A recent Environmental Health Perspectives study determined the impact of early life exposure to potent aryl hydrocarbon receptor (AHR) agonists on gut microbiota and its potential effects on metabolic health later in life. Study: Effects of Early Life Exposures to the Aryl Hydrocarbon Receptor Ligand TCDF on Gut Microbiota and Host Metabolic Homeostasis in C57BL/6J Mice . Image Credit: StoryTime Studio/Shutterstock.
com Persistent organic pollutants Persistent organic pollutants (POPs), such as 3,7,8-Tetrachlorodibenzofuran (TCDF), are widely prevalent and bioaccumulate in the environment, posing serious health risks. Exposure to POPs can lead to reproductive disorders, cancer, immune suppression, neurological issues, and metabolic diseases like obesity and diabetes. People are exposed to these pollutants mainly through high-fat foods like meat, certain fish, and dairy products.
While previous studies suggest that early-life exposure to POPs increases the risk of metabolic diseases later on, further research is needed to understand the underlying mechanisms. TCDF, a potent aryl hydrocarbon receptor (AHR) ligand, shares structural similarities with the toxic compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but differs in its elimination rate, with TCDF having a longer half-life. Studies in mice have shown that short-term exposure to dietary TCDF causes rapid gut microbial dysbiosis, disrupting host metabolism, while prolonged exposure leads to hepatic lipogenesis—an early indicator of metabolic dysfunction and steatotic liver disease, previously known as non-alcoholic fatty liver disease .
There is a concern that gut microbial dysbiosis induced by POPs exposure could impact glucose and metabolic homeostasis, potentially increasing intestinal permeability, altering short-chain fatty acids (SCFAs) or branched-chain amino acid production, inducing low-grade endotoxemia, modifying bile acid metabolism, and affecting gut hormone secretion. POPs may influence gut bacterial physiology and gene expression, further complicating their health impacts. About the study The current study investigated the physiological and metabolic effects of early life exposure to TCDF through gut microbiome composition and function changes.
The impact of TCDF was assessed using a germ-free (GF) AHR knock-out mice model. Three-week-old male mice were used to investigate the short- and long-duration effects of TCDF. These mice were trained to eat bacon-flavored dough pills for five days, after which they were fed pills containing TCDF or acetone alone.
Related Stories High BPA levels linked to increased prostate cancer risk in older men Review of fasting-mimicking diets in cancer treatment Can how often you eat meat raise your risk of colorectal cancer? To study the short and long-duration effects, the mice were sacrificed the day after the last TCDF exposure and three months after TCDF exposure, respectively. Blood samples, urine, and feces were collected for analysis. Cecal content, liver, adipose, and intestinal tissue samples were also collected for relevant analysis.
Study findings The current study revealed that early-life gut microbial dysbiosis due to environmental pollutant exposure could induce metabolic disorders later in life. While analyzing the long-duration exposure, TCDF levels in the liver of mice were found to be below the detection level for GC-MS analysis, which could be attributed to the shorter half-life of TCDF. This observation was supported by data that revealed no significant differential AHR target genes Cyp1a1 and Cyp1a2 expression in the liver and ileal.
However, for TCDF exposure at the short-duration time point, a considerably higher serum reduced glutathione (GSSG) to reduced glutathione (GSH) ratios and alkaline phosphatase (ALP) levels were recorded. Based on liver histopathology, expression of intestinal cytokine mRNA, and serum ALP and cytokines levels, no overt toxicity was observed at long-duration TCDF exposure. However, shorter periods of exposure induced weight gain and higher levels of epididymal white adipose tissue (eWAT) later in life.
An impaired glucose tolerance was observed three months after TCDF exposure. Nuclear magnetic resonance (NMR)- and mass spectroscopy (MS)-based metabolomics data revealed that short-duration TCDF exposure led to higher levels of liver lipids. A minor liver profile change was also observed three months after TCDF exposure.
The targeted gas chromatography (GC)-MS analysis revealed higher levels of hepatic fatty acids after shorter duration exposure but not at longer exposure. Similarly, mRNA expression of genes associated with de novo fatty acid biosynthesis was found to express at higher levels after short-duration exposure but not after a longer-duration exposure. Interestingly, long-duration exposure to TCDF exhibited a stronger impact on microbiota composition; in particular, a higher abundance of m ethanomethylovorans was observed.
However, five days of TCDF exposure significantly altered the relative abundance of Bifidobacterium pseudolongum, A. muciniphila , and Parasutterella excrementihominis. Both short and long-duration exposure groups exhibited no significant difference in alpha diversity.
TCDF exposure reduced SCFA synthesis later in life, along with cecal tryptophan metabolite indole-3-lactic acid (ILA) levels and mRNA expression for G protein-coupled receptors (GPCRs). Conclusions In mice, early life exposure to TCDF causes a gut microbial disruption, particularly composition and function. A potential decrease in beneficial microbes, particularly A.
muciniphila, could be reversed with supplementation. The current study provided insights into the effects of TCDF exposure on the development of metabolic diseases later in life. Tian, Y.
et al. (2024) Effects of Early Life Exposures to the Aryl Hydrocarbon Receptor Ligand TCDF on Gut Microbiota and Host Metabolic Homeostasis in C57BL/6J Mice . Environmental Health Perspectives .
132 (8). doi : https://doi.org/10.
1289/EHP13356.Research . https://ehp.
niehs.nih.gov/doi/10.
1289/EHP13356.
