Low concentration of mercury induces autophagic cell death in rat hepatocytes

Abstract

In the present study, we attempted to elucidate the induction of autophagy in rat hepatocytes by a low concentration of mercury. Hepatocytes treated with different doses of mercuric chloride (HgCl2; 1, 2.5, 5 and 10 µM) and at different time intervals (0 min, 30 min, 1 h, 2 h and 4 h) show autophagic cell death only at 5 µM HgCl2 within 30 min of incubation. At 1 and 2.5 µM HgCl2, no cell death is recorded, while apoptosis is found at 10 µM HgCl2, as evidenced by the activation of caspase 3. Autophagic cell death is confirmed by the presence of monodansylcadaverine (MDC) positive hepatocytes which is found to be highest at 1 h. Atg5-Atg12 covalent-conjugation triggers the autophagic pathway within 30 min of 5 µM HgCl2 treatment and continues till 4 h of incubation. In addition, damage-regulated autophagy modulator (DRAM) expression gradually increases from 30 min to 4 h of treatment with mercury and a corresponding linear decrease in p53 has been observed. It is concluded that a low concentration (5 µM HgCl2) of mercury induces autophagy or nonapoptotic programmed cell death following an Atg5-Atg12 covalent-conjugation pathway, which is modulated by DRAM in a p53-dependent manner.

Identification of a unique gene expression signature in mercury and 2,3,7,8-tetrachlorodibenzo-p-dioxin co-exposed cells

“…The doses are well within the range of Hg and TCDD levels in exposed humans, 40–42 animals 43 and in vitro studies. 44,45 Analysis of the differentially expressed genes (RNA-Seq) in the various exposures showed that 50% of the genes (486 out of 972) in the low-dose exposure (Fig. 1A) and 10% of the genes (190 out of 1888) in the high-dose exposure (Fig.…”

Mercuric chloride effects on adult rat oval cells-induced apoptosis

“…Despite extensive efforts to use hepatic progenitor cells as an ideal source for liver repopulation (Fausto and Campell 2003), the response of oval cells to environmental signals remain largely unknown. Mercury, a ubiquitous hepatotoxicant promotes Toxicological & Environmental Chemistry 1729 exicitotoxicity (Ung et al 2010;Farooqui and Farooqui 2011) when introduced into a system, resulting in the induction of programed cell death (Shenker, Guo, and Shapiro 2000;Ben-Ozer et al 2000;Chatterjee et al 2012Chatterjee et al , 2013b. Oval cells exposed to low concentration of Hg were able to accommodate changes at the cellular level producing minimum cell death throughout the experiment.…”

“…It is difficult to detect elongated monomeric form of these proteins to complete autophagic vacuole formation Suzuki et al 2001;Hanada et al 2007). Chatterjee et al (2012Chatterjee et al ( , 2013a recently demonstrated that ATG5-ATG12 complex facilitates LC3B mediated autophagy in Hgtreated differentiated hepatocytes within 30 min of incubation and continued until 4 hr. However, the present study demonstrated significant involvement of ATG12, LC3B, and BCL2 proteins in Hg-induced oval cell death.…”

“…There are several isoforms of ATG proteins, indicating autophagic cell death in which ATG5 and ATG12 mediate the dimerization to induce autophagosome formation Chatterjee et al 2012). It is difficult to detect elongated monomeric form of these proteins to complete autophagic vacuole formation Suzuki et al 2001;Hanada et al 2007).…”

“…10, 1722-1738, http://dx.doi.org/10.1080/02772248.2014 both eukaryotic and prokaryotic cells (Schurz, Sabater-Vilar, and Fink-Gremmels 2000). The characteristic changes in cellular level are protein precipitation, enzyme inhibition, cell swelling, nuclear degradation, ATP depletion, and mitochondrial damage (Ben-Ozer et al 2000;Patnaik et al 2010;Schlatter et al 2011;Chatterjee et al 2012Chatterjee et al , 2013aChatterjee et al , 2013b. These pathological conditions drive cytotoxicity towards different types of programed cell death (Ben-Ozer et al 2000;Ung et al 2010;Chatterjee et al 2013b).…”