The
obesity pandemic is presumed to be accelerated by
endocrine disruptors such as
phthalate-
plasticizers, which interfere with adipose tissue function. With the restriction of the
plasticizer di-(2-ethylhexyl)-phthalate (
DEHP), the search for safe substitutes gained importance. Focusing on the master regulator of adipogenesis and adipose tissue functionality, the
peroxisome proliferator-activated receptor gamma (PPARγ), we evaluated 20 alternative
plasticizers as well as their metabolites for binding to and activation of PPARγ and assessed effects on adipocyte
lipid accumulation. Among several compounds that showed interaction with PPARγ, the metabolites MINCH, MHINP, and
OH-MPHP of the
plasticizers DINCH, DINP, and DPHP exerted the highest adipogenic potential in human adipocytes. These metabolites and their parent
plasticizers were further analyzed in human preadipocytes and mature adipocytes using cellular assays and global proteomics. In preadipocytes, the
plasticizer metabolites significantly increased
lipid accumulation, enhanced
leptin and
adipsin secretion, and upregulated adipogenesis-associated markers and pathways, in a similar pattern to the PPARγ agonist
rosiglitazone. Proteomics of mature adipocytes revealed that both, the
plasticizers and their metabolites, induced oxidative stress, disturbed
lipid storage, impaired metabolic homeostasis, and led to proinflammatory and
insulin resistance promoting
adipokine secretion. In conclusion, the
plasticizer metabolites enhanced preadipocyte differentiation, at least partly mediated by PPARγ activation and, together with their parent
plasticizers, affected the functionality of mature adipocytes similar to reported effects of a high-fat diet. This highlights the need to further investigate the currently used
plasticizer alternatives for potential associations with
obesity and the
metabolic syndrome.