Case-control study of environmental toxins and risk of amyotrophic lateral sclerosis involving the national ALS registry.

OBJECTIVE: Neurotoxic chemicals are suggested in the etiology of amyotrophic lateral sclerosis (ALS). We examined the association of environmental and occupational risk factors including persistent organochlorine pesticides (OCPs) and ALS risk among cases from the Centers for Disease Control and Prevention National ALS Registry and age, sex, and county-matched controls. METHODS: Participants completed a risk factor survey and provided a blood sample for OCP measurement. ALS cases were confirmed through the Registry. Conditional logistic regression assessed associations between ALS and risk factors including OCP levels. RESULTS: 243 matched case-control pairs (61.7% male, mean [SD] age = 62.9 [10.1]) were included. Fifteen of the 29 OCPs examined had sufficient detectable levels for analysis. Modest correlations of self-reported years of exposure to residential pesticide mixtures and OCP serum levels were found (p<.001). Moreover, occupational exposure to lead including soldering and welding with lead/metal dust and use of lead paint/gasoline were significantly related to ALS risk (OR = 1.77, 95% CI: 1.11-2.83). Avocational gardening was a significant risk factor for ALS (OR = 1.57, 95% CI: 1.04-2.37). ALS risk increased for each 10 ng/g of α-Endosulfan (OR = 1.42, 95% CI: 1.14-1.77) and oxychlordane (OR = 1.24, 95% CI: 1.01-1.53). Heptachlor (detectable vs. nondetectable) was also associated with ALS risk (OR = 3.57, 95% CI: 1.50-8.52). CONCLUSION: This national case-control study revealed both survey and serum levels of OCPs as risk factors for ALS. Despite the United States banning many OCPs in the 1970s and 1980s, their use abroad and long half-lives continue to exert possible neurotoxic health effects.

Ultrafine particulate matter pollution and dysfunction of endoplasmic reticulum Ca2+ store: A pathomechanism shared with amyotrophic lateral sclerosis motor neurons?

Increased risk of neurodegenerative diseases has been envisaged for air pollution exposure. On the other hand, environmental risk factors, including air pollution, have been suggested for Amyotrophic Lateral Sclerosis (ALS) pathomechanism. Therefore, the neurotoxicity of ultrafine particulate matter (PM0.1) (PM < 0.1 µm size) and its sub-20 nm nanoparticle fraction (NP20) has been investigated in motor neuronal-like cells and primary cortical neurons, mainly affected in ALS. The present data showed that PM0.1 and NP20 exposure induced endoplasmic reticulum (ER) stress, as occurred in cortex and spinal cord of ALS mice carrying G93A mutation in SOD1 gene. Furthermore, NSC-34 motor neuronal-like cells exposed to PM0.1 and NP20 shared the same proteomic profile on some apoptotic factors with motor neurons treated with the L-BMAA, a neurotoxin inducing Amyotrophic Lateral Sclerosis/Parkinson-Dementia Complex (ALS/PDC). Of note ER stress induced by PM0.1 and NP20 in motor neurons was associated to pathological changes in ER morphology and dramatic reduction of organellar Ca2+ level through the dysregulation of the Ca2+-pumps SERCA2 and SERCA3, the Ca2+-sensor STIM1, and the Ca2+-release channels RyR3 and IP3R3. Furthermore, the mechanism deputed to ER Ca2+ refilling (e.g. the so called store operated calcium entry-SOCE) and the relative currents ICRAC were also altered by PM0.1 and NP20 exposure. Additionally, these carbonaceous particles caused the exacerbation of L-BMAA-induced ER stress and Caspase-9 activation. In conclusion, this study shows that PM0.1 and NP20 induced the aberrant expression of ER proteins leading to dysmorphic ER, organellar Ca2+ dysfunction, ER stress and neurotoxicity, providing putative correlations with the neurodegenerative process occurring in ALS.

Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.

The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.

El tratamiento con progesterona previene las alteraciones motoras inducidas por la intoxicación con semillas de cícada (Dioon spinulosum) en la rata macho / Treatment with progesterone prevented the motor impairment induced by poisoning with seeds of Cicada (Dioon spinulosum) in the male rat

El consumo crónico de semillas de cícadas ha sido asociado con enfermedades neurodegenerativas, las cuales predominan en el género masculino. En México, las semillas decícada (Dioon spinulosum) son usadas como sustituto de maíz y a nivel experimental producen un déficit motor; probablemente causado por sus componentes neurotóxicos. En este sentido, la progesterona ejerce efectos neuroprotectores contra traumatismo cerebral, hipoxia, así como la muerte neuronal inducida por colchicina en el SNC; por lo que podría prevenir los efectos neurotóxicos producidos por el consumo crónico de semillas de Dioon spinulosum en ratas, una posibilidad explorada en el presente estudio. Se emplearon 32 ratas macho de la cepa Wistar distribuidas en cuatro grupos: a) un grupo control recibió 1 ml de agua purificada (v.o.) y 0,2 ml de aceite de maíz (s.c.); b) un grupo cícada recibió 5g/kg de la semilla de cícada (v.o.) y 0,2 ml de aceite de maíz (s.c.); c) un grupo más recibió 1 ml de agua purificada (v.o.) y 3 mg/kg de progesterona (s.c.); y d) el último grupo recibió semilla de cícada y progesterona. Los tratamientos fueron administrados diariamente durante 40 días y el efecto fue evaluado en las pruebas de actividad locomotora y nado forzado a los 20, 30 y 40 días de tratamiento. El grupo cícada redujo el número de cuadros cruzados en la prueba de actividad locomotora. En la prueba de nado forzado, los animales tratados con la semilla de cícada fueron los únicos que presentaron la conducta de giro, un efecto que fue prevenido por el tratamiento previo con progesterona. La administración de vehículo y progesterona no produjo per se la conducta de giro. En conclusión, la progesterona previene las alteraciones motoras inducidas por el consumo crónico de semillas de cícada en ratas forzadas a nadar (AU)

The chronic consumption of cycad seeds has been associated with neurodegenerative diseases, which are predominant in masculine gender. In Mexico, the cycad seeds (Dioon spinulosum) are used as a maize substitute and at experimental level produce a motor deficit; probably caused by its neurotoxic compounds. Progesterone could prevent the neurotoxic effects against traumatic brain injury, hypoxia and neuronal death induced by colchicine in the CNS. In addition, progesterone could prevent these neurotoxic effects produced by the chronic administration of cycad seeds (Dioon spinulosum) in rats, a possibility explored in the present study. Male wistar rats were randomly divided in 4 groups: a) a control group received 1 ml purified water (PO) and oil (0.2 ml, s.c.);b) a cycad group received a cycad seed 5g/kg (PO) and oil (0.2 ml,s.c.); c) another group received 1 ml of purified water (PO) and progesterone (3mg/kg, s.c.) and d) the last group received cycad seed and progesterone. All treatments were administered daily during 40 days and the effect was evaluated in behavioral tests (open filed and forced swim) were conducted on 20, 30 and 40 days of treatment. The cycad group decreased the number of squares crossed in the open field whereas, in the forced swim test, rotational behavior was only observed in the group administered with cycad seeds, this effect was prevented by previous progesterone treatment. The vehicle and progesterone administration did not produce the rotational behavior per se. In conclusion, progesterone prevents the motor deficit induced by the chronic consumption of cycad seeds in forced swim rats (AU)

Enfermedad de neurona motora secundaria a saturnismo / Motor neuron disease secondary to lead poisoning

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