Impact of BPA on behavior, neurodevelopment and neurodegeneration

Bisphenol A (BPA), a compound used in the manufacturing of plastics and epoxy resins, is an endocrine disruptor with significant adverse impact on the human's health. Here, we review the animal models and clinical studies as well as the molecular and cellular mechanisms that show that BPA alters the normal function of the reproductive system, metabolism, brain function and behavior and contributes to the development of certain neurodevelopmental disorders including autism spectrum and attention-deficit and hyperactivity disorders. BPA also causes aberrant cognitive function, behavioral disturbances, and neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. It has recently been proposed that exposure to BPA may be associated with the development of certain neurodegenerative diseases and neurodevelopmental disorders; however, it is a line of research that is just emerging. This work aims to review the available information about the association between exposure to BPA and cognitive function, behavioral disturbances, neurodegenerative diseases (Parkinson�s Disease, Amyotrophic lateral sclerosis, Multiple Sclerosis), and neurodevelopmental disorders (Autism Spectrum and Attention-Deficit/Hyperactivity Disorders). Likewise, the molecular and cellular mechanisms that may be involved with these pathological conditions will be analyzed.

Diabetic female rats exhibit defensive aggression during mating / Las ratas hembra diabéticas exhiben agresión defensiva durante la cópula

Abstract Introduction Few reports have analyzed the putative association between diabetes mellitus type 1 (DM1) and aggressiveness. A previous study using a model of DM1 reported an increase in aggressive behaviors (AB) of females against the male during mating, which was prevented by insulin. However, it was unclear if such aggression was defensive or offensive. Objective To evaluate the different components of aggressiveness of hyperglycemic female rats in two distinct mating paradigms. Method DM1 was modeled in OVX Wistar rats by injecting streptozotocin (STZ) diluted in citrate buffer (50 mg/kg, i.p., for 2 consecutive days). Ten days later, female rats were treated with estradiol benzoate (10 microg, -24 hours) and progesterone (3 mg, -4 hours). A group of STZ-treated animals was administered with a long-acting insulin analogue (glargine) every 12 hours for 8 days. Aggression was recorded in non-paced mating (NPM) and paced mating (PM) paradigms. We registered: the first attack latency (FAL), the proportion of females that presented AB and its type (boxing, bites, lateral kicks and twist) and if AB were exhibited defensively or offensively. Results Hyperglycemic rats showed an increase in lateral kicks in NPM, whereas in PM they exhibited an increase in bites. These behaviors were always defensive and there were no changes in FAL. Insulin reduced AB. Discussion and conclusion Data indicate that the aggressiveness of hyperglycemic female rats is a form of defense against the proximity of the male and add information about the role of insulin on their modulation.

Resumen Introducción Pocos trabajos han evaluado la relación entre diabetes mellitus tipo 1 (DM1) y la agresividad. En un estudio se reportó un aumento en las conductas agresivas (CA) de las hembras contra el macho durante la cópula, las cuales se reducen administrando insulina. No está claro si estas CA se expresan de manera defensiva u ofensiva. Objetivo Evaluar diferentes componentes de la agresividad de ratas hembras hiperglucémicas en dos paradigmas de cópula. Método La DM1 fue modelada en ratas Wistar ovariectomizadas inyectando estreptozotocina (STZ) disuelta en buffer de citratos (50 mg/kg, i.p., durante dos días consecutivos). Diez días después, se les administró benzoato de estradiol (10 microg, -24 horas) y progesterona (3 mg, -4 horas). A un grupo tratado con STZ se le administró un análogo de insulina (glargina) cada 12 horas durante ocho días. La agresión se registró en los paradigmas de cópula no regulada (NPM) y regulada (PM). Se registraron: la latencia al primer ataque (LPA), la proporción de hembras que exhibieron alguna CA, el tipo (boxeo, mordidas, patadas laterales y giros) y si se presentaron de manera defensiva u ofensiva. Resultados Las hembras diabéticas mostraron un aumento en las patadas laterales en NPM mientras que en PM exhibieron más mordidas. Las conductas fueron defensivas, no hubo cambios en la LPA. La insulina redujo la expresión de CA. Discusión y conclusión Los datos indican que las CA de las hembras hiperglucémicas son una forma de defensa contra la proximidad del macho y agregan información sobre el papel de la insulina en su modulación.

