Environmental exposures such as drug administration, chemical contamination, and unhealthy diets can lead to toxicity or adverse effects that impose significant health and economical burdens. Addressing the mechanisms of these effects has become a critical topic. However, the majority of the current mechanistic research efforts has focused on a narrow molecular space, for example, on changes in the transcriptome in a select tissue and species, without taking into account other types of molecular, cellular, tissue, and species information. I hypothesize that development of new tools and strategies to integrate multispecies multi-tissue multicellular information will uncover new insights on environmental exposure. Hence my research aims to develop tools and apply computational analyses to understand molecular networks of different exposures and identify potential therapies. First, I built a tissue- and species-specific drug gene signature database for >900 drugs across tens of thousands of transcriptome datasets across human, mouse and rat models, and implemented a network-based repositioning tool to link drug signatures with different organ toxicities and disease therapeutics. This system was applied to validated for hyperlipidemia, non-alcoholic fatty liver disease and hepatoxicity. Next, I investigated multi- and trans-generational (F1 and F3) effect stemming from ethanol exposure on C. elegans model through single nucleus RNA-seq. I established the first comprehensive whole-organism transcriptional map of an environmental response at cell-type specific resolution. Results indicated strong alterations in metabolism, lipid transportation pathways as well as abnormal germline phenotypes among germline clusters. Finally, I investigated molecular effects of how a Western diet (high fat high sucrose) and a fructose rich diet affect metabolic regulation through single cell RNA-seq analysis of diverse cell subpopulations across different tissues (liver, adipose, hypothalamus and small intestine) in a mouse model. We identified susceptible tissues, cell types, biological pathways, and ligands mediating metabolic syndrome (Avp, Apoe, Oxt). These various projects involving different model systems, tissues, and cell types provided new analytical tools and revealed systems level insights on diverse types of environmental exposures.