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Transient Post-Natal Exposure to Xenoestrogens Induces Long-Term Alterations in Cardiac Calcium Signaling
Cassandra Tabasso1, Marie-Pauline Frossard1, Camille Ducret1
1Woman-Mother-Child Department, Division of Pediatrics, Developmental Origins of Health and Disease (DOHaD) Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1011 Lausanne, Switzerland.
Abstract:
Today, non-communicable disorders are widespread worldwide. Among them, cardiovascular diseases represent the main cause of death. At the origin of these diseases, exposure to challenges during developmental windows of vulnerability (peri-conception, in utero, and early infancy periods) have been incriminated. Among the challenges that have been described, endocrine disruptors are of high concern because of their omnipresence in the environment. Worrisomely, since birth, children are exposed to a significant number of endocrine disruptors. However, the role of such early exposure on long-term cardiac health is poorly described. In this context, based on a model of rats exposed postnatally and transiently to an estrogenic compound prototype (estradiol benzoate, EB), we aimed to delineate the effects on the adult heart of such transient early exposure to endocrine disruptors and identify the underlying mechanisms involved in the potential pathogenesis. We found that this transient post-natal exposure to EB induced cardiac hypertrophy in adulthood, with increased cardiomyocyte size. The evaluation of cardiac calcium signaling, through immunoblot approaches, highlighted decreased expression of the sarcoplasmic reticulum calcium ATPase 2 (SERCA2) and decreased Nuclear Factor of Activated T Cells (NFAT3) phosphorylation as a potential underlying mechanism of cardiac hypertrophy. Furthermore, the treatment of cardiomyocytes with EB in vitro induced a decrease in SERCA2 protein levels. Overall, our study demonstrates that early transient exposure to EB induces permanent cardiac alterations. Together, our data highlight SERCA2 down-regulation as a potential mechanism involved in the cardiac pathogenesis induced by EB. These results suggest programming of adult heart dysfunctions such as arrhythmia and heart failures by early exposure to endocrine disruptors and could open new perspectives for treatment and prevention.
Insights
Early exposure to endocrine disruptors like estradiol benzoate (EB) can cause permanent heart problems in adulthood. This transient postnatal exposure leads to cardiac hypertrophy and highlights SERCA2 down-regulation as a key mechanism.
Area of Science:
- Environmental Health
- Cardiovascular Biology
- Developmental Toxicology
Background:
- Non-communicable diseases, particularly cardiovascular diseases, are a leading global cause of death.
- Developmental periods of vulnerability (perinatal) are implicated in the origin of these diseases.
- Endocrine disruptors, ubiquitous environmental chemicals, pose a significant concern due to early-life exposure in children.
Purpose of the Study:
- To investigate the long-term cardiac effects of transient early-life exposure to endocrine disruptors.
- To identify the underlying molecular mechanisms of cardiac pathogenesis following early exposure.
- To utilize a rat model exposed postnatally to estradiol benzoate (EB) for this investigation.
Main Methods:
- Transient postnatal exposure of rats to estradiol benzoate (EB).
- Assessment of cardiac hypertrophy and cardiomyocyte size in adult rats.
- Evaluation of cardiac calcium signaling pathways, including SERCA2 expression and NFAT3 phosphorylation via immunoblotting.
- In vitro treatment of cardiomyocytes with EB to confirm effects on SERCA2 protein levels.
Main Results:
- Transient postnatal EB exposure resulted in significant cardiac hypertrophy in adult rats, characterized by enlarged cardiomyocytes.
- Key molecular changes observed include decreased sarcoplasmic reticulum calcium ATPase 2 (SERCA2) expression and reduced Nuclear Factor of Activated T Cells 3 (NFAT3) phosphorylation.
- In vitro studies confirmed that EB exposure directly reduces SERCA2 protein levels in cardiomyocytes.
Conclusions:
- Early transient exposure to estradiol benzoate (EB) induces permanent cardiac alterations, including hypertrophy.
- Down-regulation of SERCA2 is identified as a potential mechanism contributing to EB-induced cardiac pathogenesis.
- These findings suggest that early-life exposure to endocrine disruptors can program adult heart dysfunctions like heart failure and arrhythmia, opening avenues for prevention and treatment.
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