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Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
Published on: June 17, 2015
Coplanar polychlorinated biphenyls activate the aryl hydrocarbon receptor in developing tissues of two
Jeffrey C Bemis1, Daniel A Nazarenko, Thomas A Gasiewicz
1Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Abstract:
In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can have an immediate impact on developmental processes that then lead to long-term deficits in function. To define the specific tissues affected by TCDD during development, we developed a lacZ-reporter gene mouse model driven by activation of the aryl hydrocarbon receptor (AhR). Exposure to TCDD on gestational day (GD) 14 results in strong activation of the lacZ transgene in numerous tissues including fore and hind paws, ear, and genital tubercle. Experiments were conducted to examine the ability of alternative AhR ligands to activate our model system. The coplanar polychlorinated biphenyl congeners 3,4,5,3',4'-pentachlorobiphenyl (PCB126) and 3,4,3',4'-tetrachlorobiphenyl (PCB77) both induced staining in fetal tissues identical to that observed following TCDD exposure. Exposure of fetuses to the PCB mixture Aroclor 1254 and the non-coplanar congener 2,3,6,2',5'-pentachlorobiphenyl (PCB95) did not result in any activation of the lacZ transgene. In addition to the testing of alternative ligands, another line of reporter mice was generated to determine the potential influence of the site of insertion of the lacZ transgene on the reported observations. Both TCDD and the coplanar PCBs induced a similar pattern of staining in the new line as compared to that observed in the original lacZ reporter mouse line. The ability of AhR ligands, other than TCDD, to activate the AhR-mediated transgene, in combination with the insertion-site independence of the response, strengthens the data previously derived from this model and increases the utility of this system for investigations examining AhR-mediated events during development.
Insights
In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impacts development. A novel mouse model shows TCDD and certain PCBs activate the aryl hydrocarbon receptor (AhR) in fetal tissues, revealing developmental toxicity pathways.
Area of Science:
- Toxicology
- Developmental Biology
- Molecular Biology
Background:
- In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can cause immediate developmental disruptions and long-term functional deficits.
- Understanding the specific tissues affected by TCDD during critical developmental periods is crucial for assessing its toxicological impact.
Purpose of the Study:
- To develop and validate a lacZ-reporter gene mouse model for investigating aryl hydrocarbon receptor (AhR) activation during development.
- To identify specific fetal tissues responsive to TCDD and other AhR ligands.
- To assess the efficacy of alternative AhR ligands, including coplanar and non-coplanar polychlorinated biphenyls (PCBs), in activating the reporter system.
Main Methods:
- Generation of a lacZ-reporter gene mouse model driven by AhR activation.
- Exposure of pregnant mice to TCDD on gestational day 14.
- Administration of various AhR ligands, including PCB congeners (PCB126, PCB77, PCB95) and Aroclor 1254, to assess reporter gene expression in fetal tissues.
- Generation of a second reporter mouse line to evaluate insertion-site independence.
Main Results:
- TCDD exposure on gestational day 14 induced lacZ transgene activation in multiple fetal tissues, including paws, ear, and genital tubercle.
- Coplanar PCBs (PCB126 and PCB77) mimicked TCDD's tissue-specific activation pattern.
- Non-coplanar PCB95 and the PCB mixture Aroclor 1254 did not activate the reporter system.
- A second reporter mouse line confirmed similar TCDD and coplanar PCB-induced staining patterns, indicating insertion-site independence.
Conclusions:
- The developed lacZ-reporter mouse model effectively identifies AhR-mediated developmental toxicity.
- Coplanar PCBs, similar to TCDD, activate AhR in specific fetal tissues, highlighting their potential developmental risks.
- The model's robustness and insertion-site independence enhance its utility for studying AhR-mediated developmental events.
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