A carregar...
Projeto de investigação
Breast cancer chemotherapy: sympathetic overexcitation as an earlier complementary biomarker of cardiotoxicity
Financiador
Autores
Publicações
From molecular to functional effects of different environmental lead exposure paradigms
Publication . Shvachiy, Liana; Amaro-Leal, Ângela; Outeiro, Tiago; Rocha, Isabel; Geraldes, Vera
Lead is a heavy metal whose widespread use has resulted in environmental contamination and significant health problems, particularly if the exposure occurs during developmental stages. It is a cumulative toxicant that affects multiple systems of the body, including the cardiovascular and nervous systems. Chronic lead exposure has been defined as a cause of behavioral changes, inflammation, hypertension, and autonomic dysfunction. However, different environmental lead exposure paradigms can occur, and the different effects of these have not been described in a broad comparative study. In the present study, rats of both sexes were exposed to water containing lead acetate (0.2% w/v), from the fetal period until adulthood. Developmental Pb-exposed (DevPb) pups were exposed to lead until 12 weeks of age (n = 13); intermittent Pb exposure (IntPb) pups drank leaded water until 12 weeks of age, tap water until 20 weeks, and leaded water for a second time from 20 to 28 weeks of age (n = 14); and the permanent (PerPb) exposure group were exposed to lead until 28 weeks of age (n = 14). A control group (without exposure, Ctrl), matched in age and sex was used. After exposure protocols, at 28 weeks of age, behavioral tests were performed for assessment of anxiety (elevated plus maze test), locomotor activity (open-field test), and memory (novel object recognition test). Metabolic parameters were evaluated for 24 h, and the acute experiment was carried out. Blood pressure (BP), electrocardiogram, and heart (HR) and respiratory (RF) rates were recorded. Baroreflex gain, chemoreflex sensitivity, and sympathovagal balance were calculated. Immunohistochemistry protocol for NeuN, Syn, Iba-1, and GFAP staining was performed. All Pb-exposed groups showed hypertension, concomitant with a decrease in baroreflex gain and chemoreceptor hypersensitivity, without significant changes in HR and RF. Long-term memory impairment associated with reactive astrogliosis and microgliosis in the dentate gyrus of the hippocampus, indicating the presence of neuroinflammation, was also observed. However, these alterations seemed to reverse after lead abstinence for a certain period (DevPb) and were enhanced when a second exposure occurred (IntPb), along with a synaptic loss. These results suggest that the duration of Pb exposure is more relevant than the timing of exposure, since the PerPb group presented more pronounced effects and a significant increase in the LF and HF bands and anxiety levels. In summary, this is the first study with the characterization and comparison of physiological, autonomic, behavioral, and molecular changes caused by different low-level environmental lead exposures, from the fetal period to adulthood, where the duration of exposure was the main factor for stronger adverse effects. These kinds of studies are of immense importance, showing the importance of the surrounding environment in health from childhood until adulthood, leading to the creation of new policies for toxicant usage control.
Intermittent low-level lead exposure provokes anxiety, hypertension, autonomic dyfunction and neuroinflammation
Publication . Shvachiy, Liana; Geraldes, Vera; Leal, Ângela Amaro; Rocha, Isabel
Background: Exposures to lead (Pb) during developmental phases can alter the normal course of development,
with lifelong health consequences. Permanent Pb exposure leads to behavioral changes, cognitive impairment,
sympathoexcitation, tachycardia, hypertension and autonomic dysfunction. However, the effects of an intermittent lead exposure are not yet studied. This pattern of exposure has been recently increasing due to migrations, implementation of school exchange programs and/or residential changes.
Objective: To determine and compare lead effects on mammal’s behavior and physiology, using a rat model of
intermittent and permanent Pb exposures.
Methods: Fetuses were intermittently (PbI) or permanently (PbP) exposed to water containing lead acetate (0.2%
w/v) throughout life until adulthood (28 weeks of age). A control group (CTL) without any exposure to lead was
also used.
