Genetic and Environmental Factors Shaping Hearing Loss: Xenobiotics, Mechanisms and Translational Perspectives

The central mechanistic hypothesis underlying multifactorial hearing loss posits that genetic susceptibility and environmental exposures act synergistically to disrupt cochlear homeostasis through redox imbalance, mitochondrial dysfunction, and pro-inflammatory mechanisms. This gene-environment paradigm has significant translational implications: elucidating the molecular crosstalk between genetic variants and environmental factors may enable precision risk stratification and the development of targeted otoprotective strategies. The present review provides a comprehensive examination of the major determinants implicated in hearing loss. The manuscript is organized into six main sections that encompass the most relevant domains of current research. First, it offers (I) an overview of epidemiological patterns and the multifactorial nature of hearing impairment. This is followed by (II) a background synthesis of the complex genetic architecture underlying hearing loss. Next, the authors present (III) an outline of environmental determinants and exposure profiles associated with auditory dysfunction, highlighting prominent pollutant/xenobiotic classes (e.g., organic solvents and volatile aromatic hydrocarbons, heavy metals, pesticides, and especially organophosphates and persistent organochlorine compounds), followed by (IV) an analysis of oxidative stress, mitochondrial impairment, and inflammatory pathways involved in cochlear injury. Subsequently, (V) translational perspectives and integrated therapeutic approaches are discussed, with emphasis on epidemiological prevention and precision-based interventions. Finally, (VI) this review addresses current challenges and future directions in elucidating gene-environment interactions in hearing loss.