Influence of the butylparaben administration on the oxidative stress metabolism of liver, kidney and spleen

Introduction

Butylparaben is an alkyl ester compound and widely used synthetic polymer as preservative in the various industrial products including food, personal care products, cosmetics and pharmaceuticals [1]. Total daily exposure to the parabens is 76 mg, although the Acceptable Daily Intake (ADI) for them is 0–10 mg/kg Bw/day for human [2], [3]. After absorption from the skin and gastrointestinal system, butylparaben is metabolized in the detoxification organs including liver and kidney. However, some part of the parabens remains and accumulates in the body over time. There is a growing concern about adverse health effects of the butylparaben, since it has been reported that parabens can impair reproductive, developmental and redox systems by acting endocrine disrupting chemical (EDC) [4], [5], [6], [7].

Liver, kidney and spleen are responsible for the detoxification of the xenobiotics including butylparaben and other EDCs which interfere with hormones. Because of the detoxification reactions, oxidative stress increases in these organs that may cause imbalance in the cellular processes leading to the tissue damage and diseases [7], [8], [9], [10], [11]. Therefore, in this study we designed our experiments to evaluate impacts of the butylparaben on the detoxification organs which have not been studied before in the literature. Our findings may reveal butylparaben-induced impairments in the oxidative branch of pentose phosphate metabolism and glutathione dependent enzyme activities which were both tightly correlated with oxidative stress metabolisms of the detoxification organs.

Material & Method

Results

Anti-oxidant enzyme activities were impaired upon butylparaben administration in the liver, kidney and spleen tissues.

GST enzyme activity meaningfully decreased in the all butylparaben administrated groups compared to the control group, however GPx activity significantly increased in the 200 mg/kg/day dose group compared to the all other groups in the liver (Figure 1). G6PD, 6PGD and GR activities were fluctuated upon butylparaben administration in the liver (Figure 1).

Figure 1:

Anti-oxidant enzyme activities in the liver samples of male rats in control and butylparaben treatment groups. All groups are compared to CTL group and each other. All results were given as the mean ± SD of n=6 animals.

^a 200 mg/kg/day butylparaben dose group is different 400 mg/kg/day dose group (p=0.0488), ^b 100 mg/kg/day butylparaben dose group is different from CTL group (p=0.0109), ^c 200 mg/kg/day butylparaben dose group is different from CTL group (p=0.0416), ^d 400 mg/kg/day butylparaben dose group is different from CTL group (p=0.0002), ^e 200 mg/kg/day butylparaben dose group is different from CTL group (p=0.0028), ^f 200 mg/kg/day butylparaben dose group is different from 100 mg/kg/day dose group (p=0.0126), ^g 200 mg/kg/day butylparaben dose group is different from 400 mg/kg/day dose group (p=0.0002).

G6PD and GR activities significantly increased in the butylparaben treatment groups compared to the control in the kidney (Figure 2). GST activity meaningfully increased in 200 mg/kg/day butylparaben treatment group compared to the control group and other dose groups; however GPx activity significantly decreased in 200 and 400 mg/kg/day dose group compared to the other groups in the kidney samples (Figure 2).

Figure 2:

Anti-oxidant enzyme activities in the kidney samples of male rats in control and butylparaben treatment groups. All groups are compared to CTL group and each other. All results were given as the mean ± SD of n=6 animals.

^a 200 mg/kg/day butylparaben dose group is different from CTL group (p=0.0028), ^b 200 mg/kg/day butylparaben dose group is different from 100 mg/kg/day dose group (p=0.0126), ^c 200 mg/kg/day butylparaben dose group is different from 400 mg/kg/day dose group (p=0.0002), ^d 100 mg/kg/day butylparaben dose group is different from 400 mg/kg/day dose group (p= 0.0039), ^e 400 mg/kg/day butylparaben dose group is different from 200 mg/kg/day dose group (p=0.0003), ^f 400 mg/kg/day butylparaben dose group is different from 100 mg/kg/day dose group (p=0.0125), ^g 400 mg/kg/day butylparaben dose group is different from CTL group (p=0.0187), ^h 200 mg/kg/day butylparaben dose group is different from 400 mg/kg/day dose group (p<00001), ⁱ 200 mg/kg/day butylparaben dose group is different from 100 mg/kg/day dose group (p<0.0001), ^j 200 mg/kg/day butylparaben dose group is different from CTL group (p<00001), ^k 200 mg/kg/day butylparaben dose group is different from CTL group (p=0.0212), ^l 400 mg/kg/day butylparaben dose group is different from 100 mg/kg/day dose group (p=0.0370), ^m 200 mg/kg/day butylparaben dose group is different from 100 mg/kg/day dose group (p=0.0212), ⁿ 400 mg/kg/day butylparaben dose group is different from 100 mg/kg/day dose group (p=0.0370).

