Involvement of the aryl hydrocarbon receptor in PCB126-induced toxicity: effects on energy metabolism, reproduction, and development

Polychlorinated Biphenyls (PCBs) are toxic environmental pollutants which were produced commercially from the 1920’s to late 1970’s and used in paints, electrical transformers, fluorescent light ballasts, capacitors, and other applications. Their intentional production and sale were banned in late 1970’s due to their adverse health effects, but PCBs still persist in the environment due to their bioaccumulation and resistance to biodegradation properties. Among 209 different congeners, PCB126 is the most potent dioxin-like toxicant and binds avidly to AhR (Aryl hydrocarbon receptor) which is a ligand-activated transcription factor involved in the regulation of biological responses. Although PCB126 was a minor component in commercial PCB mixtures, it is routinely measured in adipose, breast milk, and placenta in humans and animals. The main source of PCB126-exposure is food, specifically fish from many bays and lakes worldwide (e.g. Puerto Rico, Chicago, etc.). PCB126 contributes more than half of the toxic equivalence (TEQ) of all AhR ligands in our food. Therefore, millions of people including pregnant mothers, children and women of childbearing age are exposed to PCB126 and other dioxin-like compounds through food. Significant number of low birth weights, miscarriages, fetal deaths, and infertility problems are assumed to be related to exposures to AhR ligands. Understanding the potential impacts of PCB126 and similar contaminants on reproductive and developmental health are critical challenges to be addressed if we want to protect mothers and developing life. The goal of this study is to understand the involvement of AhR in the reproductive and developmental toxicity of PCB126 for prenatal and adult exposure. The findings of this work showed PCB126 significantly affects pregnant mothers body weights, liver, and imbalances important hormones and gene expressions. Then, it affects placenta to disrupt placental normal function that may cause insufficient energy and nutrient supply to the fetuses. Finally, PCB126 causes miscarriages, fetal deaths, and low birth weights for even short time exposure during pregnancy. Further, our study investigated PCB126-induced impaired liver energy homeostasis including hypoglycemia (low blood sugar) and female reproductive toxicity for adult exposure. PCB126 reduces ovarian reserve and alters metabolic and inflammatory gene transcription which are associated to polycystic ovarian syndrome (PCOS), endometriosis, premature ovarian insufficiency (POI), and even cancer in ovary and uterus. This study also showed that all of these toxic effects are mediated through the AhR. In addition, this study showed that PCB126-induced toxic effects on pregnant mothers, placental impairment, and adverse pregnancy outcomes are mediated by the AhR activation. We also examined that pregnant mothers are more sensitive to PCB126 exposure than non-pregnant females.

This thesis work provided a better understanding for the mechanism of reproductive and developmental toxicity of environmental contaminants, like PCB126. Humans are exposed to a variety of AhR ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like PCBs. Recent studies show that many pesticides and polycyclic aromatic hydrocarbons (PAHs) like benzo[a]pyrene can also activate the AhR. All these compounds may act through the same receptor in an additive way, possibly together reaching toxic levels that neither of them alone shows. Therefore, the findings of this study for reproductive and developmental toxicity of PCB126 which is mediated by the AhR activation may provide the additional evidence to explore the mechanisms for other similar environmental pollutants that are adversely affecting human reproductive health.