ABSTRACT
Background Bromadiolone is the second-generation anticoagulant rodenticide widely used all over the world. Exposure to bromadiolone in early life stage can lead to neurodevelopmental toxicity, but its toxic mechanism of neurodevelopment is not clear so far. Objective To investigate the developmental neurotoxicity and mechanism of bromadiolone to zebrafish embryos. Methods Zebrafish embryos were randomly divided into four groups: a solvent control group (dimethylsulphoxide) and three bromadiolone exposure groups (0.39, 0.78, and 1.18 mg·L−1). The exposure period was from 4 h to 120 h post-fertilization. The number of spontaneous movement per minute was recorded at 24 h post-treatment. The locomotor ability of zebrafish larvae and the activity of acetylcholinesterase (AChE) were tested at 120 h post-treatment. The relative expression levels of neurodevelopment-related genes (elavl3, gap43, mbp, and syn2a) were measured by fluorescence quantitative PCR. Results Compared with the control group, the number of spontaneous movement per minute at 24 h decreased significantly in the 1.18 mg·L−1 bromadiolone exposure group (P<0.05). Compared with the control group, the total distance travelled of the zebrafish larvae in the 0.78 and 1.18 mg·L−1 bromadiolone exposure groups decreased by 60% and 69% respectively (P<0.05, P<0.01), and the total movement time decreased by 34% and 65% respectively (P<0.05, P<0.01). The AChE activity in the 1.18 mg·L−1 bromadiolone exposure group increased by 36% when compared with the control group (P<0.05). The fluorescence quantitative PCR results showed that compared with the control group, the expression levels of neurodevelopment-related genes elavl3, syn2a, and mbp were significantly down-regulated by 66%, 69%, and 65% in the 1.18 mg·L−1 bromadiolone exposure group respectively (P<0.01), the expression level of gap43 was up-regulated by 56% in the 0.78 mg·L−1 bromadiolone exposure group (P<0.01) and down-regulated by 34% in the 1.18 mg·L−1 bromadiolone exposure group (P<0.05). Conclusion Bromadiolone exposure could inhibit spontaneous movement and locomotive behavior, down-regulate the expression levels of neurodevelopment-related genes, hinder the release of neurotransmitters, and result in neurodevelopmental toxicity in the early-staged zebrafish.
ABSTRACT
Objective To study the relationship between the expression of p-AKT and HIF-1αprotein and the response of breast cancer to neoadjuvant chemotherapy.Methods A retrospective study was performed on 70 cases of breast cancer patients receiving 4-6 cycles of TEC neoadjuvant chemotherapy in Wenzhou people's hospital from January 2014 to December 2016.Immunohistochemistry was applied to the detection of p-AKT and HIF-1αexpression before chemotherapy.Neoadjuvant chemotherapy response was evaluated according to the postoperative pathology.Pathological response to G4 or complete response were considered to be response efficaciously.Chi-square test and Fisher's test were applied to analyze the correlation between these index and the efficacy of neoadjuvant chemotherapy.Results The response rate of neoadjuvant chemotherapy was 52.9%(37/70)among the 70 cases, among which the pathological complete response(PCR)was 21.4%(15/70).The positive expression of p-AKT and HIF-1α were 64.3%(45/70)and 61.4%(43/70)respectively.Statistical analysis shows that p-AKT and HIF-1α expression were associated with the response of neoadjuvant chemotherapy of breast cancer(P=0.002, P=0.035), and also associated with the PCR(P=0.001, P=0.015).Conclusion p-AKT and HIF-1αexpression in breast cancer reduce the sensitivity of neoadjuvant chemotherapy to breast cancer.Patient with negative expression may benefit more from neoadjuvant chemotherapy.