Biphasic Dose-response Induced By Environmental Pollutants And The Mechanistic Study Of Biphasic Dose-response Induced By Polychlorinated Biphenyls

The most fundamental concept used in toxicology to determine risk assessment and regulation is the dose-response relationship, for which two models have traditionally been used. The threshold model is used in the assessment of risks for non-carcinogens, and the linear non-threshold (LNT) model to extrapolate risks to very low doses of carcinogens. But many reports have revealed that the most fundamental shape of the dose response curve is neither threshold nor linear, but U-shaped. The U-shaped biphasic dose-response relationship is commonly represented hormesis. Hormesis is a dose response phenomenon, characterizes the dose-response continuum as stimulatory at low doses and inhibitory at high doses, leading to the biphasic, hormetic dose-response curve. This stimulatory effect in low concentrations of toxic chemicals on organismal metabolism has been exhibited across the spectrum of models, endpoints, and agents. Hormesis rejects the standard toxicological assumption that effects at low doses can be extrapolated from data obtained from high doses, thus challenge the current risk assessment practices.Bioassay is a useful tool in assessing environmental risk of harmful substances. During the past years, a variety of biological models such as bacteria, microalgae, cultured cells and other organisms were adapted to toxicological studies and made the toxicity testing reliable, sensitive, cost-effective, and rapid. In this study, we took luminescent bioassay and cell culture toxic test as testing models to examine whether the hormetic response is ubiquitous in testing chemicals. In luminescent bioassay, effects of Cu (â…¡), Zn (â…¡), Cd (â…¡) and Cr (â…¥) on marine and freshwater luminescent bacteria, named Photobacterium phosphorem and Vibrio qinghaiensis were studied, and biphasic dose-response curve was clearly observed. In cell culture test, the toxicity of zinc salts and PCBs were investigated in Vero cell, an established line of monkey kidney cell which is recommended for screening chemical toxicity in vitro. These chemicals showed a typical hormetic response, which stimulated Vero cell proliferation at low doses, and caused cell death at high concentrations. All our data demonstrated that hormesis response is a common phenomenon accurse in different tests with different chemicals.Although hormetic effect is a common phenomenon, the cellular mechanisms of the hormetic dose-response are not well clarified yet. In this thesis, we took Vero cell as the testing model to study the possible mechanism of biphasic dose-response relationship. The morphological and biochemical changes in Vero cell cultures manifested clear evidence of PCBs toxicity. The difference between MTT results and cellular configuration alteration indicated that different cytotoxic mechanisms might operate in the induction of cell death between PCB 126 and PCB 153 treated cells. Apoptosis was involved in PCB 153 induced cell death and alteration of membrane integrity, damage of mitochondrial function might associated with the cytotoxicity induced by PCB 153 treatment.The present data confirm that both coplanar PCB 126 and ortho-substituted PCB 153 presented low doses stimulation on Vero cells proliferation. The modulation of cell cycle with PCBs exposure might be one mechanism involved in low dose proliferation promotion. Low doses PCBs exposure significantly increased the percentage of cells in the S phase, which might associated with cell proliferation caused by low doses PCBs exposure. Meanwhile, the massive accumulation of cell in G1 phase might reflect an arrest of cells in G1 phase, which might response for the cytotoxicity of high concentration PCBs treatment. Our data showed the increase expression of CDK2, Cyclin D1 and Cyclin E caused by PCB 126 exposure, the cell proliferation promotion with coplanar PCB 126 exposure might ascribe to the release from contact inhibition caused by the AhR agonist characteristic of coplanar PCB congener. The capacity of ERK 1/2 signal transduction pathways activation was response for cell proliferation promotion in low dose PCB 153 exposure.