Yi Wang

Cadmium (Cd), a widespread environmental toxic metal, is linked to central nervous system dysfunction and neuronal structural damage, yet its mechanisms remain unclear. This study combined network toxicology with experimental validation to explore how Cd impairs dendritic integrity through neuroinflammatory pathways. Network analysis suggested that Cd-induced dendritic injury was likely mediated by inflammatory signaling pathways, with nuclear factor-erythroid 2-related factor 2 (Nfe2l2), a major redox regulator, highlighted as a candidate regulator. Therefore, we investigated the involvement of microglia-mediated neuroinflammation in Cd-induced dendritic damage and assessed the role of Nfe2l2 in this process, using Nfe2l2 knockout mice and Nfe2l2 knockdown BV2 microglia. Furthermore, primary neurons were co-cultured with conditioned media (CM) from Cd-treated microglia to evaluate how Nfe2l2-regulated neuroinflammation contributes to dendritic damage. Nfe2l2 deficiency aggravated Cd-induced dendritic damage in the hippocampus, manifested as significant reductions in dendritic length, intersections, and branch points. In parallel, Nfe2l2 deficiency also intensified Cd-induced microglial activation and neuroinflammation in the hippocampus. Consistently, Nfe2l2 knockdown amplified Cd-induced BV2 microglial activation, characterized by increased migratory and phagocytic activity, and the subsequent cytokine release. Subsequently, CM derived from these activated microglia further exacerbated neuronal dendritic damage. Moreover, Nfe2l2 knockdown diminished minocycline’s anti-inflammatory and neuroprotective effects. These results demonstrate that Cd-induced microglial activation and inflammation are central to dendritic injury, and that Nfe2l2 is essential in protecting neurons from Cd-driven neuroinflammation. Graphical Abstract

Bisphenol S (BPS), a pervasive contaminant used in consumer and industrial products, has been widely detected in human serum, urine, hair, placenta, and breast milk. Although initially studied mainly as an endocrine disruptor, accumulating evidence indicates that BPS also exerts neurotoxicity by perturbing neuroinflammatory responses, neuroendocrine regulation, and neuronal development. However, its neurotoxic profile and mechanistic basis remain incompletely defined. This review systematically retrieved and synthesized epidemiological, animal, and cellular studies published between 2000 and February 2026 across multiple databases to delineate the neurotoxic features and mechanisms of BPS. Evidence from 14 epidemiological and 76 experimental studies consistently indicates neurotoxic risk. Epidemiological data associate BPS exposure with increased risks of neuropsychiatric outcomes, including attention-deficit/hyperactivity disorder (ADHD), Alzheimer's disease (AD), and depression, often with sex-specific patterns. Animal studies show that exposure across life stages induces behavioral impairments, encompassing social deficits, cognitive and emotional disturbances, motor dysfunction, and memory decline. In vitro studies further elucidate molecular underpinnings. Mechanistically, BPS neurotoxicity involves endocrine-axis disruption, neurotransmitter imbalance, oxidative stress, and transcriptional dysregulation and extends to gut-brain axis perturbation, brain region-specific vulnerability, and neural circuit dysfunction. These pathways interact and are modified by toxicokinetics, exposure dose and timing, sex, and species. Future work should integrate longitudinal human cohorts with mechanistic studies to clarify BPS's contribution to neurological disease development and inform regulation. We propose an integrative framework summarizing BPS neurotoxicity and its key modifying factors.

Environmental exposure to per- and polyfluoroalkyl substances (PFAS) has been related to some adverse health effects. An increasing number of people are suffering from nodular goiter (NG) and papillary thyroid carcinoma (PTC), the specific types of thyroid tumors with the highest prevalence. In vivo and in vitro studies have indicated that exposure to PFAS can disrupt thyroid homeostasis and exhibit apparent endocrine-disrupting toxicity, including the decreased thyroid hormone levels and abnormal expression of thyroid-related genes. However, epidemiological evidence supporting the cause-effect relationship between PFAS exposure and the risk of NG and PTC is still lacking. We enrolled 290 participants to explore the relationship between PFAS exposure and NG/PTC risk. 21 urinary PFAS were detected by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MS/MS). Logistic regression, restricted cubic spline (RCS), Bayesian Kernel Machine Regression (BKMR) and quantile g-computation (qgcomp) models were adopted to examine effects of single and mixed PFAS exposure on NG/PTC risk. Our data showed that perfluoroheptane sulfonate (PFHpS) (P = 0.033) and perfluorohexane sulfonate (PFHxS) (P = 0.003) levels in NG cases and perfluoroheptanoic acid (PFHpA) (P = 0.008) levels in PTC cases were significantly higher than those in the controls. After adjustment for confounders, PFHxS was significantly related to higher NG/PTC risk (all P for trend < 0.05). A remarkable non-linear association was found between PFHpA exposure and PTC risk (P-overall < 0.001, P-non-linear = 0.001). The BKMR model indicated that PFAS mixtures significantly increased NG risk, with PFHxS contributing the most (groupPIP: 0.886, condPIP: 0.658). In stratified analyses, PFAS mixtures were positively associated with NG/PTC risk in females and normal-weight subjects. Our results suggest that environmental exposure to PFAS mixtures may be associated with increased NG/PTC risk, and each PFAS may contribute to NG/PTC risk in very different ways. To the best of our knowledge, this is the first epidemiological study to examine effects of PFAS exposure on NG/PTC risk.