PS-6 unleaded
gasoline (UG) and
methyl tert-butyl ether (
MTBE), an UG additive, with long-term exposure at high concentrations increased liver
tumors selectively in female mice.
PS-6 UG is a liver
tumor promoter in
N-nitrosodiethylamine-initiated female mice and produces short-term effects potentially relevant to its
tumor promoting ability. The new formulation of UG (91-01) and
MTBE were evaluated for similar short-term effects in mouse liver. Mice were exposed to 7814 ppm
MTBE, 2014 ppm 91-01 UG, or 2028 ppm
PS-6 UG vapor for 3 or 21 days, 6 hr/day, 5 day/week. Relative liver weights increased and uterine weights decreased in
MTBE-, 91-01 UG-, and
PS-6 UG-exposed mice. Because the decrease in relative uterine weight is suggestive of hormonal modulation, we evaluated the effects of
MTBE, 91-01 UG, and
PS-6 UG in vivo on hepatic 17-beta
estradiol metabolism in vitro. Gavage treatment with either blend of UG and with
MTBE increased
estrogen metabolism in isolated mouse hepatocytes. Hepatic microsomal P450 activity was assessed by 7-pentoxyresorufin-O-dealkylase (
PROD) and 7-ethoxyresorufin-O-deethylase (
EROD) activities. Similar increases in P450 content and
PROD and
EROD activities were observed in all exposed mice as compared to controls. No hepatoxicity was observed in any treatment group. The hepatic labeling index, as measured by the incorporation of
5-bromo-2'-deoxyuridine, was increased in all exposed mice at 3 days but not 21 days, indicating that
MTBE and 91-01 UG are also hepatic
mitogens. These data demonstrate that a newer blend of UG and the UG additive
MTBE elicit short-term effects similar to those of
PS-6 UG. Given that these effects are potentially related to
tumor promotion and the general lack of genotoxic activity,
MTBE and 91-01 UG may exhibit
tumor promoting activity similar to that seen with
PS-6 UG. Since the liver is under multihormonal control, the increase in hepatic
estrogen metabolism and uterine effects supports a potential role for endocrine modulations in both
MTBE-and UG-induced hepatocarcinogenesis.