G6PD, 6-PGD, GR and GPx activities increased in butylparaben dose groups compared to the control, however this change was significant for G6PD and GR activities in the spleen tissue (Figure 3). On the other hand, GST activity significantly decreased in all dose groups, but only significant change was observed in highest butylparaben treatment groups compared to the control in the spleen tissue (Figure 3).

Figure 3:

Anti-oxidant enzyme activities in the spleen samples of male rats in control and butylparaben treatment groups. All groups are compared to CTL group and each other. All results were given as the mean ± SD of n=6 animals.

^a 100 mg/kg/day butylparaben dose group is different from CTL group (p<0.0004), ^b 200 mg/kg/day butylparaben dose group is different from CTL group (p<0.0001), ^c 400 mg/kg/day butylparaben dose group is different from CTL group (p<00001), ^d 100 mg/kg/day butylparaben dose group is different from CTL group (p< 00058), ^e 200 mg/kg/day butylparaben dose group is different from CTL group (p=0.0037), ^f 400 mg/kg/day butylparaben dose group is different from CTL group (p<0.0001), ^g 400 mg/kg/day butylparaben dose group is different from CTL group (p=0.0348).

Discussion

Effects of parabens and other EDCs have been widely studied on the reproductive and developmental systems, however there is no detailed data about the butylparaben-enhance oxidative stress in the detoxification organs including liver, kidney and spleen [1], [2], [3], [4], [5], [6], [7], [8]. Since parabens and other EDCs can induce oxidative stress resulting in the tissue damage in human and wildlife, cause formation of the various diseases [4], [9], [10], [11], [15], [16].

Pentose phosphate pathway (PPP) play vital role in xenobiotic metabolism. Endocrine disruptors or any other molecules, chemicals that affects the PPP enzyme activities especially G6PD and 6-PGD will results in fail of metabolic network of the cell and the organism [11], [].

The reduced form of GSH is one of the cell’s most significant antioxidants and reduction of this molecule is directly associated with PPP’s product NADPH and the enzyme GR [9], [11], [13], [21]. Moreover, Zhang et al. reported that GSH depletion or increased oxidized GSH concentration can increase oxidative phase of PPP and cells with low levels of GSH are susceptible hemolysis in erythrocytes [22]. Thus, we evaluated antioxidant enzyme activities including G6PD, 6-PGD, GR, GST and GPx in the detoxification after butylparaben treatment as the oxidative stress biomarkers in our study. G-6-PD and GR activities significantly increased upon butylparaben treatment in the main xenobiotic detoxification tissues (Figures 1–3). GST activity meaningfully reduced in the butylparaben treated groups compared to the control in the liver and spleen (Figures 1, 3). However, GPx activity significantly increased in the liver, where significantly decreased in the kidney tissue (Figures 1, 2).

GST, GR and GPx are involving in the GSH metabolism responsible for the detoxification and oxidative stress metabolisms of xenobiotics including EDCs such as butylparaben and phthalates. Since these enzymes keep balance of the oxidized glutathione (GSSG)/GSH ratio, impairment of this ratio causes central redox homeostasis in the organisms [9], [16], [17], [23].

G6PD and 6-PGD play key role in the PPP and responsible to produce NADPH required for the function of GR, GST and GPx. Increased levels of oxidative stress may result from impairment in the antioxidant enzyme activities such as G6PD, 6-PGD, GR, GST and GPX. Elevated levels of ROS attack lipids, proteins and DNA may end up tissue injury [4], [19], [20], [23].

Liver and kidney are the major detoxification organs, where spleen is mainly responsible for the immune defense system of the organism. Butylparaben-induced impairments have been reported previously in liver, kidney and spleen. For instance, butylparaben may cause high incidence of amyloidosis and significant atrophy in the spleen [15], [16], [17], [18], [19], [23]. Moreover, Aydemir et al. reported EDC DEHP can induce tissue injury in the liver, kidney, brain and testis via elevated levels of oxidative stress [9], [10].

Overall, our data showed that oxidative stress metabolism is activated to fight against butylparaben in the liver, kidney and spleen tissues because of fluctuated antioxidant enzyme activities. Impairment in the indicated enzyme activities may damage tissue function and cause initiation of different types of diseases.

Conclusion

There is an increasing concern and attention about adverse health effects of EDCs including butylparaben.We showed first time in the literature that oxidative stress metabolism is impaired in spleen, kidney and liver tissue upon butylparaben treatment. Our results also highlighted the importance of endocrine disruptor, butylparaben on the oxidative part of PPP enzymes as an important component in the response to xenobiotic metabolism and various anabolic reactions. The present study concludes that realistic exposure to endocrine disruptors can increase the spleen enzymes and even more hazardous and may induce immunosuppression of the target organism.