Transcriptional and morphological effects of tamoxifen on the early development of zebrafish (Danio rerio)

Abstract

Tamoxifen is a widely used anticancer drug with both an estrogen agonist and antagonist effect. This study focused on its endocrine disrupting effect, and overall environmental significance. Zebrafish embryos were exposed to different concentrations (0.5, 5, 50 and 500 µg l(-1) ) of tamoxifen for 96 h. The results showed a complex effect of tamoxifen on zebrafish embryo development. For the 500 µg l(-1) exposure group, the heart rate was decreased by 20% and mild defects in caudal fin and skin were observed. Expressions of a series of genes related to endocrine and morphological changes were subsequently tested through quantitative real-time polymerase chain reaction. Bisphenol A as a known estrogen was also tested as an endocrine-related comparison. Among the expression of endocrine-related genes, esr1, ar, cyp19a1b, hsd3b1 and ugt1a1 were all increased by tamoxifen exposure, similar to bisphenol A. The cyp19a1b is a key gene that controls estrogen synthesis. Exposure to 0.5, 5, 50 and 500 µg l(-1) of tamoxifen caused upregulation of cyp19a1b expression to 152%, 568%, 953% and 2024% compared to controls, higher than the effects from the same concentrations of bisphenol A treatment, yet vtg1 was suppressed by 24% from exposure to 500 µg l(-1) tamoxifen. The expression of metabolic-related genes such as cyp1a, cyp1c2, cyp3a65, gpx1a, gstp1, gsr and genes related to observed morphological changes such as krt17 were also found to be upregulated by high concentrations of tamoxifen. These findings indicated the potential environmental effect of tamoxifen on teleost early development. Copyright © 2015 John Wiley & Sons, Ltd.

Differential activity of BPA, BPAF and BPC on zebrafish estrogen receptors in vitro and in vivo

“…However, it has been reported that estrogenic ligands can alter the basal heart rate in zebrafish embryos. Exposure to estradiol and ICI 182,780 resulted in increased heart rate in zebrafish, an effect that was attributed to modulation of the G proteincoupled estrogen receptor (GPER) pathway (Romano et al, 2016), while treatment with the anti-estrogen tamoxifen caused a decrease in the heart rate of zebrafish embryos (Xia et al, 2016). BPA treatment has been shown to impair the cardiac contractile performance of rodent hearts, an effect associated with altered intracellular calcium handling (Posnack et al, 2015).…”

Cyclosporine exacerbates ketamine toxicity in zebrafish: Mechanistic studies on drug–drug interaction

“…Similar to human CYP3A, enhanced CYP3A65 transcription in the foregut of the zebrafish larvae in response to dexamethasone and the antibiotic rifampicin confirmed that zebrafish CYP3A65 is an ortholog of the human CYP3A gene (Chang et al, ; Tseng et al, ). CYP3A65 expression in zebrafish has been used as a hepatic biomarker (Al‐Habsi et al, ; Cunha et al, ; Verstraelen et al, ; Xia et al, ) and the zebrafish embryo model was shown to detect hepatotoxicants with higher specificity than the HepG2 cells (Jones et al, ).…”

Interactions Between Bisphenol A Exposure andGSTP1Polymorphisms in Childhood Asthma

“…Tamoxifen may reverse the effects of estradiol and BPA. 36 It has also been reported that BPA metabolites can be converted into glutathione conjugates in order to be excreted in urine. Thus, the expression of the GSTP1 gene may be responsible for conjugation of BPA metabolites with glutathione, which could increase with BPA exposure.…”