{Reference Type}: Journal Article
{Title}: Comparative study of the effect of 17 parabens on PXR-, CAR- and PPARα-mediated transcriptional activation.
{Author}: Fujino C;Watanabe Y;Sanoh S;Hattori S;Nakajima H;Uramaru N;Kojima H;Yoshinari K;Ohta S;Kitamura S;
{Journal}: Food Chem Toxicol
{Volume}: 133
{Issue}: 0
{Year}: Nov 2019
{Factor}: 5.572
{DOI}: 10.1016/j.fct.2019.110792
{Abstract}: Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are members of the nuclear receptor superfamily, regulate the metabolism of endogenous substrates including hormones. Therefore, we hypothesized that parabens may alter hormone-metabolizing activities by acting on these receptors, and such changes could contribute to the endocrine-disrupting activity. To test this idea, we systematically examined the effects of 17 parabens on these receptors using reporter gene assays. Nine parabens significantly activated human and rat PXR. Parabens with C2-C5 (linear and branched) side chains were most active. Butylparaben and isobutylparaben also significantly activated rat CAR. We found that long-side-chain (C7-C12) parabens showed up to 2-fold activation of PPARα at 10 μM. Furthermore, pentylparaben and hexylparaben showed rat PXR antagonistic activity and rat CAR inverse agonistic activity. The activity of butylparaben towards PXR and CAR was lost after carboxylesterase-mediated metabolism. These findings confirm that parabens influence the activities of PXR, CAR and PPARα, and thus have the potential to contribute to endocrine disruption by altering hormone metabolism.