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Updated: Aug 3, 2026
Murine Short Axis Ventricular Heart Slices for Electrophysiological Studies
Published on: June 4, 2017
Pentachloronitrobenzene disturbed murine ventricular wall development by inhibiting cardiomyocyte proliferation via
Xiaobo Gao1, Qinghua Dan1, Chen Zhang1
1Department of Genetics, National Research Institute for Family Planning, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Abstract:
Exposure to the organochlorine fungicide pentachloronitrobenzene (PCNB) causes developmental abnormalities, including cardiac malformation. However, the molecular mechanism of PCNB cardiotoxicity remains elusive. We found that oral administration of PCNB to pregnant mice induced a hypoplastic wall with significant thinning of the compact myocardium in the developing hearts. PCNB significantly downregulates the expression of Hec1, a member of the NDC80 kinetochore complex, resulting in aberrant spindles, chromosome missegregation and an arrest in cardiomyocyte proliferation. Cardiac-specific ablation of Hec1 sharply inhibits cardiomyocyte proliferation, leading to thinning of the compact myocardium and embryonic lethality. Mechanistically, we found that activating transcription factor 3 (ATF3) transactivates Hec1 expression. Either HEC1 or ATF3 overexpression significantly rescues mitotic defects and restore the decreased proliferative ability of cardiomyocytes caused by PCNB exposure. Our findings highlight that maternal PCNB exposure disrupts embryonic cardiac function by inhibiting cardiomyocyte proliferation and interfering with ventricular wall development, partially attributed to the downregulation of the Atf3-Hec1 axis.
Insights
Maternal exposure to pentachloronitrobenzene (PCNB) disrupts heart development by inhibiting cardiomyocyte proliferation via the Atf3-Hec1 pathway, causing cardiac abnormalities and embryonic lethality.
Area of Science:
- Developmental toxicology
- Cardiovascular biology
- Molecular genetics
Background:
- Organochlorine fungicides like pentachloronitrobenzene (PCNB) are known teratogens, but the precise molecular mechanisms underlying PCNB-induced cardiotoxicity are not fully understood.
- Cardiac malformations are a significant concern in developmental toxicology, necessitating research into the cellular and molecular pathways affected by environmental exposures.
Purpose of the Study:
- To elucidate the molecular mechanism by which pentachloronitrobenzene (PCNB) exposure leads to cardiac developmental abnormalities.
- To investigate the role of the Hec1 gene and its regulatory axis in PCNB-induced cardiotoxicity and cardiomyocyte proliferation.
Main Methods:
- Oral administration of PCNB to pregnant mice to induce developmental toxicity.
- Analysis of gene expression, focusing on Hec1 and Atf3, in developing cardiac tissues.
- Assessment of cardiomyocyte proliferation, mitotic spindle formation, and chromosome segregation.
- Cardiac-specific gene ablation studies to determine the in vivo function of Hec1.
Main Results:
- PCNB exposure in mice resulted in hypoplastic cardiac walls with thinned compact myocardium.
- PCNB significantly downregulated Hec1 expression, leading to aberrant mitotic spindles, chromosome missegregation, and arrested cardiomyocyte proliferation.
- Cardiac-specific Hec1 ablation mimicked PCNB effects, causing thin myocardial walls and embryonic lethality.
- Activating transcription factor 3 (ATF3) was identified as a transactivator of Hec1, and ATF3 or HEC1 overexpression rescued PCNB-induced defects.
Conclusions:
- Maternal PCNB exposure disrupts embryonic cardiac development by inhibiting cardiomyocyte proliferation and impairing ventricular wall formation.
- The downregulation of the Atf3-Hec1 signaling axis is a key mechanism contributing to PCNB-induced cardiotoxicity.
- Targeting the Atf3-Hec1 pathway may offer therapeutic strategies to mitigate PCNB-related developmental cardiac defects.
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