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Bisphenol A impairs mitochondrial function in the liver at doses below the no observed adverse effect level.

Moon MK, Kim MJ, Jung IK, Koo YD, Ann HY, Lee KJ, Kim SH, Yoon YC, Cho BJ, Park KS, Jang HC, Park YJ - J. Korean Med. Sci. (2012)

Bottom Line: Bisphenol A (BPA) has been reported to possess hepatic toxicity.The expression levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) also increased.In HepG2 cells, 10 or 100 nM of BPA also decreased the oxygen consumption rate, ATP production, and the mitochondrial membrane potential.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
Bisphenol A (BPA) has been reported to possess hepatic toxicity. We investigated the hypothesis that BPA, below the no observed adverse effect level (NOAEL), can induce hepatic damage and mitochondrial dysfunction by increasing oxidative stress in the liver. Two doses of BPA, 0.05 and 1.2 mg/kg body weight/day, were administered intraperitoneally for 5 days to mice. Both treatments impaired the structure of the hepatic mitochondria, although oxygen consumption rate and expression of the respiratory complex decreased only at the higher dose. The hepatic levels of malondialdehyde (MDA), a naturally occurring product of lipid peroxidation, increased, while the expression of glutathione peroxidase 3 (GPx3) decreased, after BPA treatment. The expression levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) also increased. In HepG2 cells, 10 or 100 nM of BPA also decreased the oxygen consumption rate, ATP production, and the mitochondrial membrane potential. In conclusion, doses of BPA below the NOAEL induce mitochondrial dysfunction in the liver, and this is associated with an increase in oxidative stress and inflammation.

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Structure and function of hepatic mitochondria in the mice treated with BPA (0.05 mg/kg bw/day) for 5 days. (A) Morphology of hepatic mitochondria by transmission electron microscopy (500,000 × magnification). Control (A1) and BPA-treated mice (A2, A3). Normal mitochondria (arrows) and swollen and cristae-disrupted mitochondria (arrowhead). (B) Oxygen consumption rate of hepatic mitochondria. GMD, glutamate + malate + ADP; GMcD, GMD + cytochrome c; GMcDS, GMcD + succinate; FCCP, uncoupler. (C) MDA concentrations in the liver. (D) Catalase and GPx3 in the liver.
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Figure 5: Structure and function of hepatic mitochondria in the mice treated with BPA (0.05 mg/kg bw/day) for 5 days. (A) Morphology of hepatic mitochondria by transmission electron microscopy (500,000 × magnification). Control (A1) and BPA-treated mice (A2, A3). Normal mitochondria (arrows) and swollen and cristae-disrupted mitochondria (arrowhead). (B) Oxygen consumption rate of hepatic mitochondria. GMD, glutamate + malate + ADP; GMcD, GMD + cytochrome c; GMcDS, GMcD + succinate; FCCP, uncoupler. (C) MDA concentrations in the liver. (D) Catalase and GPx3 in the liver.

Mentions: We demonstrated that 1.2 mg/kg bw/day of BPA, which is lower than the NOAEL in mice (5 mg/kg bw/day), increased hepatic oxidative stress, and impaired mitochondrial function. Therefore, we treated mice with a lower dose of 0.05 mg/kg bw/day BPA. The electron microscopy findings were not consistent, and the morphology of the hepatic mitochondria varied between individual mice; the mitochondrial morphology appeared normal in some mice, but very large and swollen mitochondria were frequently observed in others (Fig. 5A). These results suggested that susceptibility to BPA could differ on an individual basis. The oxygen consumption rate of hepatic mitochondria showed no difference between 0.05 mg/kg bw/day BPA-treated mice and controls, but variations were observed between the individuals (Fig. 5B). MDA concentrations representing oxidative stress also increased compared to the controls, even in the mice treated with the lower dose of BPA, although this apparent difference was not statistically significant (Fig. 5C). GPx3 expression level also decreased in the mice treated with lower dose of BPA (Fig. 5D). Our results suggested that even the "tolerable" or "acceptable" lower dose of BPA could also induce hepatic oxidative stress and mitochondrial dysfunction, depending on individual susceptibility.


