Novel Segmented Concentration Addition Method to Predict Mixture Hormesis of Chlortetracycline Hydrochloride and Oxytetracycline Hydrochloride to Aliivibrio fischeri

International Journal of Molecular Sciences

Cunzhu Dong¹  Peng Lin²  Daizhu Lv³  Huilin Ge³  Min Zhou³  Shuhuai Li³  Mingyue Wang³  Defang Xie³  Xinfeng Yang³ 

[1] College of Plant Protection, Hainan University, Haikou 570228, China;Fujian SCUD Power Technology Co., Ltd., Fujian 350004, China;Hainan Key Laboratory of Tropical Fruit and Vegetable Products Quality and Safety, Analysis and Testing Center, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China;

关键词: antibiotics;    aliivibrio fischeri;    mixture hormesis;    cross point hypothesis;    concentration addition;    isobole;    co-toxicity coefficient;    antagonism;   

DOI  :  10.3390/ijms21020481

来源: DOAJ

【 摘 要 】

Hormesis is a concentration-response phenomenon characterized by low-concentration stimulation and high-concentration inhibition, which typically has a nonmonotonic J-shaped concentration-response curve (J-CRC). The concentration addition (CA) model is the gold standard for studying mixture toxicity. However, the CA model had the predictive blind zone (PBZ) for mixture J-CRC. To solve the PBZ problem, we proposed a segmented concentration addition (SCA) method to predict mixture J-CRC, which was achieved through fitting the left and right segments of component J-CRC and performing CA prediction subsequently. We selected two model compounds including chlortetracycline hydrochloride (CTCC) and oxytetracycline hydrochloride (OTCC), both of which presented J-CRC to Aliivibrio fischeri (AVF). The seven binary mixtures (M1−M7) of CTCC and OTCC were designed according to their molar ratios of 12:1, 10:3, 8:5, 1:1, 5:8, 3:10, and 1:12 referring to the direct equipartition ray design. These seven mixtures all presented J-CRC to AVF. Based on the SCA method, we obtained mixture maximum stimulatory effect concentration (EC_m) and maximum stimulatory effect (E_m) predicted by SCA, both of which were not available for the CA model. The toxicity interactions of these mixtures were systematically evaluated by using a comprehensive approach, including the co-toxicity coefficient integrated with confidence interval method (CTCICI), CRC, and isobole analysis. The results showed that the interaction types were additive and antagonistic action, without synergistic action. In addition, we proposed the cross point (CP) hypothesis for toxic interactive mixtures presenting J-CRC, that there was generally a CP between mixture observed J-CRC and CA predicted J-CRC; the relative positions of observed and predicted CRCs on either side of the CP would exchange, but the toxic interaction type of mixtures remained unchanged. The CP hypothesis needs to be verified by more mixtures, especially those with synergism. In conclusion, the SCA method is expected to have important theoretical and practical significance for mixture hormesis.

【 授权许可】

Unknown