The effects of mono (2-ethylhexyl) phthalate, mono-n-butyl phthalate and ethanol on PPARs in MCF-7 human breast cancer cells

Proc Amer Assoc Cancer Res, Volume 47, 2006 374 Di(2-ethylhexyl)phthalate (DEHP) and di- n -butyl phthalate (DBP) belong to a group of chemicals that are used as plasticizers in a wide range of products and are environmental contaminants at levels significant for humans. Both compounds are known reproductive toxins in rodents and DEHP also induces rodent hepatocarcinogenesis in a process believed to be mediated via the peroxisome proliferator-activated receptor α (PPARα). DEHP and DBP are metabolized to their respective active metabolite monoesters, mono-(2-ethylhexyl) phthalate (MEHP) and mono- n -butyl phthalate (MBP). There have been no studies of the effects of these agents on PPARs in breast cancer cell lines. Ethanol is another modulator of PPARs, since changes in PPARβ occur in B12 oligodendrocyte cells upon ethanol exposure. Epidemiological studies show a positive correlation between alcohol intake and breast cancer risk. However, there have been no studies of the effects of ethanol on PPARs in breast cancer cell lines. We hypothesized that MEHP and/or MBP would affect the transactivation of human PPAR isoforms in MCF-7 cells and that ethanol would change the expression of PPARs in MCF-7 cells.. Using a gene reporter assay we looked at the activation of human PPARα, PPARβ and PPARγ by MEHP and MBP. MEHP activated both PPARα and PPARγ but had no activity towards PPARβ. MBP while unable to act as an agonist towards any PPAR isoform showed antagonistic activity against human PPARγ and PPARβ. Using real time RT-PCR we looked at the transcription of PPAR isoforms in the presence of increasing concentrations of ethanol and saw isoform specific effects. Given that the effects of PPARα, PPARβ and PPARγ activation in human breast cells appears to be opposing (PPARα and PPARβ activators in breast cells cause an increase in proliferation, while PPARγ activation in breast cells is associated with differentiation and an inhibition of cell proliferation), the consequences of MEHP and ethanol in the breast are likely to be complex.