Obesidad, síndrome metabólico y percepción olfativa / Obesity, metabolic syndrome and olfactory perception

En la actualidad, la obesidad y el síndrome metabólico son enfermedades que representan un grave problema global de salud pública. A consecuencia de ello, en las últimas décadas ha aumentado el interés por estudiar los efectos de estas patologías sobre el funcionamiento del sistema nervioso central. Uno de los aspectos más ignorados en la bibliografía ha sido el impacto que tienen sobre los sistemas sensoriales, entre los que se encuentra el olfato. El sistema olfativo se relaciona con distintas funciones vitales, como activar mecanismos de defensa, contribuir a la inducción de reflejos apetitivos y digestivos, y reconocer individuos de su misma especie, e incluso tiene implicaciones sociosexuales. Se sabe que, además, desempeña un papel importante en la ingesta de alimentos, en la decisión de lo que se va a consumir, en los mecanismos de apetito y saciedad y, por ende, está involucrado en el desarrollo de obesidad. Estudios clínicos han demostrado que pacientes con obesidad presentan hiposmia con mayor frecuencia en comparación con sujetos delgados de la misma edad. También se han encontrado alteraciones en el olfato de roedores que presentan obesidad o rasgos similares a los del síndrome metabólico del humano. Las causas por las cuales existe esta asociación apenas están comenzando a investigarse; en este trabajo se revisan los estudios que han intentado entenderla desde un enfoque clínico y preclínico, así como los mecanismos biológicos que hasta el momento se han explorado en la bibliografía

Nowadays, it is well accepted that obesity and metabolic syndrome are diseases that constitute a global public health issue. In consequence, the interest in the study of the effects these pathologies produce in the central nervous system has greatly increased in the last decades. One of the most overlooked topics in the literature is the impact they exert in sensory systems, among which is olfaction. The olfactory system is related to a number of vital functions, like the activation of defense mechanisms, contribution to appetitive and digestive reflexes, recognition of conspecifics, and even has socio-sexual implications. It has been discovered that the olfactory system also plays a crucial role in food intake, the choice of foods, appetite and satiety mechanisms; therefore, it is involved in obesity development. Clinical studies have proven that obese patients exhibit hyposmia more frequently than aged-matched healthy controls. Olfactory alterations have also been found in obese rodents or in animals with similar features of human metabolic syndrome. The causes of this association are still being investigated. This work reviews the studies that have tried to understand this association from a preclinical and clinical approach as well as those biological mechanisms that could be involved. The evidences here presented suggest that obesity and metabolic syndrome affect the adequate function of olfactory sensory system

Does Chronic Hyperglycemia Affect Female Rat Sexual Behavior? Differences in Paced and Non-Paced Mating.

INTRODUCTION: Diabetes mellitus has been associated with sexual dysfunction; however, in women this relationship is controversial. A study using a model of type 2 diabetes mellitus (DM2) failed to find a reduced receptivity in the non-paced mating (NPM), but the appetitive aspects of female sexual behavior have not been evaluated, for example, in the paced mating (PM) paradigm. AIM: To evaluate all components of female sexual behavior (in NPM and PM) in a model of DM2 using ovariectomized (OVX) (treated with steroids) or intact female rats (non-OVX) in natural proestrus. METHODS: Neonatal females (3-4 days) were administered streptozotocin (STZ, 70 mg/kg, intraperitoneally) or citrate buffer. At week 8, a glucose tolerance test was performed. At week 10, half of the females were OVX, and in the other half (non-OVX) the estrous cycle was monitored. At the twelfth week, the sexual behavior tests were conducted; OVX females were treated with estradiol benzoate (10 µg, -24 hours) and progesterone (3 mg, -4 hours), whereas the non-OVX were evaluated on vaginal proestrus. MAIN OUTCOME MEASURES: We registered in NPM and PM receptivity (lordosis quotient and intensity), as well as the number of proceptive and aggressive behaviors. Additionally, in PM we calculated the percentage of exits and the return latencies after receiving stimulation and the time the female remained in the male's compartment. RESULTS: The STZ-treated females presented glucose intolerance and were hyperglycemic. Neonatal STZ treatment provoked changes in the females' sexual behavior depending on the paradigm and the hormonal condition. In the NPM, STZ-OVX females had decreased lordosis quotient and intensity and increased aggression, whereas, in the STZ-non-OVX females, there was a decrease in proceptivity; such changes were not observed in PM. Regardless of whether the STZ-treated females were OVX, they failed to perform the pacing behavior. CLINICAL IMPLICATION: These data support the idea that chronic mild hyperglycemia, like that observed in DM2 (which represents 90% of the clinical cases), provokes marginal changes in most aspects of female sexual behavior. STRENGTHS & LIMITATIONS: The main strength of this work is the evaluation of consummatory and motivational aspects of female sexual behavior in a model of DM2. The main limitation is the duration of the experimental design that does not resemble the course of the disease in humans. No histologic or biochemical analyses were performed. CONCLUSION: These results suggest that chronic hyperglycemia produces decreases in sexual behavior. Hernández-Munive AK, Rebolledo-Solleiro D, Fernández-Guasti A. Does Chronic Hyperglycemia Affect Female Rat Sexual Behavior? Differences in Paced and Non-Paced Mating. J Sex Med 2019;16:1130-1142.

