Modulation of Ethanol-Metabolizing Enzymes by Developmental Lead Exposure: Effects in Voluntary Ethanol Consumption

Abstract

This review article provides evidence of the impact of the environmental contaminant lead (Pb) on the pattern of the motivational effects of ethanol (EtOH). To find a mechanism that explains this interaction, the focus of this review article is on central EtOH metabolism and the participating enzymes, as key factors in the modulation of brain acetaldehyde (ACD) accumulation and resulting effect on EtOH intake. Catalase (CAT) seems a good candidate for the shared mechanism between Pb and EtOH due to both its antioxidant and its brain EtOH-metabolizing properties. CAT overactivation was reported to increase EtOH consumption, while CAT blockade reduced it, and both scenarios were modified by Pb exposure, probably as the result of elevated brain and blood CAT activity. Likewise, the motivational effects of EtOH were enhanced when brain ACD metabolism was prevented by ALDH2 inhibition, even in the Pb animals that evidenced reduced brain ALDH2 activity after chronic EtOH intake. Overall, these results suggest that brain EtOH metabolizing enzymes are modulated by Pb exposure with resultant central ACD accumulation and a prevalence of the reinforcing effects of the metabolite in brain against the aversive peripheral ACD accumulation. They also support the idea that early exposure to an environmental contaminant, even at low doses, predisposes at a later age to differential reactivity to challenging events, increasing, in this case, vulnerability to acquiring addictive behaviors, including excessive EtOH intake.

Silencing brain catalase expression reduces ethanol intake in developmentally-lead-exposed rats

“…Although most of its industrial applications have been banned or are strictly regulated, lead (Pb) is still considered a public health concern due to its persistence in the environment globally. Several evidences indicate that developmental Pb exposure induces cognitive impairment, behavioral disturbances, and an altered response to drugs, including ethanol, both in children and laboratory animals (Mason et al, 2014;Virgolini et al, 2017). The stimulant and/or motivational responses to ethanol have been attributed to acetaldehyde (ACD), a metabolite generated in the brain primarily by the action of catalase (CAT), an enzyme of minor importance in liver ethanol metabolism Gill et al, 1992).…”

Brain ethanol-metabolizing enzymes are differentially expressed in lead-exposed animals after voluntary ethanol consumption: Pharmacological approaches

“…Pb itself increases both, CAT activity and several EtOH responses when administered either acutely to adult animals (Correa et al, 1999b), or chronically to developmental rats (Valenzuela et al, 1989;Mattalloni et al, 2013) or chickens (Somashekaraiah et al, 1992). Interestingly, we have demonstrated that pharmacological (Mattalloni et al, 2013) or molecular (Mattalloni et al, 2019) manipulations of this enzyme have a direct impact on CAT activity and voluntary EtOH intake in developmentally Pb-exposed rats (reviewed in Virgolini et al, 2017). Similarly, CAT inhibition with specific antagonists such as 3-amino 1,2,4-triazole (AT) or sodium azide reduced both EtOH-induced locomotor activity (Sanchis-Segura et al, 1999;Correa et al, 2001) and the drug's anxiolytic responses (Correa et al, 2008).…”

“…Although several industrial applications have been banned or restricted, neurobehavioral alterations are still reported in environmentally-Pb-exposed children. Experimental evidences in rodents indicate an enhanced vulnerability to the stimulating and motivational effects of ethanol (EtOH) as result of Pb exposure (Nation et al, 1986;Correa et al, 1999a;Virgolini et al, 2017). Since brain acetaldehyde accumulation is considered a key component of these responses (Aragon and Amit, 1985;Quertemont et al, 2005;Israel et al, 2015), EtOH metabolism emerged as an important aspect to consider when evaluating the mechanism that underlies the Pb-EtOH interaction.…”

“…In this regard, we have recently demonstrated that CY increased EtOH intake by reducing brain mitochondrial ALDH2 activity in rodents when the drug was administered directly in the brain. Interestingly, basal brain ALDH2 activity was lower in the Pb-exposed animals which had consumed EtOH compared to their control counterparts (Mattalloni et al, 2017), suggesting that central acetaldehyde accumulation make these animals more vulnerable to the development of excessive EtOH intake (reviewed in Virgolini et al, 2017).…”

The intertwining between lead and ethanol in the model organism Caenorhabditis elegans

“…They also consumed more EtOH than their respective controls and presented enhanced locomotor activity after the last voluntary consumption session ( Mattalloni et al, 2013 ; Mattalloni et al, 2017 ). As with worms, we ascribed these effects to differences in the activity of the enzymes involved in EtOH oxidation (results not shown, reviewed in Virgolini et al, 2017 ) and their interrelation with oxidative stress ( Virgolini et al, 2019 ), although the participation of the DAergic system was not assessed and thus cannot be discarded. Thus, despite the differences in the experimental design and animal model used in these approaches, we observed in both cases enhanced stimulant and motivational responses to EtOH as a consequence of early-life Pb exposure.…”