Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals.

Environmental exposure to endocrine-disrupting chemicals (EDCs) can lead to metabolic disruption, resulting in metabolic complications including adiposity, dyslipidemia, hepatic lipid accumulation, and glucose intolerance. Hepatic nuclear receptor activation is one of the mechanisms mediating metabolic effects of EDCs. Here, we investigated the potential to use a repeated dose 28-day oral toxicity test for identification of EDCs with metabolic endpoints. Bisphenol A (BPA), pregnenolone-16α-carbonitrile (PCN), and perfluorooctanoic acid (PFOA) were used as reference compounds. Male and female wild-type C57BL/6 mice were orally exposed to 5, 50, and 500 µg/kg of BPA, 1000, 10 000, and 100 000 µg/kg of PCN and 50 and 300 µg/kg of PFOA for 28 days next to normal chow diet. Primary endpoints were glucose tolerance, hepatic lipid accumulation, and plasma lipids. After 28-day exposure, no changes in body weight and glucose tolerance were observed in BPA-, PCN-, or PFOA-treated males or females. PCN and PFOA at the highest dose in both sexes and BPA at the middle and high dose in males increased relative liver weight. PFOA reduced plasma triglycerides in males and females, and increased hepatic triglyceride content in males. PCN and PFOA induced hepatic expression of typical pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR)α target genes, respectively. Exposure to BPA resulted in limited gene expression changes. In conclusion, the observed changes on metabolic health parameters were modest, suggesting that a standard repeated dose 28-day oral toxicity test is not a sensitive method for the detection of the metabolic effect of EDCs.

The KEAP1-NRF2 pathway: Targets for therapy and role in cancer.

The KEAP1-NRF2 pathway is the key regulator of cellular defense against both extrinsic and intrinsic oxidative and electrophilic stimuli. Since its discovery in the 1990s, its seminal role in various disease pathologies has become well appreciated, motivating research to elucidate the intricacies of NRF2 signaling and its downstream effects to identify novel targets for therapy. In this graphical review, we present an updated overview of the KEAP1-NRF2 signaling, focusing on the progress made within the past ten years. Specifically, we highlight the advances made in understanding the mechanism of activation of NRF2, resulting in novel discoveries in its therapeutic targeting. Furthermore, we will summarize new findings in the rapidly expanding field of NRF2 in cancer, with important implications for its diagnostics and treatment.

Interspecific interactions between the rare tooth fungi Creolophus cirrhatus, Hericium erinaceus and H. coralloides and other wood decay species in agar and wood.

Creolophus cirrhatus, Hericium erinaceus and H. coralloides were paired against over 20 other wood decay fungi from beech (Fagus sylvatica) covering a range of ecological strategies, on 2% malt agar (MA), 0.5% MA, 0.5% MA adjusted to -1.25 MPa by addition of KCl, 0.5% MA adjusted to pH 4 with KOH/H3PO4 and 0.5% MA under 5% O2/30% CO2 all at 20 degrees C. Creolophus cirrhatus and H. coralloides were also paired against 17 other species in wood, incubated at 20 degrees for 36-38 wk. They were average to good combatants, deadlocking with or replacing over half of the antagonists, H. erinaceus being slightly more combative than the other two species. Outcomes in wood were representative of those in agar. Abiotic conditions altered the outcomes slightly, reduced water potential favouring C. cirrhatus and H. erinaceus. Overall extension rate of C. cirrhatus and H. erinaceus often increased in the presence of antagonists. There was prolific production of fruit bodies in controls and interactions, though notably not under altered gaseous regime. Results are discussed in an ecological context.