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. In addition in conditionate human gene expression, POPs may influence gut bacterial physiology and gene expression, further complicating their health impacts.
The gut microbiota plays crucial roles in maintaining human health. Mounting evidence suggests that the gut microbiota affects glucose and metabolic homeostasis. Possible mechanisms linking the gut microbiota to glucose homeostasis may include increased intestinal permeability, low-grade endotoxemia, changes in the production of short-chain fatty acids or branched-chain amino acids, alterations in bile acid metabolism, and effects on the secretion of gut hormones. The composition and functions of the gut microbiota are strongly influenced by diet, drugs, and environmental pollutants. Importantly, growing evidence suggests that disrupted bacterial communities promoted by interventions such as antibiotic treatment early in life were associated with an increased risk of diseases in adulthood.
A study performed at the University of San Francisco 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. The investigation 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 Methanomethylovorans was observed. However, five days of TCDF exposure significantly altered the relative abundance of Bifidobacterium pseudolongum, Akkermansia muciniphila and Parasutterella excrementihominis. TCDF exposure reduced SCFA synthesis later in life, along with cecal tryptophan metabolite indole-3-lactic acid (ILA) levels.
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. Recently, the same research team demonstrated in mice that early life exposure to 3,3′,4,4′,5-pentacholorobiphenyl (PCB 126), one of the most acutely toxic polychlorinated biphenyl (PCB) congeners with a long half-life (17 d in mouse and 4.5 y in human), had a substantial impact on bacteria in adulthood at the community structure, metabolic, and functional levels, independent of diet. These information raise the possibility that microbial toxicity could be a key target of early life exposure to environmental pollutants, potentially contributing to an increased risk of metabolic disorders later in life.
Therefore, TCDF exposure on the development of metabolic diseases (es. type 2 diabetes and obesity) later in life may start from influences on gut microbiota.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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