Sex-dependent neurotoxicity of environmental toxicants: a narrative review

Environmental pollutants, whether naturally occurring or manufactured for commercial use, are pervasive in modern ecosystems. Endocrine disruptors, particulate matter, and micro- and nanoplastics are especially concerning because of their ubiquity, persistence, resistance to degradation, and bioaccumulation. Their global dispersal enables widespread human exposure and poses systemic health risks. The brain, with limited antioxidant capacity and a lipid-rich composition, is highly vulnerable to pollutant-induced injury. It exhibits sex-dependent differences in neurotransmission, neuroanatomy, glial populations, and neuroinflammatory responses, which can shape susceptibility to environmental insults. Yet the direct effects of environmental toxicants on the brain remain incompletely defined, partly because many toxicology studies have used only male animals, lacked sex-stratified analyses, or omitted sex altogether. Converging evidence from epidemiological, animal, and cellular studies links pollutant exposure to sex-dependent neurotoxic outcomes spanning neurodevelopmental and neurodegenerative disorders and functional impairments, reflecting intrinsic differences between male and female brains. This review synthesizes current knowledge on sources and exposure routes of key pollutants-endocrine disruptors, particulate matter, and micro- and nanoplastics-along with their sex-dependent neurotoxic effects and underlying mechanisms. Recognizing sex-dependent vulnerabilities is essential to inform public health policies, targeted interventions, and regulatory strategies to prevent pollutant-associated brain diseases.