Bisphenol A impairs mitochondrial function in the liver at doses below the no observed adverse effect level.

Moon MK, Kim MJ, Jung IK, Koo YD, Ann HY, Lee KJ, Kim SH, Yoon YC, Cho BJ, Park KS, Jang HC, Park YJ - J. Korean Med. Sci. (2012)

Structure and function of hepatic mitochondria in the mice treated with BPA (0.05 mg/kg bw/day) for 5 days. (A) Morphology of hepatic mitochondria by transmission electron microscopy (500,000 × magnification). Control (A1) and BPA-treated mice (A2, A3). Normal mitochondria (arrows) and swollen and cristae-disrupted mitochondria (arrowhead). (B) Oxygen consumption rate of hepatic mitochondria. GMD, glutamate + malate + ADP; GMcD, GMD + cytochrome c; GMcDS, GMcD + succinate; FCCP, uncoupler. (C) MDA concentrations in the liver. (D) Catalase and GPx3 in the liver.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369451&req=5

Figure 5: Structure and function of hepatic mitochondria in the mice treated with BPA (0.05 mg/kg bw/day) for 5 days. (A) Morphology of hepatic mitochondria by transmission electron microscopy (500,000 × magnification). Control (A1) and BPA-treated mice (A2, A3). Normal mitochondria (arrows) and swollen and cristae-disrupted mitochondria (arrowhead). (B) Oxygen consumption rate of hepatic mitochondria. GMD, glutamate + malate + ADP; GMcD, GMD + cytochrome c; GMcDS, GMcD + succinate; FCCP, uncoupler. (C) MDA concentrations in the liver. (D) Catalase and GPx3 in the liver.
Mentions: We demonstrated that 1.2 mg/kg bw/day of BPA, which is lower than the NOAEL in mice (5 mg/kg bw/day), increased hepatic oxidative stress, and impaired mitochondrial function. Therefore, we treated mice with a lower dose of 0.05 mg/kg bw/day BPA. The electron microscopy findings were not consistent, and the morphology of the hepatic mitochondria varied between individual mice; the mitochondrial morphology appeared normal in some mice, but very large and swollen mitochondria were frequently observed in others (Fig. 5A). These results suggested that susceptibility to BPA could differ on an individual basis. The oxygen consumption rate of hepatic mitochondria showed no difference between 0.05 mg/kg bw/day BPA-treated mice and controls, but variations were observed between the individuals (Fig. 5B). MDA concentrations representing oxidative stress also increased compared to the controls, even in the mice treated with the lower dose of BPA, although this apparent difference was not statistically significant (Fig. 5C). GPx3 expression level also decreased in the mice treated with lower dose of BPA (Fig. 5D). Our results suggested that even the "tolerable" or "acceptable" lower dose of BPA could also induce hepatic oxidative stress and mitochondrial dysfunction, depending on individual susceptibility.

Bottom Line: Bisphenol A (BPA) has been reported to possess hepatic toxicity.The expression levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) also increased.In HepG2 cells, 10 or 100 nM of BPA also decreased the oxygen consumption rate, ATP production, and the mitochondrial membrane potential.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
Bisphenol A (BPA) has been reported to possess hepatic toxicity. We investigated the hypothesis that BPA, below the no observed adverse effect level (NOAEL), can induce hepatic damage and mitochondrial dysfunction by increasing oxidative stress in the liver. Two doses of BPA, 0.05 and 1.2 mg/kg body weight/day, were administered intraperitoneally for 5 days to mice. Both treatments impaired the structure of the hepatic mitochondria, although oxygen consumption rate and expression of the respiratory complex decreased only at the higher dose. The hepatic levels of malondialdehyde (MDA), a naturally occurring product of lipid peroxidation, increased, while the expression of glutathione peroxidase 3 (GPx3) decreased, after BPA treatment. The expression levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) also increased. In HepG2 cells, 10 or 100 nM of BPA also decreased the oxygen consumption rate, ATP production, and the mitochondrial membrane potential. In conclusion, doses of BPA below the NOAEL induce mitochondrial dysfunction in the liver, and this is associated with an increase in oxidative stress and inflammation.

Show MeSH
Related in: MedlinePlus