In vitro neurotoxic hazard characterization of different tricresyl phosphate (TCP) isomers and mixtures

Abstract

A B S T R A C TExposure to tricresyl phosphates (TCPs), via for example contaminated cabin air, has been associated with health effects including the so-called aerotoxic syndrome. While TCP neurotoxicity is mainly attributed to ortho-isomers like tri-ortho-cresyl phosphate (ToCP), recent exposure and risk assessments indicate that ToCP levels in cabin air are very low. However, the neurotoxic potential of non-ortho TCP isomers and TCP mixtures is largely unknown. We therefore measured effects of exposure (up to 48 h) to different TCP isomers, mixtures and the metabolite of ToCP (CBDP: cresyl saligenin phosphate) on cell viability and mitochondrial activity, spontaneous neuronal electrical activity, and neurite outgrowth in primary rat cortical neurons.The results demonstrate that exposure to TCPs (24-48 h, up to 10 mM) increases mitochondrial activity, without affecting cell viability. Effects of acute TCP exposure (30 min) on neuronal electrical activity are limited. However, electrical activity is markedly decreased for the majority of TCPs (10 mM) following 48 h exposure. Additional preliminary data indicate that exposure to TCPs (48 h, 10 mM) did not affect the number of neurites per cell or average neurite length, except for TmCP and the analytical TCP mixture (Sigma) that induced a reduction of average neurite length.The combined neurotoxicity data demonstrate that the different TCPs, including ToCP, are roughly equipotent and a clear structure-activity relation is not apparent for the studied endpoints. The noobserved-effect-concentrations (1 mM) are well above current exposure levels indicating limited neurotoxic health risk, although exposures may have been higher in the past. Moreover, prolonged and/or repeated exposure to TCPs may exacerbate the observed neurotoxic effects, which argues for additional research.

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

“…Differences in species or methods used to quantify neurites could be responsible for the discrepancies between these two studies. It is plausible that the number of neurites in the study by Duarte et al (2016) were not affected, but that the morphology was altered. Alternatively, it is possible that the number of neurons in the study by Hausherr et al (2014) was not altered, while the area of each neurite was reduced.…”

“…Additionally, T O CP dose-dependently inhibited neurite outgrowth in SH-SY5Y cells following 24 h treatment with 200, 500, and 1000 μM, and an autophagy inhibitor prevented and reversed this growth inhibition, indicating a critical role for autophagy in T O CP-induced neurite changes at high doses (Chen et al, 2013). At lower doses (10 μM), exposure to T O CP for 48 h did not decrease neurite number or outgrowth in rat primary cortical neurons, as measured by immunocytochemistry (Duarte et al, 2016). Esterase activity was also not significantly reduced under these exposure conditions.…”

“…Changes in length, number, or branching patterns of axons or dendrites have been linked to psychiatric manifestations in patients, including depression, anxiety, AD, and PD (Marsden, 2013; Rubia et al, 2014; Canu et al, 2015; Negrón-Oyarzo et al, 2016). Axonal length, neurite length, neurite number, and dendritic branching in neuronal culture systems have also been shown to be altered following exposure to a variety of OPs, including CPF (Howard et al, 2005; Yang et al, 2008; Speed et al, 2012), DZ (Pizzurro et al, 2014a,b), parathion (Yousefpour et al, 2006; Berríos et al, 2015), and T O CP (Chen et al, 2013; Duarte et al, 2016; Hausherr et al, 2016). For example, in primary cultures of sympathetic neurons, CPF inhibited axon outgrowth but promoted dendritic arborization (Howard et al, 2005).…”

Cognitive impairment and neuronal damage in Alzheimer's disease are malleable

“…Additionally, TOCP dose-dependently inhibited neurite outgrowth in SH-SY5Y cells following 24 h treatment with 200, 500, and 1000 µM, and an autophagy inhibitor prevented and reversed this growth inhibition, indicating a critical role for autophagy in T CP -induced neurite changes at high doses (Chen et al 2013). At lower doses (10 µM), exposure to T CP for 48 h did not decrease neurite number or outgrowth in rat primary cortical neurons, as measured by immunocytochemistry (Duarte et al 2016). Esterase 37 activity was also not significantly reduced under these exposure conditions.…”

“…Changes in length, number, or branching patterns of axons or dendrites have been linked to psychiatric manifestations in patients, including depression, anxiety, AD, and PD (Canu et al 2015;Marsden 2013;Negron-Oyarzo et al 2016;Rubia et al 2014). Axonal length, neurite length, neurite number, and dendritic branching in neuronal culture systems have also been shown to be altered following exposure to a variety of OPs, including CPF (Howard et al 2005;Speed et al 2012;Yang et al 2008), DZ (Pizzurro et al 2014a, b), parathion (Berrios et al 34 2015;Yousefpour et al 2006), and TOCP (Chen et al 2013;Duarte et al 2016;Hausherr et al 2016). For example, in primary cultures of sympathetic neurons, CPF inhibited axon outgrowth but promoted dendritic arborization (Howard et al 2005).…”