Transcriptome analysis reveals differences in developmental neurotoxicity mechanism of methyl-, ethyl-, and propyl-...

Studies on the comparison of developmental (neuro) toxicity of parabens are currently limited, and unharmonized concentrations between phenotypic observations and transcriptome analysis hamper the understanding of their differential molecular mechanisms. Thus, developmental toxicity testing was conducted herein using the commonly used methyl- (MtP), ethyl- (EtP), and propyl-parabens (PrP) in zebrafish embryos. With a benchmark dose of 5%, embryonic-mortality-based point-of-departure (M-POD) values of the three parabens were determined, and changes in locomotor behavior were evaluated at concentrations of 0, M-POD/50, M-POD/10, and M-POD, where transcriptome analysis was conducted to explore the underlying neurotoxicity mechanism. Higher long-chained parabens were more toxic than short-chained parabens, as determined by the M-POD values of 154.1, 72.6, and 24.2 µM for MtP, EtP, and PrP, respectively. Meanwhile, exposure to EtP resulted in hyperactivity, whereas no behavioral effect was observed with MtP and PrP. Transcriptome analysis revealed that abnormal behaviors in the EtP-exposed group were associated with distinctly enriched pathways in signaling, transport, calcium ion binding, and metal binding. In contrast, exposure to MtP and PrP mainly disrupted membranes and transmembranes, which are closely linked to abnormal embryonic development rather than neurobehavioral changes. According to the changes in the expressions of signature mRNAs, tentative transcriptome-based POD values for each paraben were determined as MtP (2.68 µM), EtP (3.85 µM), and PrP (1.4 µM). This suggests that different molecular perturbations initiated at similar concentrations determined the extent and toxicity outcome differently. Our findings provide insight into better understanding the differential developmental neurotoxicity mechanisms of parabens.