Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast

The phthalates di(2-ethylhexyl)phthalate (DEHP) and di-n-butyl phthalate (DBP) are environmental contaminants with significant human exposures. 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 alpha (PPAR alpha). DEHP and DBP are metabolised to their respective monoesters, mono-(2-ethylhexyl)phthalate (MEHP) and mono-n-butyl phthalate (MBP), which are the active metabolites. MEHP also activates another member of the PPAR subfamily, PPAR gamma. The effects of PPAR alpha and PPAR gamma activation in human breast cells appears to be opposing; PPAR alpha activators in breast cells cause an increase in proliferation, while PPAR gamma activation in breast cells is associated with differentiation and an inhibition of cell proliferation. Further to this the activation of the PPARs is cell and ligand specific, suggesting the importance of examining the effect of MEHP and MBP on the activation of PPAR alpha, PPAR beta and PPAR gamma in human breast. We used the common model of human breast cancer MCF-7 and examined the ability of MEHP and MBP to activate human PPARs in this system. The ability of MBP and MEHP to block PPAR responses was also assessed. We found that both human PPAR alpha and PPAR gamma were activated by MEHP whereas MEHP could not activate PPAR beta. MBP was unable to activate any PPAR isoforms in this breast model, despite being a weak peroxisome proliferator in liver, although MBP was an antagonist for both PPAR gamma and PPAR beta. Our results suggest that the toxicological consequences of MEHP in the breast could be complex given the opposing effects of PPAR alpha and PPAR gamma in human breast cells. (c) 2005 Elsevier Ireland Ltd. All rights reserved