br Acknowledgements br Introduction Thus damage to the

Acknowledgements
Introduction Thus, damage to the NS 11021 may produce severe consequences (National Research Council, 1992). Indeed, though the nervous system has several compensatory and adaptive mechanisms, it is vulnerable to toxic insult, due to its inability to regenerate after lethal damage and because of a number of intrinsic characteristics (e.g., its dependence upon aerobic metabolism, the presence of axonal transport, the process of neurotransmission) (Office of Technology Assessment, 1990, National Research Council, 1992). Moreover, the developing nervous system is more susceptible to neurotoxic chemicals. For this reason, several neurotoxicants are primarily developmental neurotoxicants, and show different toxicity during development and in adulthood (Giordano and Costa, 2012). A large number of environmental contaminants are able to induce neurotoxicity, defined as any adverse effect on the central or peripheral nervous system. Depending on their chemical profile, time of exposure, and dose, the environmental contaminants may affect the nervous system both directly and indirectly (Cannon and Greenamyre, 2011, Manivannan et al., 2015, Wani et al., 2015). Indeed, neurotoxicity can also manifest as a consequence of damage to other organ, such as, for example, damage to hepatic or cardiovascular structures. In particular, pollutants may induce morphological changes (e.g. neuronopathy, axonopathy, myelinopathy, and other gliopathies) and neurochemical changes in humans (Genc et al., 2012, Wani et al., 2015). These effects are considered adverse, even if they are mild, transient or reversible: in fact, they lead to impaired function and structure of nervous system (Giordano and Costa, 2012). Several data suggest an association between the onset of neurologic impairment and exposures to environmental pollutant. More studies show that neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, may be correlated with exposure to environmental contaminant (Elbaz and Moisan, 2008, Lauer, 2010, Genc et al., 2012). Similarly, exposure to environmental neurotoxicants has also been associated with neurodevelopmental disorders (Giordano and Costa, 2012).
Autophagy Autophagy is a well-conserved intracellular process resulting in the irreversible degradation of cellular constituents, which takes place in all eukaryotic cells. The term “autophagy” [self (auto)-eating (phagy)] was introduced by Christian de Duve in 1963, and the process was first identified in yeast cells under starvation condition (Klionsky, 2008). Since then, autophagy has been extensively studied, with the discover of 32 autophagy-related genes (ATGs), earlier identified in the Saccharomyces cerevisiae and in the Pichia pastoris, and later also in higher eukaryotes (Pyo et al., 2012, Orrenius et al., 2013). Autophagy is characterized by the formation of vesicles (autophagosomes), able to fuse with lysosome (mammals) or vacuole (plant, fungi), where the degradation of damaged parts of cytoplasm occurs (Todde et al., 2009). The lysosomal hydrolases degrade the damaged material and convert it in monomeric units, useful for cell survival. This event can in some instances be preceded by an additional step in which the autophagosome initially merges with the endosomal vesicles and only subsequently with lysosomes (Glick et al., 2010). Autophagy occurs in almost all cell types and it is useful to maintain cellular homeostasis, allowing cellular differentiation, tissue remodelling, growth control, cell defence, and adaptation to adverse environments (Cuervo, 2004). Indeed, under conditions of cellular stress (e.g. oxidative stress and starvation), autophagy participates in cell survival, providing the cells with all the substances necessary for energy production (Rodolfo et al., 2016). Inhibition of autophagy caused by several factors accelerates cell death in mammals (Orrenius et al., 2013). For example, increasing age causes a progressive decline in the ability of the autophagic process to remove the damaged intracellular components (Cuervo et al., 2005). In contrast, dietary caloric restriction is able to stimulate autophagy (as indicated by an increase of autophagosomes) and to protect nerve cells, thereby improving learning and memory abilities (Dong et al., 2016). Sometimes, however, an increase in the number of autophagosomes may reflect a reduction in autophagosome turnover or the inability to remove the new autophagosome formation (Wong and Cuervo, 2010, Klionsky et al., 2016). However, autophagy may also be a double-edged sword, as in addition to a protective role, it may also contribute to cell death (Zhang et al., 2016). For this reason, autophagy can be defined as a type II programmed cell death (Bursch et al., 2000, Berry and Baehrecke, 2008), to distinguish it from apoptosis.