RESUMEN
Lead is widely distributed in the environment and has become a global public health issue. It is well known that lead exposure induces not only neurodevelopmental toxicity but also neurodegenerative diseases, with learning and memory impairment in the later stage. However, the molecular mechanisms remain elusive. The present study investigated the effects of early life and lifetime lead exposure on cognition and identified the molecular mechanisms involved in aged rats. The results herein demonstrated that the lead concentration in peripheral blood and brain tissues in aged rats was significantly increased in a lead dose-dependent manner. High-dose lead exposure caused cognitive functional impairment in aged rats, concomitant with a longer escape latency and a lower frequency of crossing the platform via Morris water maze testing compared to those in the control and low-dose lead exposure groups. Importantly, neuron functional defects were still observed even in early life lead exposure during the prenatal and weaning periods in aged rats. The neurotoxicity induced by lead exposure was morphologically evidenced by a recessed nuclear membrane, a swollen endoplasmic reticulum, and mitochondria in the neurons. Mechanistically, the exposure of aged rats to lead resulted in increasing free calcium concentration, reactive oxygen species, and apoptosis in the hippocampal neurons. Lead exposure increased RyR3 expression and decreased the levels of p-CaMKIIα/CaMKIIα and p-CREB/CREB in the hippocampus of aged rats. These findings indicated that early life lead exposure-induced cognition disorder was irreversible in aged rats. Lead-induced neurotoxicity might be related to the upregulation of RyR3 expression and high levels of intracellular free calcium with increasing lead concentration in injured neurons.
Asunto(s)
Conducta Animal , Señalización del Calcio , Cognición , Disfunción Cognitiva/metabolismo , Hipocampo/metabolismo , Intoxicación del Sistema Nervioso por Plomo en Adultos/metabolismo , Neuronas/metabolismo , Compuestos Organometálicos , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Factores de Edad , Animales , Apoptosis , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Reacción de Fuga , Femenino , Hipocampo/patología , Hipocampo/fisiopatología , Intoxicación del Sistema Nervioso por Plomo en Adultos/fisiopatología , Intoxicación del Sistema Nervioso por Plomo en Adultos/psicología , Masculino , Aprendizaje por Laberinto , Neuronas/patología , Fosforilación , Ratas Sprague-Dawley , Tiempo de Reacción , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Organic lead compounds are potent neurotoxins which can result in death even from small exposures. Traditionally, these compounds are found in fuel stabilizers, anti-knock agents, and leaded gasoline. Cases of acute organic lead intoxication have not been reported for several decades. We report a case of a 13-year-old Iraqi male who unintentionally ingested a fuel stabilizer containing 80-90% tetraethyl lead, managed at our combat support hospital. The patient developed severe neurologic symptoms including agitation, hallucinations, weakness, and tremor. These symptoms were refractory to escalating doses of benzodiazepines and ultimately required endotracheal intubation and a propofol infusion. Adjunctive therapies included chelation, baclofen, and nutrition provided through a gastrostomy tube. The patient slowly recovered and was discharged in a wheelchair 20 days after ingestion, still requiring tube feeding. Follow-up at 62 days post-ingestion revealed near-resolution of symptoms with residual slurred speech and slight limp. This case highlights the profound neurotoxic manifestations of acute organic lead compounds.