Aihua Zhang

Epidemiological evidence suggests that developmental arsenic (As) exposure increases behavioral abnormalities in offspring. However, how placental neuroendocrine function and sex-specific responses contribute to these effects remains poorly understood. Here, we demonstrate that maternal As exposure induces trophoblastic damage, vascular disruption, and placental labyrinth thinning, leading to placental dysplasia, fetal growth restriction, and sex-specific behavioral outcomes in offspring. Integrated transcriptomic and neurobehavioral analyses revealed sex-dependent alterations primarily involving neurodevelopmental pathways and transporter dysfunction. Concurrently, neurotransmitter metabolomic profiling identified profound disturbances in tryptophan, tyrosine, and amino acid metabolism in the placenta and fetal brain. Bayesian benchmark dose (BMD) modeling revealed that points of departure (PoDs) followed the rank order, such that metabolomic (mPoDs) < neurobehavioral (nPoDs) < apical (aPoDs). Notably, alterations in the tryptophan pathway were the most sensitive early perturbations observed, with BMDL10 values for 5-hydroxy-l-tryptophan of 3.73 μg/L in females and 4.17 μg/L in males, respectively. Overall, this exploratory framework provides evidence for placental neuroendocrine toxicity of As and highlights its potential relevance for refined environmental risk assessment.

Developmental exposure to arsenic (As) has been linked to irreversible adverse health outcomes in offspring. However, the underlying molecular mechanisms remain a mystery. Here, maternal mice were exposed to As via drinking water. Subsequently, the hippocampi of their offspring were collected at different developmental stages to explore the dynamic changes during hippocampal maturation and the effects of As. Time-series RNA-seq analysis revealed a significant temporal correlation between As neurodevelopmental toxicity and the mRNA expression profile of the hippocampal region during critical postnatal developmental windows. Further, downregulation of genes associated with neurogenesis and telomere maintenance was observed. Notably, dynamic changes in hippocampal telomeres were observed in response to As exposure, with critically shortened telomeres inhibiting neural stem cells (NSCs) proliferation, impairing neuroblast maturation, and reducing the number and size of neurospheres. Additionally, the populations of BrdU⁺ and MAP2⁺ cells were decreased while GFAP⁺ cells were increased, indicating a decline in NSCs stemness. Furthermore, As exposure significantly impaired dendritic complexity in the hippocampus of mice, altered dendritic spine morphology, and disrupted synaptic ultrastructure, ultimately leading to cognitive impairment. These findings highlight the importance of analyzing telomere dynamics in environmental toxicology and offer insights into the neurotoxic mechanisms of maternal As on offspring development.

Arsenic is an environmental metalloid contaminant known to induce multi-system and multi-organ damage, yet the precise toxicological mechanisms remain unclear. Moreover, effective low-toxicity interventions or treatments are lacking. This study aims to investigate the potential ameliorative effects of Rosa roxburghii Tratt juice (RRTJ) on metabolic disorders in arsenicosis patients, with a focus on plasma metabolite profiles. Using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), we analyzed the plasma metabolic profiles of arsenicosis patients before and after RRTJ intervention. After RRTJ intervention, significant alterations were observed in the plasma levels of 61 metabolites, with 30 metabolites upregulated and 31 downregulated. These metabolites were predominantly involved in six key biological pathways, including taurine and hypotaurine metabolism, histidine metabolism, β-alanine metabolism, glycine, serine, and threonine metabolism, pentose and glucuronate interconversions, as well as cysteine and methionine metabolism. In conclusion, RRTJ intervention may effectively alleviate metabolic disorders associated with arsenic toxicity, potentially through its antioxidant, anti-inflammatory effects and regulation of methylation pathways.

Arsenic is a detrimental environmental toxicant linked to neurological damage; however, the mechanisms involved remain incompletely understood. Chronic proinflammatory responses are thought to play a central role in arsenic-induced neurotoxicity. Astrocytes, which are the predominant glial cells in the central nervous system (CNS), release significant amounts of proinflammatory cytokines upon overactivation. However, the molecular mechanisms driving this response remain to be elucidated. This study aimed to elucidate the mechanisms underlying arsenic-induced astrocyte activation and the subsequent neuronal damage, both in vivo and in vitro. In a rat model of arsenic exposure, significant neuropathological damage was detected in the CA3 region of the hippocampus. Specifically, markers of astrocyte activation, such as glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS), as well as the inflammatory cytokine interleukin (IL)-1β, were significantly upregulated, and apoptosis was markedly increased, indicating neurotoxic damage. Furthermore, in vitro experiments revealed that arsenic exposure induced substantial upregulation of cyclic GMP–AMP synthase (cGAS), stimulator of interferon genes (STING), GFAP, iNOS, and IL-1β in astrocytes, accompanied by an increase in IL-1β secretion into the culture supernatant. In addition, co-culturing neurons with conditioned medium from arsenic-exposed astrocytes resulted in significant neuronal apoptosis. Importantly, the cGAS-STING pathway inhibitor H-151 effectively suppressed the arsenic-induced astrocyte activation and IL-1β secretion, while also reducing neuronal apoptosis in the conditioned medium. Collectively, these results indicate that arsenic exposure activates the cGAS-STING signaling pathway in astrocytes, enhancing proinflammatory activation and IL-1β expression, which in turn mediates neuronal apoptosis, representing a critical mechanism underlying arsenic-induced neurotoxicity.