Academic journal article Environmental Health Perspectives

Molecular Mechanism of Acrylamide Neurotoxicity: Lessons Learned from Organic Chemistry

Academic journal article Environmental Health Perspectives

Molecular Mechanism of Acrylamide Neurotoxicity: Lessons Learned from Organic Chemistry

Article excerpt

Acrylamide (ACR) is a water-soluble alkene used in the production of polymers and gels that have various commercial applications. For example, polyacrylamide preparations are used in the cosmetic, paper, and textile industries; in ore processing; and as soil conditioners and flocculants for wastewater treatment (Friedman 2003; Smith and Oehme 1991; Tilson 1979). Coincidental with the burgeoning industrial use of ACR monomer in the 1950s, it was quickly realized that cumulative neurotoxicity characterized by ataxia, skeletal muscle weakness, cognitive impairment, and numbness of the extremities was a potential outcome of occupational exposure (Deng et al. 1993; Garland and Patterson 1967; He et al. 1989; reviewed by Friedman 2003; Smith and Oehme, 1991; Spencer and Schaumburg 1974a; Tilson 1979). Early research involving laboratory animals showed that exposure to ACR monomer produced a neurotoxicity syndrome that resembled the neurological symptoms of human intoxication (reviewed by LoPachin and Lehning 1994; Spencer and Schaumburg 1974b; Tilson 1979). Morphological studies conducted during the late 1960s and early 1970s suggested that both human and experimental ACR neurotoxicities were associated with cerebellar Purkinje cell death and degeneration of distal axons and nerve terminals in the peripheral and central nervous systems (PNS and CNS, respectively) (reviewed by LoPachin 2004; LoPachin and Lehning 1994; LoPachin et al. 2003). In addition to characteristic neurotoxicity in adult humans and animals, there is more recent experimental evidence, albeit controversial, that prenatal and perinatal exposure of rodent pups to ACR causes neurodevelopmental toxicity (e.g., Friedman et al. 1999; Garey and Paule 2010; Takahashi et al. 2009).Whereas the majority of research indicates selective targeting of nervous tissue, rodent studies have also suggested that ACR causes reproductive toxicity [e.g., decreased litter size, DNA strand breaks (Tyl et al. 2000)] and an increased incidence of certain tumors [e.g., mammary gland fibroadenomas in female rats, tunica vaginalis mesotheliomas in male rats (Friedman et al. 1995; Johnson et al. 1986)]. However, to date, there is little evidence that these experimental non-neurotoxic consequences have human relevance (Haber et al. 2009; Mucci et al. 2003; Rice 2005).

Thus, the majority of evidence suggests that ACR exposure across broad daily dose-rates causes selective neurotoxicity in humans and laboratory animals. The early morphological descriptions of ACR neuropathy provided a framework for subsequent research that attempted to decipher the molecular mechanisms of neurotoxicity (reviewed by Friedman 2003; Howland 1985; Miller and Spencer 1985; LoPachin and Lehning 1994; Tilson 1979). Although many putative mechanisms and sites of ACR action were tested, for example, inhibition of [Na.sup.+]/[K.sup.+]-ATPase and the resulting reverse operation of the axolemmal [Na.sup.+]/[Ca.sup.2+]-exchanger (LoPachin and Lehning 1994), reduced fast axonal transport (Sickles et al. 2002) and inactivation of enzymes involved in neuronal energy production (Spencer et al. 1979), the identification of a necessary and sufficient neurotoxic process remained elusive. However, these early hypotheses were not developed within the framework that xenobiotics can produce toxicity by interacting directly with specific sites on cellular macromolecules (e.g., enzymes) and that this interaction is dictated by the chemical nature of the toxicant (Cohen et al. 1997; Coles 1984-1985; Hinson and Roberts 1992; see also Liebler 2008; LoPachin and DeCaprio 2005). Therefore, by understanding toxicant chemistry, plausible molecular-level sites and mechanisms of action can be predicted. In this review, we discuss the chemical nature of ACR (a soft electrophile) and how this determines the corresponding sites of protein adduction (soft nucleophilic sulfhydryl thiolates on cysteine residues). Basic recognition of the chemistry of toxicant-target reactions has led the development and testing of a rational mechanistic hypothesis of ACR neurotoxicity (see below). …

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