Joint toxic effects of the type-2 alkene electrophiles

Abstract

Human populations are exposed to complex environmental mixtures of acrolein, methylvinyl ketone (MVK) and other type-2 alkenes. Many members of this chemical class are electrophiles that possess a common molecular mechanism of toxicity; i.e., protein inactivation via formation of stable cysteine adducts. Therefore, acute or chronic exposure to type-2 alkene mixtures could represent a health risk due to additive or synergistic interactions among component chemicals. Despite this risk, there is little experimental information regarding the joint effects of type-2 alkenes. In the present study we used sum of toxic units (TUsum = ΣTUi) to assess the relative toxicity of different type-2 alkene mixtures. These studies involved well characterized environmental type-2 alkene toxicants and included amide (acrylamide; ACR), ketone (methyl vinyl ketone; MVK), aldehyde (2-ethylacrolein; EA) and ester (methyl acrylate; MA) derivatives. In chemico analyses revealed that both binary and ternary mixtures could deplete thiol groups according to an additive joint effect at equitoxic and non-equitoxic ratios; i.e., TUsum = 1.0 ± 0.20. In contrast, analyses of joint effects in SNB19 cell cultures indicated that different permutations of type-2 alkene mixtures produced mostly synergistic joint effects with respect to cell lethality; i.e., TUsum < 0.80. A mixture of ACR and MA was shown to produce joint toxicity in a rat model. This mixture accelerated the onset and development of neurotoxicity relative to the effects of the individual toxicants. Synergistic effects in biological models might occur when different cellular proteomes are targeted, whereas additive effects develop when the mixtures encompasses a similar proteome.

Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation

“…Since the ten LDE identified by Petersen and associates all possess an α,β-unsaturated carbonyl system, they likely exert toxicity via a shared tendency to form Michael adducts on cysteine groups in target proteins. During study of toxicodynamic interactions within binary and ternary mixtures of α,βunsaturated electrophiles, LoPachin et al noted a potential for significant synergistic interactions 21 between malondialdehyde and acrolein, two LDE that are implicated in ALD but are also known targets for scavenging by hydralazine [75]. The possibility that hydralazine might suppress the onset of steatosis during chronic alcohol intoxication by mitigating the toxicological consequences of interactions between structurally related endogenous LDEs is a question to which we now turn.…”

Monohalogenated acetamide-induced cellular stress and genotoxicity are related to electrophilic softness and thiol/thiolate reactivity

“…EPA, 2002). In fact, experiments with α,β-unsaturated carbonyl derivatives, showed additive toxicity in binary and ternary mixtures in vitro and in an in vivo model (Zhang et al, 2016). Work by Dawson and colleagues showed that HANs and halogenated ethyl acetates (α-halogenated carbonyl containing compounds) generated, in some cases, dose additive toxicity within and among these chemical classes (Dawson et al, 2010; Dawson et al, 2011; Dawson et al, 2014).…”

Physicochemical and FT-IR analyses of some freshwater and inflow wastewater-treated effluents in the Eastern Cape Province of South Africa

“…Alkenes are toxic and carcinogenic pollutants, which may enter the food through packaging materials. Acute or chronic exposure to some alkenes can cause significant damage to organs and systems (Zhang et al, 2016). The vinylidene peaks in the samples might be due to pollutants, and biotic, and abiotic degradation of polyvinylidene products in the industrial and municipal wastewaters (Benson, 2003).…”