Abstract
Para (p)-phenylenediamine and its toxic metabolites induce excess reactive oxygen species formation that results in bladder voiding dysfunction. We determined the effects of synthetic Ni-containing superoxide dismutase mimics and the role of oxidative stress in p-phenylenediamine-induced urinary bladder dysfunction. P-phenylenediamine (60 μg/kg/day) was intraperitoneally administered for 4 weeks to induce bladder injury in female Wistar rats. Synthetic Ni-containing superoxide dismutase mimics, WCT003 (1.5 mg/kg) and WCT006 (1.5 mg/kg), were then intraperitoneally administered for 2 weeks. Transcystometrograms were performed in urethane-anesthetized rats. The in vitro and in vivo reactive oxygen species levels and pathological changes in formalin-fixed bladder sections were evaluated. Western blotting and immunohistochemistry elucidated the pathophysiological mechanisms of oxidative stress-induced apoptosis, autophagy, and pyroptosis. P-phenylenediamine increased voiding frequency, blood and urinary bladder levels of reactive oxygen species, and neutrophil and mast cell infiltration. It also upregulated biomarkers of autophagy (LC3 II), apoptosis (poly (ADP-ribose) polymerase), and pyroptosis (Caspase 1). WCT003 and WCT006 ameliorated reactive oxygen species production, inflammation, apoptosis, autophagy, pyroptosis, and bladder hyperactivity. P-phenylenediamine increased oxidative stress, inflammatory leukocytosis, autophagy, apoptosis, and pyroptosis formation within the urinary bladder. Novel synthetic nickel-containing superoxide dismutase mimics relieved p-phenylenediamine-induced bladder inflammation and voiding dysfunction.
Highlights
Para-phenylenediamine (PPD) is a common ingredient in hair and leather dyes [1, 2]
We determined the effects of synthetic Ni-containing superoxide dismutase mimics and the role of oxidative stress in p-phenylenediamine-induced urinary bladder dysfunction
After WCT003 or WCT006 treatment (Figure 2), the inter-contraction interval (ICI) in both groups significantly increased compared to PPD group (P < 0.05)
Summary
Para-phenylenediamine (PPD) is a common ingredient in hair and leather dyes [1, 2]. 33% of women over age 18 and 10% of men over age 40 in North America and Europe use hair dye [3]. PPD poisonings have been reported in developing countries due to its widespread industrial application [4, 5]. The International Agency for Research on Cancer (IARC) suggested that there was inadequate evidence that personal use of hair dye entails www.impactjournals.com/oncotarget Control group PPD group. People receiving tattoos could bear a higher risk of PPD absorption [10]. The significant public health impact of widespread applications of PPD and the associated health risks should be considered
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