Abstract
Early life exposure to environmental chemicals can cause developmental neurotoxicity (DNT). The impairment of key neurodevelopmental processes such as neurite outgrowth inhibition can be used as endpoints for screening of DNT effects. We quantified neurite-specific effects using the ratio of effect concentrations for cytotoxicity and neurite outgrowth inhibition (SRcytotoxicity). Baseline cytotoxicity, the minimal toxicity of any chemical, was used to quantify enhanced cytotoxicity (toxic ratio, TR) and neuronal-specific toxicity (SRbaseline) by comparing baseline cytotoxicity with the effects on cell viability and neurite outgrowth, respectively. The effects on cell viability and neurite length were measured based on image analysis in human neuroblastoma SH-SY5Y cells. Baseline cytotoxicity was predicted from hydrophobicity descriptors using a previously published model for SH-SY5Y cells. Enhanced cytotoxicity and neuronal-specific toxicity were more often observed for hydrophilic chemicals, which indicates that they are more likely to act through specific modes of action (MOA) on cell viability and neurite outgrowth. Hydrophobic chemicals showed a tendency to act through baseline toxicity without showing specific or enhanced toxicity, but were highly potent considering their low effect concentrations for both cytotoxicity and neurite outgrowth inhibition. The endpoint-specific controls (narciclasine, colchicine, cycloheximide, and rotenone), two carbamates (3-hydroxycarbofuran and carbaryl), and two redox cyclers (diquat and paraquat) showed distinct neurite-specific effects (SRcytotoxicity > 4). By comparing neurite-specific effects with enhanced cytotoxicity, one can explain whether the observed effects involve specific inhibition of neurite outgrowth, other specific MOAs, or merely baseline toxicity arising from hydrophobicity.
Highlights
The developing nervous system is vulnerable to exposure to environmental chemicals (Giordano and Costa 2012)
The selection of the endpoint-specific controls was originally based on specific effects on neurite outgrowth observed in Lund human mesencephalic (LUHMES) cells considering the ratio between EC50 and IC50 (Krug et al 2013)
The effect for all endpoint-specific controls detected with the present experimental setup in SH-SY5Y cells corresponded well with cytotoxicity and neurite outgrowth inhibition observed in LUHMES cells by Krug et al (2013), which confirmed the performance of our assay
Summary
The developing nervous system is vulnerable to exposure to environmental chemicals (Giordano and Costa 2012). Despite the high relevance for human health, developmental neurotoxicity (DNT) is only conditionally considered in chemical safety assessment by current OECD test guideline (OECD TG 426). These test guidelines represent in vivo test with developing rats and are very demanding in terms of DNT has been reported for many environmental chemicals, in particular, pesticides DNT of pesticides in non-target organisms is supported by experimental and epidemiological evidence (Bjorling-Poulsen et al 2008), and commonly used pesticides were confirmed to inhibit neurite outgrowth in PC-12 cells (Christen et al 2017). Many pesticides of concern for DNT in humans or animals provoked effects in multiple DNT-related endpoints in DNT in vitro testing battery (Masjosthusmann et al 2020)
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