The Crosstalk of PCB126 and Hypoxia Sensing Pathways: Effect on Adipocyte Metabolism and Development

This thesis evaluated how lipophilic persistent organic pollutants, which accumulate in lipid-rich tissues, and hypoxia, which may develop during adiposity excess, influence adipose tissue functions. A narrative review and two experimental studies were conducted. In the review, we summarize how the hypoxic environment within adipose tissue can modify its functionality, impacting the secretion of adipokines, promoting inflammation, and potentially contributing to metabolic disturbances associated with obesity. We also examine the interplay between dioxin-like polychlorinated biphenyl-PCB126 and hypoxia, evaluating their combined impact on adipose tissue functions. Both hypoxia and PCBs have demonstrated effects on adipose tissue functions. The signaling pathways induced by PCB126 and hypoxia may crosstalk, as they share a common transcription factor: aryl hydrocarbon receptor nuclear translocator (ARNT). In a first study, using primary human subcutaneous adipocytes (hSA) acutely co-exposed to different levels of PCB126 (48 h) and hypoxia (24 h), a unidirectional crosstalk was confirmed, with hypoxia significantly inhibiting PCB126-induced cytochrome P450 (CYP1A1) transcription. Acriflavine (ACF), an HIF-1α inhibitor, partially restores this induction under hypoxia. Additionally, hypoxia and PCB126 elicit distinct effects on the secretion of key adipokines (leptin, adiponectin, (interleukin)- IL-6 and IL-8), emphasizing a lack of apparent crosstalk between these factors. Building upon these insights, the second study broadens the scope to examine the combined effects of PCB126 and hypoxia on hSA differentiation, glucose metabolism, and inflammation. Employing pre-differentiation PCB126 exposure and subsequent differentiation under prolonged hypoxia on hSA, results indicate that pre-differentiation PCB126 exposure leads to diminished adenosine triphosphate (ATP) content, reduced glucose uptake, and suppressed leptin expression in mature adipocytes. Under normoxia, PCB126 has limited effects on differentiation, but under hypoxia, preadipocyte differentiation is significantly impaired, marked by decreased lipid accumulation and downregulation of key adipocyte genes including peroxisome proliferator-activated receptor-gamma (PPARγ) and adiponectin. Hypoxia induces increased glucose uptake and glucose transporter 1 (GLUT1) expression, coupled with a loss of adipocytes' insulin response and GLUT4 expression. The combined exposure to PCB126 and hypoxia exhibits additive effects on adipose tissue inflammation, evidenced by increased expression of pro-inflammatory adipokines IL-6 and IL-8. While PCB126 does not directly impact human preadipocyte differentiation, it does influence subsequent adipocyte populations, as indicated by lower ATP levels and absolute glucose uptake. This research provides valuable insights into the complex interactions of environmental factors with adipose tissue physiology, contributing to our understanding of potential links between persistent organic pollutant (POP) exposure, hypoxia, and the development of chronic metabolic disorders.