Long-term exposure of zebrafish to bisphenol S impairs stress function of hypothalamic-pituitary-interrenal axis and causes anxiety-like behavioral responses to novelty.

Bisphenol S (BPS), a main substitute of bisphenol A, has been reported to induce multiple endocrine disrupting effects on animals, however, whether it can interfere with the corticosteroid-endocrine system still remains unknown. Furthermore, previous studies mainly investigated the influences of environmental pollutants on corticosteroid levels and gene expressions of hypothalamic-pituitary-interrenal/adrenal (HPI/A) axis, while the downstream toxic effects caused thereafter have not yet been fully elucidated. Considering the key role of cortisol, a primary corticosteroid hormone in teleost, in mediating stress adaptation and the highly positive correlation between cortisol level and anxious phenotype in the novel environment, we hypothesized that an imbalanced cortisol homeostasis due to environmental pollutant exposure may further affect the behavioral responses to novelty stress. In the present study, zebrafish, a valuable model in studying human stress physiology and anxiety behavior, were exposed to BPS from embryos to adults (120 days) at environmentally relevant concentrations (1 and 10 μg/L) and 100 μg/L. Results found that long-term exposure to BPS increased whole-body cortisol levels and caused abnormal expressions of HPI axis genes. Moreover, the excessive cortisol levels may be due to the inhibition of cortisol catabolism and excretion, as evidenced by the down-regulated expressions of hydroxysteroid 11-beta dehydrogenase 2 and hydroxysteroid 20-beta dehydrogenase 2 genes. More importantly, as we speculated, excessive cortisol levels may be responsible for the occurrence of anxiety-like behavioral responses indicated by longer latency, fewer time spent in the upper half, and more erratic movements in a 6-min novel tank test. Overall, our study provides basic data for the comprehensive understanding of BPS toxicity, and emphasizes environmental health risks of BPS in inducing anxiety syndrome at environmentally realistic concentrations.