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In this study, the endocrine-disrupting (ED) potency of metabolites from brominated flame retardants (BFRs) was determined. Metabolites were obtained by incubating single-parent compound BFRs with phenobarbital-induced rat liver microsomes. Incubation extracts were tested in seven in vitro bioassays for their potency to compete with thyroxine for binding to transthyretin (TTR), to inhibit estradiol-sulfotransferase (E2SULT), to interact with thyroid hormone-mediated cell proliferation, and to (in-)activate the androgen, progesterone, estrogen, or aryl hydrocarbon receptor. For most BFRs, TTR-binding potencies, and to a lesser extent E2SULT-inhibiting potencies, significantly increased after biotransformation. Microsomal incubation had less pronounced effects on other ED modes of action, due to low biotransformation efficiency and background activities determined in control incubations without BFRs. Moreover, cell-based bioassays suffered from cytotoxicity from metabolites of lower-brominated polybrominated diphenyl ethers. For the environmentally relevant 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), six hydroxylated metabolites were identified. Individual metabolites had TTR-binding and E2SULT-inhibiting potencies 160-1600 and 2.2-220 times higher than BDE-47 itself, whereas their combined potencies in a realistic mixture were well predicted via concentration addition. In combination with other environmentally relevant hydroxylated organohalogens acting on TTR-binding and E2SULT inhibition, internal exposure to BFR metabolites may significantly contribute to the overall risk of endocrine disruption.

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Gastroesophageal cancers are a major cause of death worldwide and treatment outcomes remain poor. Adequate predictive biomarkers have not been identified. Microsatellite instability (MSI) as a result of mismatch repair deficiency is present in four to twenty percent of gastroesophageal cancers and has been associated with favorable survival outcomes compared to microsatellite stable tumors. This prognostic advantage may be related to immunosurveillance, which may also explain the favorable response to immune checkpoint inhibition observed in MSI high (MSI-H) tumors. The value of conventional cytotoxic treatment in MSI-H tumors is unclear and results on its efficacy range from detrimental to beneficial effects. Here the recent data on MSI as a predictive factor for outcome of gastroesophageal cancer treatment is reviewed.