Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals.
Brecht AttemaOuti KummuSini PitkänenJonna WeisellTaina VuorioErika PennanenMaria VorimoJaana RysäSander KerstenAnna-Liisa LevonenJukka HakkolaPublished in: Archives of toxicology (2024)
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.
Keyphrases
- gene expression
- high dose
- body weight
- wild type
- healthcare
- public health
- physical activity
- poor prognosis
- body mass index
- insulin resistance
- binding protein
- type diabetes
- low dose
- mental health
- metabolic syndrome
- stem cell transplantation
- human health
- climate change
- health information
- mass spectrometry
- endothelial cells
- social media
- single molecule
- diabetic rats