Influence of sex and estrous cycle on blood glucose levels, body weight gain, and depressive-like behavior in streptozotocin-induced diabetic rats.

Depression is the most common psychiatric disorder in diabetic patients, showing higher rates in women than in men. This comorbidity has been studied in rodents using the streptozotocin (STZ)-induced diabetes (DM) model, consistently reporting a depressive-like profile in males. Few articles have examined these disturbances in females (ovariectomized or combined with male rats) yielding controversial results. This work was aimed to study whether there are sex differences in the depressive-like profile of STZ-treated male and naturally cycling female Wistar rats. We also analyzed the possible influence of the estrous cycle in females. DM was induced by injecting STZ (50 mg/kg, i.p.) in 2 consecutive days. Ten days later, the depressive-like profile was assessed in the Forced-Swim Test (FST). Locomotion and motor coordination were also evaluated. Body weight and blood glucose levels were registered at the beginning and at the end of the experiment; the estrous cycle, food and water intake were daily monitored. All diabetic subjects showed increased blood glucose levels, polyphagia, polydipsia and decreased body weight as compared to controls, but males were more susceptible to STZ-treatment than females pooled in all phases of the estrous cycle. After treatment with STZ, males and females in proestrus/estrus (P/E) exhibited a depressive-like profile in the FST (increased immobility and reduced swimming); females in metestrus/diestrus were unaffected. The only sex difference observed was a more pronounced reduced swimming in STZ-treated P/E females compared with hyperglycemic males. No changes in locomotion or motor coordination were found. This work emphasizes estrous cycle differences in STZ-treated rats, and in the resultant depressive-like profile. It also supports clinical evidences made in women with DM and stresses the importance of studying STZ-treated naturally cycling females and their estrous cycle phases.

Reduced Lordosis and Enhanced Aggression in Paced and Non-Paced Mating in Diabetic Female Rats.

BACKGROUND: Clinical studies have shown altered sexual function in people with diabetes; basic science studies, using the streptozotocin (STZ)-induced animal model of type 1 diabetes mellitus (DM1), have consistently reported decreased sexual behavior in hyperglycemic female animals, but features of sexual motivation and aggressive behavior have not been explored in these animals. AIM: To study several parameters that denote sexual motivation in STZ-treated female rats and to compare behavioral features of sexual behavior and aggression in non-paced mating (NPM) and paced mating (PM) conditions. METHODS: DM1 was induced by injecting STZ (diluted in citrate buffer) at a dose of 50 mg/kg intraperitoneally over 2 consecutive days into ovariectomized Wistar rats. 10 days later, female rats were treated with estradiol benzoate (10 µg, -24 hours) and progesterone (3 mg, -4 hours); their sexual behavior (including lordosis quotient, lordosis intensity, and proceptivity) and aggression were evaluated under NPM and PM conditions. Body weight, blood glucose levels, and spontaneous ambulatory activity also were measured. A group of STZ-treated animals was administered a long-acting insulin analogue (glargine) every 12 hours for 8 days, and their sexual and aggressive behaviors were evaluated in NPM. OUTCOMES: We quantified body weight, blood glucose level, spontaneous ambulatory activity, and sexual and aggressive behaviors in NPM and PM; the time the female rats spent interacting with the male rat or in the male rat's chamber also was registered in PM. RESULTS: Compared with controls, STZ-treated ovariectomized rats lost body weight, had increased blood glucose levels, and had unchanged spontaneous ambulatory activity. In the PM and NPM conditions, animals showed decreased lordosis quotient and lordosis intensity, increased aggression, and unaltered proceptivity, although in NPM the effects of STZ treatment on aggression were more drastic and were completely prevented by insulin. In PM no differences were found between diabetic and control female rats in the time interacting with the male rat or in the male rat's chamber. CLINICAL TRANSLATION: These findings support the observation of increased prevalence of sexual dysfunctions and aggression in the clinical setting of DM1. STRENGTHS AND LIMITATIONS: The main strength of this study is that it analyzed sexual behavior under PM and NPM conditions and aggression in STZ-treated female rats. Its main limitations are that the model of DM1 represents only 10% of the affected population and that no specific treatment is proposed for the sexual dysfunctions. CONCLUSION: These results suggest that STZ-treated rats have decreased sexual receptivity in NPM and PM, accompanied by increased aggressiveness in NPM. Hernández-Munive AK, Rebolledo-Solleiro D, Ventura-Aquino E, Fernández-Guasti A. Reduced Lordosis and Enhanced Aggression in Paced and Non-Paced Mating in Diabetic Female Rats. J Sex Med 2018;15:124-135.

