaluated the reproductive and developmental toxicity of PROP by exposing two generations (F1 and F2) of male rats to this fungicide, since a previous study from our lab reported that PROP has anti-estrogenic and anti-androgenic activities (Costa et al., 2015) in the male parental (P) generation. The F1 males were exposed to PROP (4 or 20mg/kg) through germ cells (via the P generation), intra uterus, and lactation, following treatment by gavage from post-natal day (PND) 21 to 120, while the F2 generation was exposed through germ cells, intra uterus, and lactation. The parameters observed in both F1 and F2 generations were: body weight, anogenital distance (PND 0 and 21), ontogenic reflex, testosterone plasmatic levels, testis weight, and testicular histomorphology (PND 21); and in the F1 generation only: preputial separation (PND 40), sexual behavior, organ weights, testosterone and estradiol plasmatic levels (PND 120), sperm count and morphology, and testicular histomorphology at adulthood. In the F1 and F2 generations, PROP (4mg/kg) presented a decrease in testosterone levels, and in the F1 decreases in the vas deferens weight, without hormonal and functional changes of the reproductive organs, either at 4mg/kg or at 20mg/kg, in adulthood. Based on the results of this work, PROP did not alter the gonadal-endocrine parameters under these exposure conditions in rats.
Assuntos
Disruptores Endócrinos/toxicidade , Fungicidas Industriais/toxicidade , Reprodução/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Testículo/efeitos dos fármacos , Triazóis/toxicidade , Animais , Animais Recém-Nascidos , Estradiol/sangue , Feminino , Lactação , Masculino , Exposição Materna/efeitos adversos , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Medição de Risco , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Fatores de Tempo , Testes de Toxicidade CrônicaRESUMO
OBJECTIVES: To examine oxidative & nitrosative stress (O&NS) biomarkers at the end of term in relation to perinatal affective symptoms, neuro-immune biomarkers and pregnancy-related outcome variables. METHODS: We measured plasma advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical trapping antioxidant parameter (TRAP), -sulfhydryl (-SH), peroxides (LOOH) and paraoxonase (PON)1 activity in pregnant women with and without prenatal depression and non-pregnant controls. RESULTS: Pregnancy is accompanied by significantly increased AOPP and NOx, and lowered TRAP, -SH and LOOH. Increased O&NS and lowered LOOH and -SH levels are associated with prenatal depressive and physio-somatic symptoms (fatigue, pain, dyspepsia, gastro-intestinal symptoms). Increased AOPP and NOx are significantly associated with lowered -SH, TRAP and zinc, and with increased haptoglobin and C-reactive protein levels. Increased O&NS and lowered TRAP and PON 1 activity, at the end of term predict mother (e.g. hyperpigmentation, labor duration, caesarian section, cord length, breast milk flow) and baby (e.g. sleep and feeding problems) outcome characteristics. CONCLUSIONS: Pregnancy is accompanied by interrelated signs of O&NS, lowered antioxidant defenses and activated neuro-immune pathways. Increased O&NS at the end of term is associated with perinatal depressive and physio-somatic symptoms and may predict obstetric and behavioral complications in mother and baby.
Assuntos
Depressão Pós-Parto/fisiopatologia , Transtorno Depressivo/fisiopatologia , Inflamação/fisiopatologia , Mães , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Adulto , Produtos da Oxidação Avançada de Proteínas , Arildialquilfosfatase/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Depressão Pós-Parto/sangue , Transtorno Depressivo/sangue , Feminino , Humanos , Inflamação/sangue , Óxido Nítrico/sangue , GravidezRESUMO
There is evidence that the acute phase of schizophrenia (SCZ) is accompanied by specific changes in oxidative and nitrosative stress (O&NS) biomarkers. There are, however, no firm data regarding these biomarkers in chronic SCZ. Therefore, this study aimed to delineate O&NS biomarkers in patients with chronic SCZ. 125 outpatients with SCZ and 118 controls were enrolled. The markers included lipid hydroperoxides (LOOH), advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP) and paraoxonase 1 (PON-1) activity. Immune-inflammatory markers known to be altered in SCZ were also measured: leptin, IL-6, soluble TNF receptors (sTNF-Rs) and the chemokines CCL-11 and CCL-3. There were no significant associations between chronic SCZ and the O&NS markers (AOPP, NOx, LOOH) and the anti-oxidants PON-1 and TRAP. Leptin, sTNF-R, CCL-3 and CCL-11 were significantly higher in SCZ. There were significant associations between pro-inflammatory and O&NS biomarkers (leptin/CCL-8 and AOPP; IL-6 and NOx; CCL-3 and LOOH; CCL-3/IL-6/NOx and TRAP). In conclusion, there were significant intercorrelations between inflammatory and O&NS pathways, which play a role in the pathophysiology of chronic SCZ. O&NS markers and the enzyme PON-1 are not useful as biomarkers in chronic stable polymedicated SCZ patients.