Anxiety was assessed by elevated plus maze (EPM) and locomotor activity and exploration by open field test
(OFT). Blood pressure (BP), electrocardiogram (ECG), heart rate (HR), respiratory frequency (RF), sympathetic
and parasympathetic activity and baro- and chemoreceptor reflex profiles were evaluated.
Immunohistochemistry protocol for the assessment of neuroinflammation, neuronal loss (NeuN), gliosis and
synaptic alterations (Iba-1, GFAP, Syn), were performed at the hippocampus. One-way ANOVA with Tukey’s
multiple comparison between means were used (significance p < 0.05) for statistical analysis.
Results: The intermittent lead exposure produced a significant increase in diastolic and mean BP values, concomitant with a tendency to sympathetic overactivity (estimated by increased low-frequency power) and
without significant changes in systolic BP, HR and RF. A chemoreceptor hypersensitivity and a baroreflex impairment were also observed, however, less pronounced when compared to the permanent exposure. Regarding
behavioral changes, both lead exposure profiles showed an anxiety-like behavior without changes in locomotor
and exploratory activity. Increase in GFAP and Iba-1 positive cells, without changes in NeuN positive cells were
found in both exposed groups. Syn staining suffered a significant decrease in PbI group and a significant increase
in PbP group.
Conclusion: This study is the first to show that developmental Pb exposure since fetal period can cause lasting
impairments in physiological parameters. The intermittent lead exposure causes adverse health effects, i.e,
hypertension, increased respiratory frequency and chemoreflex sensitivity, baroreflex impairment, anxiety,
decreased synaptic activity, neuroinflammation and reactive gliosis, in some ways similar to a permanent exposure, however some are lower-grade, due to the shorter duration of exposure.
This study brings new insights on the environmental factors that influence autonomic and cardiovascular
systems during development, which can help in creating public policy strategies to prevent and control the
adverse effects of Pb toxicity.
Persistent effects on cardiorespiratory and nervous systems induced by long-term lead exposure : results from a longitudinal study
Publication . Shvachiy, Liana; Geraldes, Vera; Amaro-Leal, Ângela; Rocha, Isabel
Long-term lead (Pb) exposure alters the normal development of the nervous system and physiology. It affects multiple organ systems, causing hypertension, cardiorespiratory dysfunction, being a well-known neurotoxin, inducing changes in neurogenesis, neurodegeneration, and glial cells. However, studies of the developmental effects of lead and its outcomes throughout life are lacking. Determine morphofunctional, behavioral, and cognitive developmental effects of long-term lead exposure at three different ages. Wistar rats were exposed to a Pb-acetate solution from fetal period until adulthood and compared to a non-exposed control group. General behavior and cognitive skills were evaluated by behavioral tests and physiological data and cardiorespiratory reflexes measured. Neurodegeneration, neuroinflammation, and synaptic activity were assessed by immunohistochemistry. Lead exposure caused long-lasting anxiety-like behavior and strong long-term memory impairment without changes in locomotor and exploratory activity. Hypertension was observed at all time points, concomitant with baroreflex impairment and increased chemoreflex sensitivity. Persistent neuroinflammation, transient synaptic overexcitation without neurodegeneration was observed. Long-term Pb exposure, since fetal period, causes long-lasting anxiety-like behavior, concomitant with hypertension, without general motor skills impairment. Synaptic overexcitation, reactive astrogliosis, and microgliosis could underlie behavioral and long-term memory changes, which might have been caused during developmental phases and consolidated during adulthood. Also, alterations observed in the cardiorespiratory reflexes can explain persistent hypertension. This longitudinal study identifies and characterizes lead toxicity nature and magnitude, important to devise and test potential interventions to attenuate the long-term harmful effects of lead on the nervous and cardiovascular systems.
Unidades organizacionais
Descrição
Palavras-chave
Contribuidores
Financiadores
Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
OE
Número da atribuição
SFRH/BPD/119315/2016