Endocrine disrupting effects of parabens in zebrafish (Danio rerio): New insights from transcriptomics, metabolomics, and molecular dynamics simulation

Parabens (PBs), a group of widely used synthetic preservatives with potential endocrine-disrupting activity, have been detected with increasing frequency in organisms and environmental matrices. This study assessed the endocrine hormone interference effects of four typical PBs, namely methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP), in zebrafish and elucidated the probable underlying mechanisms. Transcriptomic and metabolomic analyses showed that the differentially expressed genes and metabolites were associated with the tyrosine metabolism, arachidonate metabolism, and glycerophospholipid metabolism, indicating they were essential precursors of steroid hormone biosynthesis and metabolism. Histopathological analysis revealed impaired gonad development in the zebrafish exposed to PBs, in accordance with the significantly increased vitellogenin (VTG) and estradiol (E2) levels. Furthermore, molecular dynamics simulation suggested that the four PBs could preferentially to activate zebrafish estrogen receptor (zfERβ2) to regulate the downstream pathways. Disruption of the amino acid metabolism and lipid metabolism, and activation of zfERβ2 signaling pathway were found to be the key mechanisms for the endocrine-disrupting effect of PBs. The endocrine disrupting effects of PBs were found to be dependent on the shared oxybenzene on their structures, with the degree of interference determined largely by the elongation of their alkyl groups. These findings provide new insights into the endocrine disrupting effects of PBs and could help better assess their risk to human health.