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Abstract The increment of eryptosis in lead-exposed workers has been associated with oxidative stress, having as the main mediator [Ca2+] i. However, other molecules could participate as signals, such as PLA 2 and SMase, which have been proposed to increase PGE 2 and ceramides, both involved in the increment of PS externalization due to osmotic stress. To study the role of these enzymes in lead intoxication, we studied 30 lead exposed workers and 27 non-lead exposed individuals. We found, compared to non-exposed subjects, lead intoxication characterized by high blood lead concentration (median = 39.1 μg/dL), and low δ -ALAD activity (median = 348 nmol of porphobilinogen/h/mL); oxidative stress with high lipid peroxidation (median = 1.31 nmol of malondialdehyde/mL) and low TAC (median = 370 mM Trolox equivalents); a higher enzymatic activity of PLA 2 (median = 518 AFU/mg) and SMase (median = 706 AFU/mg) and higher eryptosis (median = 0.92% PS externalization). Correlation and conditional probability analyses permit to associate oxidative stress and eryptosis with high PLA 2 activity. However, high SMase activity was only associated with PLA 2 activity. The role of these enzymes in the signal path to eryptosis induced by oxidative stress in lead-exposed workers is discussed. Highlights • Lead exposition induces high blood lead concentration in workers • Lead intoxication in workers is characterized by low δ-ALAD activity • Lead exposed workers have cellular oxidative damage and low antioxidant state • Phosphatidylserine exposure is induced by oxidative stress in lead exposed workers • PLA 2 and SMase are mediators of eryptosis associated with oxidative stress [ABSTRACT FROM AUTHOR]

Lead intoxication can generate pro-inflammatory conditions that have been proposed to be associated with cell injuries and oxidative stress. The pro-inflammatory state can participate in the pathophysiology of this toxicity to generate immune response dysfunctions, which could condition the presence of clinical manifestations and susceptibility to infections already described in lead-exposed patients. In the present work, we study workers of a battery recycler factory (n = 24) who are chronically exposed to lead and compared them with non‐lead exposed workers (n = 17). Lead-exposed workers had high lead concentrations in blood (med 69.8 vs. 1.7 μg/dL), low δ-ALAD activity (med 149 vs. 1100 nmol PBG/h/mL), high lipid peroxidation (med 0.86 vs. 0.69 nmol/mL) and high erythrocytes apoptosis (med 0.81 vs. 0.50% PS externalization) in relation to non‐lead exposed workers. Also, lead-exposed workers had a high incidence of signs and symptoms related to lead intoxication and a higher frequency of infections. The higher leukocyte apoptosis (med 18.3 vs. 8.2% PS externalization) and lower basal TNF-α concentration (med 0.38 vs. 0.94 pg/mL) in lead-exposed workers imply an immune response dysfunction; however, there was no difference in the TNF-α concentration when leukocytes were stimulated with lipopolysaccharide in whole blood (med 44 vs. 70 pg/mL), suggesting that lead-exposed workers might develop adaptation mechanisms to reduce basal TNF-α release through downregulation processes proposed for this cytokine. • Lead-intoxicated workers have oxidative damage and apoptosis in erythrocytes • Leukocyte apoptosis is high in lead-exposed workers • Intoxicated workers have low Tumor Necrosis Factor-alpha (TNF-α) concentrations • Lipopolysaccharide-stimulated TNF-α concentration is lead exposure independent • Lead-intoxicated workers suffer a high infection frequency [ABSTRACT FROM AUTHOR]