Increased anxiety-like behavior is associated with the metabolic syndrome in non-stressed rats.

Metabolic syndrome (MS) is a cluster of signs that increases the risk to develop diabetes mellitus type 2 and cardiovascular disease. In the last years, a growing interest to study the relationship between MS and psychiatric disorders, such as depression and anxiety, has emerged obtaining conflicting results. Diet-induced MS rat models have only examined the effects of high-fat or mixed cafeteria diets to a limited extent. We explored whether an anxiety-like behavior was associated with MS in non-stressed rats chronically submitted to a high-sucrose diet (20% sucrose in drinking water) using three different anxiety paradigms: the shock-probe/burying test (SPBT), the elevated plus-maze (EPM) and the open-field test (OFT). Behaviorally, the high-sucrose diet group showed an increase in burying behavior in the SPBT. Also, these animals displayed both avoidance to explore the central part of the arena and a significant increase in freezing behavior in the OFT and lack of effects in the EPM. Also, high-sucrose diet group showed signs of an MS-like condition: significant increases in body weight and body mass index, abdominal obesity, hypertension, hyperglycemia, hyperinsulinemia, and dyslipidemia. Plasma leptin and resistin levels were also increased. No changes in plasma corticosterone levels were found. These results indicate that rats under a 24-weeks high-sucrose diet develop an MS associated with an anxiety-like behavior. Although the mechanisms underlying this behavioral outcome remain to be investigated, the role of leptin is emphasized.

Dopamine D1 receptor activity is involved in the increased anxiety levels observed in STZ-induced diabetes in rats.

Epidemiological surveys have indicated that anxiety disorders are more frequent in diabetic patients than in the general population. Similar results have been shown in animal studies using the streptozotocin (STZ)-induced diabetes model. The mechanisms underlying this relationship are not clearly understood, but it has been suggested that alterations in the dopaminergic neurotransmission, which plays an important role in the amygdaloid modulation of fear and anxiety, may be involved. The aim of this study was to ascertain whether or not the amygdaloid DA D1 receptors are involved in the increase of anxiety-like behavior observed in "diabetic" animals. Adult Wistar male rats were injected with STZ (50mg/kg, i.p.) in two consecutive days and subjected to the Shock-Probe Burying Test 10days after the beginning of treatment. STZ-treated rats showed a significant increase in immobility/freezing behavior whereas no effects were elicited in latency to bury, burying behavior itself and the number of shocks received during testing as compared with non-diabetic controls. These results suggest the triggering of a passive coping response in the STZ-treated rats. Interestingly, immobility/freezing behavior was reversed following the intra-amygdaloid dopamine D1 receptor blockade by the local microinfusion of SCH23390 (100ng/side). Autoradiographic experiments showed a selective increase of [(3)H]-SCH23390 binding in the ventral intercalated paracapsular islands of STZ-treated rats when compared to the non-treated control group. Our results suggest that a hyperdopaminergic state involving DA D1 receptors within the amygdala may have a role in the increase of anxiety observed in diabetic rats.

Role of thirst and visual barriers in the differential behavior displayed by streptozotocin-treated rats in the elevated plus-maze and the open field test.

