Di-(2-ethylhexyl)
phthalate (
DEHP) is used extensively in many personal care and consumer products, resulting in widespread non-occupational human exposure through multiple routes and media.
DEHP has various deleterious effects including hepatotoxicity. p53
protein is a central sensor in cell apoptosis. In order to clarify the roles of p53 in
DEHP-induced hepatotoxicity, Sprague-Dawley (SD) rats were dosed daily with
DEHP by gavage for 30 days; BRL cells (rat liver cell line) were treated with
DEHP for 24 h after pretreatment with NAC or
small interfering RNA (
siRNA). Results indicated that after exposure to
DEHP, hepatic histological changes such as hepatocyte
edema, vacuolation and hepatic sinusoidal dilation, and increased apoptosis index were observed. In the liver,
DEHP induced oxidative stress and DNA damage, which activated p53 in vivo and in vitro. Pretreatment with NAC significantly reduced ROS level and p53 expression in BRL cells. The suppressed Mdm2 also contributed to p53 accumulation. Activated p53 mediated hepatocyte apoptosis via the intrinsic mitochondrial pathway, inhibiting anti-apoptotic Bcl-2 and Bcl-xL and inducing pro-apoptotic Bax,
cytochrome c and
caspases. In p53-silenced BRL cells, hepatocyte apoptosis mediated by p53 was attenuated.
PCNA protein level was upregulated after p53 gene silencing. However, the Fas/FasL apoptotic pathway did not exhibit activated signs in
DEHP-caused hepatotoxicity. Taken together,
DEHP-caused oxidative stress and Mdm2 downregulation contribute to p53 activation. The p53-dependent apoptotic pathway plays critical and indispensable roles in
DEHP-induced hepatotoxicity, while the Fas/FasL pathway does not involve in this molecular event.