NMR metabolomics study of chronic low-dose exposure to a cocktail of persistent organic pollutants.

Nowadays, exposure to endocrine-disrupting chemicals (EDCs), including persistent organic pollutants (POPs), is one of the most critical threats to public health. EDCs are chemicals that mimic, block, or interfere with hormones in the body's endocrine system and have been associated with a wide range of health issues. This innovative, untargeted metabolomics study investigates chronic low-dose internal exposure to a cocktail of POPs on multiple tissues that are known to accumulate these lipophilic compounds. Interestingly, the metabolic response differs among selected tissues/organs in mice. In the liver, we observed a dynamic effect according to the exposure time and the doses of POPs. In the brain tissue, the situation is the opposite, leading to the conclusion that the presence of POPs immediately gives a saturated effect that is independent of the dose and the duration of exposure studied. By contrast, for the adipose tissues, nearly no effect is observed. This metabolic profiling leads to a holistic and dynamic overview of the main metabolic pathways impacted in lipophilic tissues by a cocktail of POPs.

Merging the exposome into an integrated framework for "omics" sciences.

The exposome concept encourages holistic consideration of the non-genetic factors (environmental exposures including lifestyle) that influence an individual's health over their life course. However, disconnect between the concept and practical application has promoted divergent interpretations of the exposome across disciplines and reinforced separation of the environmental (emphasizing exposures) and biological (emphasizing responses) research communities. In particular, while knowledge of biological responses can help to distinguish actual (i.e. experienced) from potential exposures, the inclusion of endogenous processes has generated confusion about the position of the exposome in a multi-omics systems biology context. We propose a reattribution of "exposome" to exclusively represent the totality of contact with external factors that a biological entity experiences, and introduce the term "functional exposomics" to denote the systematic study of exposure-phenotype interaction. This reoriented definition of the exposome allows a more readily integrable dataset for multi-omics and systems biology research.

[What do we know about effects of the endocrine disruptors on metabolism and obesity?] / Que sait-on de l'action des perturbateurs endocriniens sur le métabolisme et l'obésité?

WHAT DO WE KNOW ABOUT EFFECTS OF THE ENDOCRINE DISRUPTORS ON METABOLISM AND OBESITY? Some endocrine disruptors (EDs) are suspected to be involved in the increase of the prevalence of obesity and metabolic diseases. Data from epidemiological, in vivo, in vitro and in silico studies suggest that EDs may exert their effects on numerous tissues involved in energy metabolism and in the regulation of appetite: adipose tissue, liver, muscle, pancreas, gut and hypothalamus. Their effects are due to: disruptions of the carbohydrate and lipid homeostasis in these organs, via the activation of specific nuclear receptors or transcriptional factors, disturbances in communication between these organs, and epigenetic mechanisms, involved for example in intergenerational effects. The characterization of the effects of EDs on endocrine systems is still under investigations in several European and international projects and initiatives, with the aim to establish new validated regulatory tests for ED identification.

QUE SAIT-ON DE L'ACTION DES PERTURBATEURS ENDOCRINIENS SUR LE MÉTABOLISME ET L'OBÉSITÉ ? Certains perturbateurs endocriniens (PE) semblent être impliqués dans l'augmentation de la prévalence de l'obésité et des maladies métaboliques. Les données provenant d'études épidémiologiques, in vivo, in vitro et in silico suggèrent que les PE exerceraient leurs effets sur de nombreux tissus impliqués dans le métabolisme énergétique ou la régulation de l'appétit : tissu adipeux, foie, muscle, pancréas, intestin et hypothalamus. Les effets sont liés : aux perturbations de l'homéostasie glucido-lipidique dans ces organes, via l'activation de récepteurs nucléaires ou facteurs transcriptionnels spécifiques ; aux perturbations de la communication entre ces organes et aux mécanismes épigénétiques, impliqués par exemple dans les effets intergénérationnels. La caractérisation des effets des PE sur les systèmes endocriniens se poursuit, au sein d'initiatives et de projets européens et internationaux qui, à terme, mèneront à la mise en place de tests réglementaires validés pour l'identification des perturbateurs endocriniens.

Effects of Common Pesticides on Prostaglandin D2 (PGD2) Inhibition in SC5 Mouse Sertoli Cells, Evidence of Binding at the COX-2 Active Site, and Implications for Endocrine Disruption.

BACKGROUND: There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects. OBJECTIVES: We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis. METHODS: Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket. RESULTS: The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos-methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances-o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)-showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor. CONCLUSIONS: Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrine-disrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action. CITATION: Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016. Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse Sertoli cells, evidence of binding at the COX-2 active site, and implications for endocrine disruption. Environ Health Perspect 124:452-459; http://dx.doi.org/10.1289/ehp.1409544.

The effect of network biology on drug toxicology.

INTRODUCTION: The high failure rate of drug candidates due to toxicity, during clinical trials, is a critical issue in drug discovery. Network biology has become a promising approach, in this regard, using the increasingly large amount of biological and chemical data available and combining it with bioinformatics. With this approach, the assessment of chemical safety can be done across multiple scales of complexity from molecular to cellular and system levels in human health. Network biology can be used at several levels of complexity. AREAS COVERED: This review describes the strengths and limitations of network biology. The authors specifically assess this approach across different biological scales when it is applied to toxicity. EXPERT OPINION: There has been much progress made with the amount of data that is generated by various omics technologies. With this large amount of useful data, network biology has the opportunity to contribute to a better understanding of a drug's safety profile. The authors believe that considering a drug action and protein's function in a global physiological environment may benefit our understanding of the impact some chemicals have on human health and toxicity. The next step for network biology will be to better integrate differential and quantitative data.