The neurotoxic effects and the underlying mechanisms of new pollutants

With the rapid advancement of chemistry, thousands of new chemical compounds are synthesized every day, and to date, more than 219 million chemicals have been registered globally. Although these chemicals bring considerable convenience to our daily lives by supporting a wide range of industrial, agricultural, and consumer applications, various categories of these substances have been reported to pose significant risks to human health. As a result, many of them have been classified as new pollutants. The appropriate and effective regulation of new pollutants has become a global concern, and enhancing regulatory strategies represents a critical step toward achieving the national goal of “Health China”. In response to this challenge, China has proposed a systematic three-step strategy—“screening-assessment-regulation”—for the comprehensive management of new pollutants. The initial step involves the rapid identification of pollutants that pose high health risks from among the vast and ever-growing number of chemical substances. To accomplish this, a comprehensive and in-depth understanding of the toxicological targets and underlying toxic mechanisms of new pollutants is urgently required. Extensive epidemiological investigations, as well as experimental studies utilizing both in vivo and in vitro models, have demonstrated that the nervous system is one of the most vulnerable target organs affected by new pollutants. This review summarizes the neurotoxic effects of representative categories of new pollutants, including per- and polyfluoroalkyl substances (PFAs), phthalate acid esters (PAEs), brominated flame retardants (BFRs), pharmaceuticals, and personal care products (PPCPs), among others. Among the documented neurotoxic effects associated with exposure to these substances, hallmark adverse neurological outcomes include histopathological changes in brain tissue, impaired neurodevelopment, exacerbation of neurodegenerative processes, and the occurrence of mood disorders. In terms of the underlying neurotoxic mechanisms, this review discusses multiple identified toxicological pathways involved in mediating these effects. Neuroimmune responses—particularly oxidative stress and neuroinflammation—represent typical biological events triggered by exposure to new pollutants, which can further lead to damage or even death of neuronal cells. In addition, new pollutants can disrupt the synthesis and metabolism of neurotransmitters or interfere with neural signal transduction by targeting neurotransmitter receptors, thereby impairing normal neural functions. Furthermore, due to their strong endocrine-disrupting potential, new pollutants render the neuroendocrine system particularly susceptible to damage. Disruption of neuroendocrine signaling can not only directly affect neurons and interfere with neurogenesis, but also indirectly disturb neuronal and synaptic development by altering the physiological functions of immune cells. Recent advances have further underscored the critical role of epigenetic modifications in mediating the neurotoxicity induced by new pollutants. These substances have been found to influence DNA methylation, histone modification, and non-coding RNA activity, thereby disrupting the expression of key downstream genes involved in neurodevelopment and neuroprotection, ultimately resulting in adverse neurological outcomes. This review further explores the urgent challenges that remain in current research on the neurotoxicity of new pollutants and proposes that future studies should focus on the following key areas: (1) the development of artificial intelligence-powered high-throughput screening strategies based on established adverse outcome pathways of new pollutants; (2) the identification of novel neurotoxic targets and mechanisms from an interdisciplinary neuroscience perspective, such as how new pollutants disrupt the bidirectional regulation between the peripheral system and the central nervous system; (3) the establishment of a new framework for accurately assessing the neurotoxicological risks of new pollutants under real-world environmental exposure scenarios, including both chemical–chemical co-exposure and more complex physical–chemical co-exposure. This review aims to deepen the understanding of the neurotoxicological risks posed by new pollutants and to provide theoretical support for advancing new pollutant management strategies in China, thereby contributing to the realization of the “Healthy China” initiative.