Human paraoxonase (PON1) is a polymorphic, high-density lipoprotein (HDL)-associated esterase that hydrolyzes the toxic metabolites of several organophosphorus (OP) insecticides and nerve agents. The activity polymorphism is determined by a Gln/Arg (Q/R) substitution at position 192. Injection of purified PON1 protects animals from OP poisoning. In the present study, we investigated the in-vivo function of PON1 for detoxifying organophosphorus insecticides in PON1-knockout mice that were challenged via dermal exposure with diazoxon, diazinon and paraoxon. PON1-knockout mice were extremely sensitive to diazoxon. Doses (2 and 4 mg/kg) that caused no cholinesterase (ChE) inhibition in wild-type mice were lethal to the knockout mice, which also showed slightly increased sensitivity to the parent compound diazinon. Surprisingly, these knockout mice did not show increased sensitivity to paraoxon. In-vitro assays indicated that the PON1R192 isoform hydrolyzed diazoxon less rapidly than did the PON1Q192 isoform. In-vivo analysis, where PON1-knockout mice received the same amount of either PON1(192) isoform via intraperitoneal (i.p.) injection 4 h prior to exposure, showed that both isoforms provided a similar degree of protection against diazoxon, while PON1R192 conferred better protection against chlorpyrifos-oxon than PON1Q192. Injection of purified rabbit PON1 or either human PON1(192) isoform did not protect PONI-knockout mice from paraoxon toxicity, nor did over-expression of the human PON1R192 transgene in wild-type mice. Kinetic analysis of the two human PON1(192) isoforms revealed that the catalytic efficiency (Vmax/Km) determines the in-vivo efficacy of PON1 for organophosphorus detoxication. The results indicate that PON1 plays a major role in the detoxication of diazoxon and chlorpyrifos oxon but not paraoxon.
The aim of this study was to identify the health hazards and possible exposure surveillance markers of workers exposed to nanoparticles during manufacturing and application in comparison to a group of unexposed workers. For this longitudinal study, we recruited 158 nanomaterial-handling workers and 104 non-exposed workers from 14 manufacturing plants in Taiwan (baseline). Among them, 124 nanomaterial-handling workers and 77 unexposed workers were monitored 6 months later. We investigated pulmonary and cardiovascular disease markers, inflammation and oxidative stress markers, antioxidant enzymes and genotoxicity markers. Antioxidant enzymes (superoxide dismutase, glutathione peroxidase) and cardiovascular markers (vascular cell adhesion molecule, paraoxonase) were significantly associated with nanomaterial-handling during the 6-month follow-up period. In addition, the small airway damage marker (Clara cell protein 16) and lung function test parameters were also significantly associated with handling nanomaterials. The study markers and lung function tests are possible markers that could be useful for surveillance of nanomaterial-handling workers.
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