Bisphenol A (BPA) is an organic compound to which human populations are ubiquitously exposed. Epidemiological data suggest BPA exposure might be associated with higher rates of diabetes and reproductive anomalies. Health concerns also include transgenerational consequences, but these mechanisms are crudely defined. Similarly, little is known about synergistic interactions between BPA and other substances. Here we show that acute and chronic exposure to BPA causes genome-wide modulation of several functionally coherent genetic pathways in the fruit fly Drosophila melanogaster. In particular, BPA exposure causes massive downregulation of testis-specific genes and upregulation of ribosome-associated genes widely expressed across tissues. In addition, it causes the modulation of transposable elements that are specific to the ribosomal DNA loci, suggesting that nucleolar stress might contribute to BPA toxicity. The upregulation of ribosome-associated genes and the impairment of testis-specific gene expression are significantly enhanced upon BPA exposure with a high-sugar diet. Our results suggest that BPA and dietary sugar might functionally interact, with consequences to regulatory programs in both reproductive and somatic tissues. E XPOSURE to environmental toxins is widespread. It is well documented, for instance, that human populations are commonly exposed to bisphenol A (BPA), bis(2-ethylhexyl) phthalate (DEHP), dioxins, and other organic molecules produced at industrial scales. Toxins might act by modulating epigenetic pathways to change the expression of genes and normal cellular homeostasis and could result in transgenerational consequences. The fast pace at which new compounds are invented and become ubiquitous in the environment poses a challenge to safety assessment. This challenge emerges not only from the large number of compounds to evaluate, but also from the high dimensionality of toxic responses across tissue types and developmental stages. This is further aggravated by the potential for unexpected synergism among toxins in mixtures. Sensitivity might also be strongly dependent on the specific epigenomic features and genetic makeup of an individual (Du et al. 2004).Genomic analyses have uncovered levels of human genetic variation not surmised a few decades ago (e.g., Sudmant et al. 2010). Cost-effective epigenetic and physiological models are needed for (i) addressing tissue-specific responses to toxins, (ii) gaining insights into mechanisms of epigenetic toxicity, and (iii) evaluating the manifestation of these responses across naturally occurring genotypes. In particular, cost-effective models with massive publicly available genetic information (Zwarts et al. 2011; King et al. 2012a,b;Mackay et al. 2012) might allow for genome-wide evaluation of toxic responses and assessment of coexposure outcomes in conjunction with the evaluation of unique individual responses.BPA is one of the most abundantly produced chemicals worldwide, reaching an annual volume .4 million tons (Burridge 2003). Multi...