Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor alpha-independent pathway.
Di(2-ethylhexyl)phthalate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator-activated receptor alpha (PPARalpha). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPARalpha, we compared DEHP-induced tumorigenesis in wild-type and Pparalpha-null mice. Mice of each genotype were divided into three groups, and treated for 22 months with diets containing 0, 0.01 or 0.05% DEHP. Surprisingly, the incidence of liver tumors was higher in Pparalpha-null mice exposed to 0.05% DEHP (25.8%) than in similarly exposed wild-type mice (10.0%). These results suggest the existence of pathways for DEHP-induced hepatic tumorigenesis that are independent of PPARalpha. The levels of 8-OHdG increased dose-dependently in mice of both genotypes, but the degree of increase was higher in Pparalpha-null than in wild-type mice. NFkappaB levels also significantly increased in a dose-dependent manner in Pparalpha-null mice. The protooncogene c-jun-mRNA was induced, and c-fos-mRNA tended to be induced only in Pparalpha-null mice fed a 0.05% DEHP-containing diet. These results suggest that increases in oxidative stress induced by DEHP exposure may lead to the induction of inflammation and/or the expression of protooncogenes, resulting in a high incidence of tumorigenesis in Pparalpha-null mice.
Ito
Yuki
Y
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Yamanoshita
Osamu
O
Asaeda
Nobuyuki
N
Tagawa
Yoshiaki
Y
Lee
Chul-Ho
CH
Aoyama
Toshifumi
T
Ichihara
Gaku
G
Furuhashi
Koichi
K
Kamijima
Michihiro
M
Gonzalez
Frank J
FJ
Nakajima
Tamie
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D001483:Base Sequence; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000235:genetics; D007249:Inflammation; D007564:Japan; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology; D047493:PPAR alpha / Q000378:metabolism*; D010795:Phthalic Acids / Q000009:adverse effects* / Q000494:pharmacology; D016133:Polymerase Chain Reaction
D052002:NF-kappa B p50 Subunit; D047493:PPAR alpha; D010795:Phthalic Acids; C035983:dimethoxyethyl phthalate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000410:Alanine Transaminase; D003849:Deoxyguanosine