Regulatory effects of dioxin-like and non-dioxin-like PCBs and other AhR ligands on the antioxidant enzymes paraoxonase 1/2/3

Abstract

Paraoxonase 1 (PON1), an antioxidant enzyme, is believed to play a critical role in many diseases, including cancer. PCBs are widespread environmental contaminants known to induce oxidative stress and cancer and to produce changes in gene expression of various pro-oxidant and antioxidant enzymes. Thus, it appeared of interest to explore whether PCBs may modulate the activity and/or gene expression of PON1 as well. In this study, we compared the effects of dioxin-like and non-dioxin-like PCBs and of various aryl hydrocarbon receptor (AhR) ligands on PON1 regulation and activity in male and female Sprague-Dawley rats. Our results demonstrate that (i) the non-dioxin-like PCB154, PCB155, and PCB184 significantly reduced liver and serum PON1 activities, but only in male rats; (ii) the non-dioxin-like PCB153, the most abundant PCB in many matrices, did not affect PON1 messenger RNA (mRNA) level in the liver but significantly decreased serum PON1 activity in male rats; (iii) PCB126, an AhR ligand and dioxin-like PCB, increased both PON1 activities and gene expression; and (iv) even though three tested AhR ligands induced CYP1A in several tissues to a similar extent, they displayed differential effects on the three PONs and AhR, i.e., PCB126 was an efficacious inducer of PON1, PON2, PON3, and AhR in the liver, while 3-methylcholantrene induced liver AhR and lung PON3, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR agonist, increased only PON3 in the lung, at the doses and exposure times used in these studies. These results show that PCBs may have an effect on the antioxidant protection by paraoxonases in exposed populations and that regulation of gene expression through AhR is highly diverse.

Keywords: 3-MC; AhR; Non-dioxin-like PCB; PCB126; PON1; PON2; PON3; TCDD.

Figure 1. Highly ortho- chlorinated PCBs 154, 155, and 184 reduce PON1 activity in rat liver and serum

Male and female rats received injections of PCB154 low: 2× 50 μmol/kg, PCB154 high: 2× 100 μmol/kg, PCB155: 2× 100 μmol/kg), PCB184: 2× 100 μmol/kg. Results are expressed as mean ± SEM (n=6), Statistical significance: P<0.05, a. treatment vs corn oil, b. female vs corresponding male (serum only).

Figure 2. PCB 126 increased liver PON1 and PCB 153 lowered the serum PON1 activity

Male rats received one ip injection of PCB 153 (100 μmol/kg) or PCB 126 (5 μmol/kg) and were euthanized 6 days later. Results are expressed as mean ± SEM (n=4), a. significance (p<0.05) of treatment vs corn oil.

Figure 3. PCB 126 increased liver gene expression of PON1, 2, 3, and AhR while PCB 153 had no effect on these genes

Male rats were treated with PCB 153 (100 μmol/kg) or PCB 126 (5 μmol/kg). Results are expressed as mean ± SEM (n=4), a: significance (P<0.05) of treatment vs corn oil.

Figure 4. 3-MC and PCB 126, but not TCDD increased liver PON1 activity

Male rats received ip injections of 3-MC (3 daily injections of 300 μmol/kg), PCB 126 (1× 5 μmol/kg) or TCDD (1× 0.16 μmol/kg) and were killed on day 4. Results are expressed as mean ± SEM (n=2–3). a. significant differences (P<0.05) of treatment vs corn oil.

Figure 5. Different AhR agonists (3-MC, PCB 126 and TCDD) have varying effect on PON1, PON2, PON3 gene expression in liver, lung, and thymus

Male rats received 3-MC (3× 300 μmol/kg), PCB 126 (1× 5 μmol/kg) or TCDD (1× 0.16 μmol/kg). Results are expressed as mean ± SEM (n=2–3), a. significant (P<0.05) effect of treatment vs corn oil.