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Background: Rapid economic development in China has produced serious ecological, environmental, and health problems. Neurotoxicity has been recognized as a major public health problem. The Chinese government, research institutes, and scientists conducted extensive studies concerning the source, characteristics, and mechanisms of neurotoxicants. Objectives: This paper presents, for the first time, a comprehensive history and review of major sources of neurotoxicants, national bodies/legislation engaged, and major neurotoxicology research in China. Methods: Peer-reviewed research and pollution studies by Chinese scientists from 1991 to 2015 were examined. PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) were the major search tools. Results: The central problem is an increased exposure to neurotoxicants from air and water, food contamination, e-waste recycling, and manufacturing of household products. China formulated an institutional framework and standards system for management of major neurotoxicants. Basic and applied research was initiated, and international cooperation was achieved. The annual number of peer-reviewed neurotoxicology papers from Chinese authors increased almost 30-fold since 2001. Conclusions: Despite extensive efforts, neurotoxicity remains a significant public health problem. This provides great challenges and opportunities. We identified 10 significant areas that require major educational, environmental, governmental, and research efforts, as well as attention to public awareness. For example, there is a need to increase efforts to utilize new in vivo and in vitro models, determine the potential neurotoxicity and mechanisms involved in newly emerging pollutants, and examine the effects and mechanisms of mixtures. In the future, we anticipate working with scientists worldwide to accomplish these goals and eliminate, prevent and treat neurotoxicity. Citation: Cai T, Luo W, Ruan D, Wu YJ, Fox DA, Chen J. 2016. The history, status, gaps, and future directions of neurotoxicology in China. Environ Health Perspect 124:722–732; http://dx.doi.org/10.1289/ehp.1409566

Background Long-term exposure of arsenite leads to human skin cancer. However, the exact mechanisms of arsenite-induced human skin carcinogenesis remain to be defined. Objectives In this study, we investigated the potential role of PI-3K/Akt/cyclin D1in the transformation of human keratinocytic cells upon arsenite exposure. Methods We used the soft agar assay to evaluate the cell transformation activity of arsenite exposure and the nude mice xenograft model to determine the tumorigenesis of arsenite-induced transformed cells. We used the dominant negative mutant and gene knockdown approaches to elucidate the signaling pathway involved in this process. Results Our results showed that repeated long-term exposure of HaCat cells to arsenite caused cell transformation, as indicated by anchorage-independent growth in soft agar. The tumorigenicity of these transformed cells was confirmed in nude mice. Treatment of cells with arsenite also induced significant activation of PI-3K and Akt, which was responsible for the anchorage-independent cell growth induced by arsenite exposure. Furthermore, our data also indicated that cyclin D1 is an important downstream molecule involved in PI-3K/Akt–mediated cell transformation upon arsenite exposure based on the facts that inhibition of cyclin D1 expression by dominant negative mutants of PI-3K, and Akt, or the knockdown of the cyclin D1 expression by its specific siRNA in the HaCat cells resulted in impairing of anchorage-independent growth of HaCat cells induced by arsenite. Conclusion Our results demonstrate that PI-3K/Akt–mediated cyclin D1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect.