Intermittent low-level lead exposure causes lifelong neuro and cardio impairments
-
1
Centro Cardiovascular da Faculdade de Medicina da Universidade de Lisboa, Portugal
-
2
Institute of Physiology, Faculty of Medicine, University of Lisbon, Portugal
-
3
Universidade de Lisboa, Portugal
Lead is a toxic metal which widespread use has resulted in environmental contamination and significant health problems. It is a cumulative toxicant that affects multiple body systems, including the cardiovascular, hematopoietic, reproductive, and renal systems. Lead is also a well-known neurotoxin, inducing changes in neurogenesis, neurodegeneration and changes on glial cells. These changes in the molecular and cellular processes lead to cognitive and behaviour alterations, particularly during developmental phases, persisting throughout the lifetime. Most of the studies that have been performed in both humans and animals were focused in a continuous chronic exposure to lead. This lead exposure causes behavioural changes, cognitive impairment and hypertension associated with sympathoexcitation, baroreceptor reflex hyposensitivity and increased chemoreceptor reflex sensitivity. However, the effects of an intermittent lead exposure are scarce and standardized animal models are non-existent, which has been increasing in the last years due to migrations, implementation of school exchange programs and/or residential changes.
Therefore, the overall purpose of this study was to evaluate lead effects on mammal’s physiology, by an integration of behavioural, cognitive, morphofunctional and critical autonomic and cardiorespiratory parameters in a newly developed animal model of intermittent low-level lead exposure.
The animal model of intermittent lead exposure (PbI group) was developed by replacing the tap water of seven-day pregnant Wistar females with 0.2% (p/v) solution of lead acetate. After being weaned at 21 days, rat pups, both sexes, were exposed to lead via drinking water (as mothers) until 12 weeks. A lead-free period was completed between 12 and 20 weeks and animals were exposed for the second time between 20 and 28 weeks of age.
At 12, 20 and 28 weeks of age, behavioural tests were performed for anxiety (Elevated Plus Maze Test), locomotor activity (Open Field Test), spatial working memory (Y-Maze) and episodic long-term memory (Novel Object Recognition test) assessment. Basal physiological parameters, namely blood pressure (BP), electrocardiogram (ECG), heart rate (HR) and respiratory frequency (RF) were recorded at the same timepoints in the acute experiment. Baroreflex gain (BRG), chemoreflex sensitivity (ChS), cardiovascular variability were also evaluated for autonomic function characterization.
Immunohistochemistry studies for neuronal nuclear antigen (NeuN), Synaptophysin (Syn), ionized calcium binding adapter molecule-1 (Iba-1) and Glial fibrillary acidic protein (GFAP) stainings were performed in brain slices, and confocal imaging acquired and stainings quantified at dentate gyrus (DG) of the hippocampus. A control group of Wistar rats without lead exposure (with normal drinking water), of both sexes, underwent the same protocol of evaluation in the same time-points. Student T-test and one-way ANOVA with Tukey’s multiple comparison between means were used (significance p<0.05) for statistical analysis.
Our data showed a clear association between lead exposure, hypertension and cardiorespiratory reflexes impairment, without heart rate changes. We demonstrated, for the first time that lead intermittent exposure causes adverse health effects, i.e, hypertension, sympathetic overactivity, increased chemoreflex sensitivity and baroreflex impairment. In fact, at 28 weeks, PbI group of animals had a less severe hypertension when compared to the earlier timepoints. Moreover, the effect on diastolic blood pressure produced by lead exposure was more evident than that of systolic blood pressure.
Regarding the autonomic data, in our study, the overactivity of the sympathetic nervous system, evaluated by the LF band, is concomitant with baroreceptor reflex impairment and/or hypertension. This means that the sympathetic nervous system may be involved in the modulation of the baroreceptor reflexes responses or in the hypertension development due to lead exposure.
Concerning the effect of lead at behavioural level, lead-exposed group, evaluated at three different time points, had behavioural changes, namely anxiety, hyperactivity and/or long-term memory impairment and molecular changes in the hippocampus region, more specifically, reactive astrogliosis and microgliosis were detected, indicating the presence of neuroinflammation. Also, these changes seem to be enhanced when a second exposure occurs (intermittent exposure), along with a synaptic loss.
In summary, this study shows, that exposure to lead during the developmental phase can alter the normal course of growth, with lifelong health consequences. Thus, the second exposure to lead only served to strengthen (e.g. or weaken (e.g. hypertension) some of the toxicological effects that were already installed in the body after the first contact with this heavy metal, since foetal period until adulthood, which is the most susceptible period to adverse health effects. Therefore, we can theorize that the different effects of lead toxicant mainly depend on the total duration of lead exposure and that the start of the exposure is crucial for toxicological effects. This is the first study with the development and characterization of physiological, behavioural and molecular changes, as well as calculating autonomic effects by mathematical tools of the intermittent exposure to low levels of lead, from the foetal period to adulthood, with a longitudinal approach, evaluating the effects in the key time-points. However, more studies must be performed, with a deeper characterization of molecular and cellular changes, as well as to determine a link between neurodegenerative diseases and this type of exposure.
Finally, the more knowledge we acquire about lead toxicity and new types of possible exposures, the easier it will be to create public policy strategies to eliminate this toxic heavy metal from the environment and to prevent further exposure and to alleviate the already affected individuals.
Acknowledgements
Vera Geraldes acknowledges the post-doctoral fellow given by the Fundação para a Ciência e Tecnologia (FCT) (Ref: SFRH/BPD/119315/2016). All authors acknowledge the H2020 project no. 689691 and H2020 project no. 692340.
Keywords:
intermittent lead exposure,
Behavioural changes,
autonomic dysfunction,
Neuroinflammation,
Cardiorespiratory impairment
Conference:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.
Presentation Type:
Poster presentation
Topic:
Neurodevelopment / Regeneration
Citation:
Shvachiy
L,
Geraldes
V,
Amaro-Leal
 and
Rocha
I
(2019). Intermittent low-level lead exposure causes lifelong neuro and cardio impairments.
Front. Cell. Neurosci.
Conference Abstract:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019).
doi: 10.3389/conf.fncel.2019.01.00013
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
16 Apr 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
MD. Liana Shvachiy, Centro Cardiovascular da Faculdade de Medicina da Universidade de Lisboa, Lisbon, 1649-028, Portugal, shvachiy.liana@gmail.com