Pentachloronitrobenzene disturbed murine ventricular wall development by inhibiting cardiomyocyte proliferation via Hec1 downregulation

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.