In vitro disruption of the retinoic acid signaling pathway by industrial chemicals and pharmaceuticals

Abstract

Disruption of the retinoid signaling pathway by environmental chemicals is currently not directly assessed in regulatory testing. Although in vitro and in silico methods are available to assess disruption of this modality, more data on the selectivity and in vivo predictivity of specific assays are needed. To address this, we tested twenty-one pesticides and pharmaceuticals for their ability to agonize or antagonize the retinoic acid receptor alpha (RARα) or to inhibit the activity of aldehyde dehydrogenases (ALDH1As). Experimental data was generated using a RARα reporter gene assay and a cell line stably transfected to express two isoforms of ALDH1A for enzyme inhibition assay. The measured output of the latter was synthesized retinoic acid (RA) converted from added retinal. RARα antagonism predictions were obtained from the Danish (Q)SAR Database. Several test compounds acted as RAR agonists, while only a few inhibited ALDH1As, suggesting that the two assays together provide a more comprehensive view of how compounds impact RA signaling. Some substances were active in only one of the in vitro assays, highlighting the importance of including both models to avoid false negatives. No clear pattern was seen to suggest that either endpoint was more predictive of in vivo effects. Collectively, these findings underscore the need to include more assays for detecting different mechanisms of retinoid signal disruption in future testing regimens relying less on in vivo toxicity observation and more on predictive methods.