Conflicting results have been obtained by several groups when studying the effects of streptozotocin (STZ)-treated rats in the elevated plus-maze (EPM). Since thirst is a prominent feature in STZ-induced diabetic-like condition, we studied whether the walls of the closed arms of the EPM, by limiting the search for water in the environment, may contribute to the observed differential behavioral outcomes. The aim of this study was to ascertain whether visual barriers within the EPM have an influence on the behavior of STZ-treated rats in this test of anxiety. A striking similarity between STZ-treated (50 mg/kg, i.p., in two consecutive days) and water deprived rats (72 h) was found in exploratory behavior in the EPM, showing an anxiolytic-like profile. However the anxiolytic response of STZ-treated rats exposed to the EPM shifts into an anxiogenic profile when they are subsequently tested in the open-field test, which unlike the EPM is devoid of visual barriers. Likewise, water deprived rats (72 h) also showed an anxiogenic profile when they were exposed to the open-field test. Our results indicate that experimental outcomes based on EPM observations can be misleading when studying physiological or pathological conditions, e.g. diabetes, in which thirst may increase exploratory behavior.

Acute response of hypophysiotropic thyrotropin releasing hormone neurons and thyrotropin release to behavioral paradigms producing varying intensities of stress and physical activity.

The activity of the hypothalamus-pituitary-thyroid (HPT) axis is essential for energy homeostasis and is differentially modulated by physical and by psychological stress. Contradictory effects of stressful behavioral paradigms on TSH or thyroid hormone release are due to type, length and controllability of the stressor. We hypothesized that an additional determinant of the activity of the HPT axis is the energy demand due to physical activity. We thus evaluated the response of thyrotropin releasing hormone (TRH) neurons of the hypothalamic paraventricular nucleus (PVN) in Wistar male rats submitted to the elevated plus maze (EPM), the open field test (OFT), or restraint, and sacrificed within 1h after test completion; the response to OFT was compared during light (L) or dark (D) phases. Locomotion and anxiety behaviors were similar if animals were tested in L or D phases but their relation to the biochemical parameters differed. All paradigms increased serum corticosterone concentration; the levels of corticotropin releasing hormone receptor 1 and of glucocorticoid receptor (GR) mRNAs in the PVN were enhanced after restraint or OFT-L. Levels of proTRH mRNA increased in the PVN after exposure to EPM-L or OFT-D; serum levels of thyrotropin (TSH) and T(4) only after OFT-D. In contrast, restraint decreased TRH mRNA and serum TSH levels, while it increased TRH content in the mediobasal hypothalamus, implying reduced release. Expression of proTRH in the PVN varied proportionally to the degree of locomotion in OFT-D, while inversely to anxiety in the EPM-L, and to corticosterone in EPM-L and OFT-D. TRH mRNA levels were analyzed by in situ hybridization in the rostral, middle and caudal zones of the PVN in response to OFT-D; they increased in the middle PVN, where most TRH hypophysiotropic neurons reside; levels correlated positively with the velocity attained in the periphery of the OF and negatively, with anxiety. Variations of serum TSH levels correlated positively with locomotor activity in EPM-L and OFT-L or -D, while negatively to serum corticosterone levels in all paradigms. These results support the proposal that the hypophysiotropic PVN TRH neurons are activated by short term physical activity but that this response may be blunted by the inhibitory effect of stress.

The acute response of the amygdalar TRH system to psychogenic stressors varies dependent on the paradigm and circadian condition.

Central administration of thyrotropin releasing hormone (TRH) reduces anxiety; amygdalar TRH expression is inversely proportional to the anxious behavior displayed in the elevated plus maze performed during the dark phase (EPM-D). To better understand the role of TRH in amygdala function, we evaluated the expression of TRH and the elements involved in its transmission in various stressful paradigms and how they associated with behavior. Wistar male rats were exposed to restraint (RES), EPM, or the open field test (OFT) and sacrificed 0-60 min afterwards; OFT, RES and EPM were performed during the light (L), and OFT during the dark phase. Restraint increased amygdalar levels of proCRH mRNA, without change in proTRH. All paradigms augmented corticosterone release, highest after OFT-L that also enhanced proCRH mRNA levels and decreased those of proTRH. OFT-D activated the TRH system. Levels of anxiety or locomotion were similar in animals tested in light or dark phases but their association with biochemical parameters differed. ProTRH expression and TRH release correlated positively with decreased anxiety in EPM-L and in OFT-D. No association with anxiety was detected in OFT-L where proCRH and proTRH expression correlated with locomotion supporting their involvement in arousal. The responses of TRH amygdalar systems appeared modulated by the extent of the stress response and by the circadian conditions. Increased proTRH expression of animals exposed to OFT-D was specifically observed in the cortical nucleus of the amygdala, area involved in processing fear stimuli; these TRH neurons may thus be part of a circuit with anxiolytic properties.