Animals and humans are exposed each day to a multitude of chemicals in the air, water and food. They have developed a battery of enzymes and transporters that facilitate the biotransformation and elimination of these compounds. Moreover, a majority of these enzymes and transporters are inducible due to the activation of xenobiotic receptors which act as transcription factors for the regulation of their target genes (such as xenobiotic metabolizing enzymes, see below §4 for the AhR). These receptors include several members of the nuclear/steroid receptor family (CAR for Constitutive Androstane Receptor, PXR for Pregnane X Receptor) but also the Aryl hydrocarbon Receptor or AhR, a member of the bHLH-PAS family (basic Helix-Loop-Helix - Period/ARNT/Single minded). In addition to the regulation of xenobiotic metabolism, numerous alternative functions have been characterized for the AhR since its discovery. These alternative functions will be described in this review along with its endogenous functions as revealed by experiments performed on knock-out animals.

Investigation of the toxicity triggered by chemicals on the human brain has traditionally relied on approaches using rodent in vivo models and in vitro cell models including primary neuronal cultures and cell lines from rodents. The issues of species differences between humans and rodents, the animal ethical concerns and the time and cost required for neurotoxicity studies on in vivo animal models, do limit the use of animal-based models in neurotoxicology. In this context, human cell models appear relevant in elucidating cellular and molecular impacts of neurotoxicants and facilitating prioritization of in vivo testing. The SH-SY5Y human neuroblastoma cell line (ATCC® CRL-2266™) is one of the most used cell lines in neurosciences, either undifferentiated or differentiated into neuron-like cells. This review presents the characteristics of the SH-SY5Y cell line and proposes the results of a systematic review of literature on the use of this in vitro cell model for neurotoxicity research by focusing on organic environmental pollutants including pesticides, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), flame retardants, PFASs, parabens, bisphenols, phthalates, and PAHs. Organic environmental pollutants are widely present in the environment and increasingly known to cause clinical neurotoxic effects during fetal & child development and adulthood. Their effects on cultured SH-SY5Y cells include autophagy, cell death (apoptosis, pyroptosis, necroptosis, or necrosis), increased oxidative stress, mitochondrial dysfunction, disruption of neurotransmitter homeostasis, and alteration of neuritic length. Finally, the inherent advantages and limitations of the SH-SY5Y cell model are discussed in the context of chemical testing.

Since the initial development of the exposome concept, much effort has been devoted to the characterisation of the exposome through analytical, epidemiological, and toxicological/mechanistic studies. There is now an urgent need to link the exposome to human diseases and to include exposomics in the characterisation of environment-linked pathologies together with genomics and other omics. Liver diseases are particularly well suited for such studies since major functions of the liver include the detection, detoxification, and elimination of xenobiotics, as well as inflammatory responses. It is well known that several liver diseases are associated with i) addictive behaviours such as alcohol consumption, smoking, and to a certain extent dietary imbalance and obesity, ii) viral and parasitic infections, and iii) exposure to toxins and occupational chemicals. Recent studies indicate that environmental exposures are also significantly associated with liver diseases, and these include air pollution (particulate matter and volatile chemicals), contaminants such as polyaromatic hydrocarbons, bisphenol A and per-and poly-fluorinated substances, and physical stressors such as radiation. Furthermore, microbial metabolites and the "gut-liver" axis play a major role in liver diseases. Exposomics is poised to play a major role in the field of liver pathology. Methodological advances such as the exposomics-metabolomics framework, the determination of risk factors' genomic and epigenomic signatures, and cross-species biological pathway analysis should further delineate the impact of the exposome on the liver, opening the way for improved prevention, as well as the identification of new biomarkers of exposure and effects, and additional therapeutic targets.

Breast cancer (BC) is one of the most common causes of cancer in the world and the second leading cause of cancer deaths among women. Mortality is associated mainly with the development of metastases. Identification of the mechanisms involved in metastasis formation is, therefore, a major public health issue. Among the proposed risk factors, chemical environment and pollution are increasingly suggested to have an effect on the signaling pathways involved in metastatic tumor cells emergence and progression. The purpose of this article is to summarize current knowledge about the role of environmental chemicals in breast cancer progression, metastasis formation and resistance to chemotherapy. Through a scoping review, we highlight the effects of a wide variety of environmental toxicants, including persistent organic pollutants and endocrine disruptors, on invasion mechanisms and metastatic processes in BC. We identified the epithelial-to-mesenchymal transition and cancer-stemness (the stem cell-like phenotype in tumors), two mechanisms suspected of playing key roles in the development of metastases and linked to chemoresistance, as potential targets of contaminants. We discuss then the recently described pro-migratory and pro-invasive Ah receptor signaling pathway and conclude that his role in BC progression is still controversial. In conclusion, although several pertinent pathways for the effects of xenobiotics have been identified, the mechanisms of actions for multiple other molecules remain to be established. The integral role of xenobiotics in the exposome in BC needs to be further explored through additional relevant epidemiological studies that can be extended to molecular mechanisms.