The report "Toxicity Testing in the 21st Century" by the National Academy of Sciences (2007) envisioned that the animal testing in vivo can eventually be replaced by a combination of in silico and in vitro approaches, the need to identify in vitro systems to screen chemicals has grown. A significant public health challenge for toxicologists has been the need to identify chemicals for their potential to cause reproductive and developmental (R/D) toxicity. Risk assessment for the R/D toxicity is particularly challenging since R/D toxicity is highly complex, involving interactions between multiple organs and organ systems at different time points and life stages. Chronic in vivo toxicity tests for R/D assessment use the largest number of animals and yet these study designs are criticized for their low power. We have been developing the in vitro"Mini-testis", which mimics the in vivo spermatogenesis. This in vitro "Mini-testis" can be used to discriminate known developmentally or reproductive toxicants by integrating genomic and metabolomics. We are developing pathways-based high content and high throughput assays to makes prediction of adverse effects on the R/D toxicity from exposure, and paves the way for both accelerated testing of compound and significantly reduces use of animals.
Occupational health and safety (OHS) of workers is one of my research topics for years, especially exposure to new ozone depleting alternatives and new nano-materials. The emerging of new techniques always brings us new opportunity for better life, but it also brings challenges into the OHS for the workers and their community. 1-Bromopropane (1-BP) is a halogenated alkane, introduced into the workplace as an ozone depleting alternative solvent (ODA) after the discovery of the reproductive and hematopoietic toxicities of 2-brompropane (2-BP) in workers (Kim et al., 1997; Yu et al., 1999; Yu et al., 2001). Since its approval as an ODA from Environmental Protection Agency (EPA) ((USEPA), 2007), its usage is estimated to be around 20 million pounds/year, and is thus categorized as a high-production volume chemical for electronic parts cleaning and dry cleaning as well as in the synthesis for pharmaceuticals and pesticides (Eisenberg and Ramsey, 2010). Its wide usage in industry could result in widespread human exposure in the workplace (Administration, 1999; Anderson et al., 2010; Program, 2013). Since our first report of the neurotoxicity of 1-BP in animals (Yu et al., 1998), a dozen human cases of neurotoxicity have been reported with manifestations of 1-BP toxicity (Ichihara et al., 2002; Ichihara et al., 2004a; Ichihara et al., 2004b; Ichihara et al., 2004c; Majersik et al., 2007; Raymond and Ford, 2007; Smith et al., 2011; Samukawa et al., 2012). Most recently, the NTP reported a dose-dependent effect of carcinogenesis in both rats and mice (Morgan et al., 2011; Program, 2013). The potential for human exposure to 1-BP and the reports of adverse effects associated with potential occupational exposure to high levels of 1-BP have increased the need to understand the potential mechanism of these adverse effects in rats, mice as a means of understanding human risk in workers. It is also becoming increasingly important to establish an occupational exposure limit (OEL) for 1-BP in order to prevent the adverse effect on the exposed population. Therefore, we are currently developing a physiologically-based pharmacokinetic modeling (PBPK)to conduct an integrated quantitative risk assessment for 1-BP. Unlike classical pharmacokinetic models, a Bayesian PBPK model includes species-specific physiological, chemical, and biochemical parameters, allowing for extrapolation of animal data to humans. An integrated modeling effort and its application to quantification of health risk assessment would increase our confidence in the simulated results of 1-BP, and will provide significantly improved tool to set the occupational exposure levels for 1-BP.
Advances in computer sciences with equally significant developments in molecular biology and chemistry are providing toxicology with a powerful new toolbox. This toolbox of computational models promises to increase the efficiency and the effectiveness by which the hazards and risks of environmental chemicals are determined. Progress in this field facilitates the transformative shift called for in the recent report on toxicology in the 21st century by the National Research Council. We are developing and applying high-throughput, high-content biomarker assays including genomic, proteomic, epigenetic and metabolomics to develop systems biology approach to understand the mode of action of adverse effects by exposure to environmental chemicals. Systems based quantitative evaluation of pathway perturbations via comprehensive profiling experiments, and the elucidation of the molecular mechanisms of specific toxicities will expedite the discovery of biomarker for early detection and prevention of human diseases.
Microscopy images contain rich information about the state of cells. HCA empowered with advanced automation of image acquisition enables to measure several parameters simultaneously in a single cell based analysis. Our laboratory is focusing on developing advanced High-Content Analysis (HCA), including phenotypic and high-content screening of 3D cell culture models, multiplex assays, and HCS image analysis and modeling, in physiologically-relevant cellular models. Our goal is to gain mechanistic understanding of mode of action or adverse outcome pathways of toxicants and to develop a predictive computational model of the involved mechanisms. Patterns of morphological changes ("profiles") from cells in response to perturbation or toxicants are used to identify similarities and differences between various chemicals with the ultimate goal to identify the causes and potential cures of disease.
3D cell culture models for toxicity screening
High-Content phenotypic screening
HCS image analysis and modeling
Organoids and organotypic cell culture
Quantitative systems toxicology