High Intake of Dietary Sugar Enhances Bisphenol A (BPA) Disruption and Reveals Ribosome-Mediated Pathways of Toxicity

Abstract

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...

Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes

“…To further address the time scale in which coupling between 5S and 45S elements emerges, we investigated the hypothesis that environmental triggers might rapidly induce concerted CN expansions and contractions in the rDNA loci. In particular, it has recently been suggested that bisphenol A (BPA) disrupts the expression of the genes coding for proteins of the small and large ribosome, and could cause nucleolar stress (44). Disruption in the expression of nucleolar components might cause rDNA instability and trigger concerted modulation of rDNA CN across the 5S and 45S loci.…”

Interaction between bisphenol A and dietary sugar affects global gene transcription in Drosophila melanogaster

“…Here we describe the dataset generated in the study published recently by Branco and Lemos (2014) [11] . The dataset shows that the effect of the organic compound BPA on genome-wide gene expression of D. melanogaster can be enhanced by the ingestion of sugar.…”

“…After 5 days laying eggs, adult flies were removed and the vials kept at 25 °C to collect the new emerged flies. Newly emerged adult males were aged for 48 h in the same rearing condition before they were flash-frozen in liquid nitrogen and stored at − 80 °C [11] .…”

Epigenetics as an answer to Darwin’s “special difficulty,” Part 2: natural selection of metastable epialleles in honeybee castes

“…The selection of metastable epialleles in Drosophila is well-established in our laboratory ( Ruden et al, 2003 , 2008 , 2009 ; Sollars et al, 2003 ; Ruden and Lu, 2008 ) and in other laboratories ( Carrera et al, 1998 ; Ruden and Lu, 2008 ; Tariq et al, 2009 ; Gangaraju et al, 2010 ; Valtonen et al, 2012 ; Branco and Lemos, 2014 ; Le Thomas et al, 2014 ; Nystrand and Dowling, 2014 ; Somer and Thummel, 2014 ; Stern et al, 2014 ; Wei et al, 2015 ). We showed, for instance, that stress, or the inactivation of the chaperone protein Hsp90, can activate a metastable epiallele of the Kruepple Incomplete facets-1 ( Kr If-1 ) allele, which causes ectopic large bristle outgrowths (ELBOs) to protrude from the eyes ( Sollars et al, 2003 ).…”