#C127 Di(2-ethylhexyl)phthalate Alters the Metabolism of Estrogen in Young Female Mice. Daniel Sepkovic, Leon Bradlow, Hackensack Univ. Medical Ctr., Hackensack, NJ. Introduction- Studies have suggested that phthalate ester plasticizers may play a role in premature sexual development in girls 8 years old or younger. It is our hypothesis that increased risk for hormone related cancers might be associated with this disorder. The risk could be enhanced due to earlier estrogen exposure coupled with aberrant estrogen metabolism. We investigated the effects of the phthalate ester di(2-ethylhexyl)phthalate (DEHP) on the metabolism of estrogen in young mice. Methods-Swiss Webster mice were divided into groups and put on DEHP containing diets. The doses chosen bracket the lowest observed adverse effect level (LOAEL) that was established at 5000ppm DEHP by Hazelton for B6CF1 female mice since the LOAEL for Swiss Webster mice has not yet been determined. The other groups were 1000ppm and 10000ppm DEHP. A control group that received AIN76A diet only was also included. Urine samples were prepared and analyzed for 6 estrogen metabolites and for DEHP by stable isotope dilution gas chromatography-mass spectrometry (GC-MS). Urine samples were collected after 3 and 6 days on the respective diets. Results-The selected estrogen metabolites analyzed were significantly lower in all of the DEHP groups when compared to control group values. There was a reduction in 4-OHE1 levels in the experimental groups. This effect may have been caused by an inhibition of cytochrome 1B1. DEHP has been shown to inhibit this cytochrome in rat V9 cells. Similarly, the observed reductions in 2-OHE1 in the treatment groups may be accounted for by DEHP inhibition of Cyp-1A2. The conversion of E2 to E1 is also reduced in the DEHP fed groups. Urinary DEHP concentrations were measured in each group after 3 and 6 days of DEHP administration. Analysis was performed by GC-MS in SIM mode using ion fragments 149, 167, and 279 m/z. 149m/z constitutes the base ion of DEHP. Dose-dependent increases in DEHP concentrations were observed during both time periods. We have confirmed the authenticity of the DEHP measurements by obtaining a complete mass spectrum from a mouse urine sample that received 10000ppm DEHP for 6 days. Conclusions-The results show that DEHP influences the metabolic pathways of estrogen. DEHP perturbs the normal metabolism of estradiol in several ways. Absolute levels of E2 are reduced in the experimental groups probably because of aromatase inhibition. Aromatase is responsible for the conversion of androgens to estrogen. Simultaneously, cytochrome inhibition prevents the further conversion of E2 to its primary metabolites. This results in an increased E2 to total estrogen metabolite ratio in the experimental groups. Concentrations of E1 are reduced after DEHP administration suggesting that the conversion of E2 to E1 by 17b-hydroxysteroid dehydrogenase is affected by DEHP. Less E1 would then be available for further Phase 1 metabolism via the C-2, C-16 or C-4 pathways. Relatively higher circulating levels of an active estrogen like E2 coupled with decreased metabolism of E2 may enhance premature feminization in male offspring and premature sexual development in female offspring. Frontiers in Cancer Prevention Research, 2003 AACR Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.