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. 2014 Sep 27;67(6):1031–1038. doi: 10.1007/s10616-014-9742-z

Effect of chemotherapy exposure prior to pregnancy on fetal brain tissue and the potential protective role of quercetin

Z Doğan 1, S Kocahan 2,3,✉, E Erdemli 4, E Köse 5, I Yılmaz 6, Z Ekincioğlu 7, N Ekinci 7, Y Turkoz 4
PMCID: PMC4628923  PMID: 25260542

Abstract

Cyclophosphamide (CYC) and doxorubicin (DOX) are among the most effective and widely used anticancer chemotherapeutic drugs. Potential chemopreventive and chemotherapeutic functions have recently been attributed to flavonoids. We hypothesized that Quercetin (QR) would protect against the toxic effects of chemotherapeutic agents applied prior to pregnancy. Rats were treated with the chemotherapeutic drugs CYC (27 mg/kg) and DOX (1.8 mg/kg) applied in a single intraperitoneal dose once every 3 weeks for 10 weeks. QR was administered at a dose of 10 mg/kg/day by oral gavage. 48 h following the experimental chemotherapy exposure, female rats were transferred to cages containing male rat for mating. Fetal brain tissues were removed from fetuses extracted by cesarean section on the 20th day of gestation for evaluation of antioxidant parameters. A significant increase in superoxide dismutase and malondialdehyde activity was observed in CYC and DOX treatment groups relative to the control group (p < 0.05). Similarly, carnitine acylcarnitine translocase and Glutathione activity was significantly reduced in the CYC and DOX groups relative to the control group (p < 0.05). Our results indicate that the use of chemotherapeutic drugs before pregnancy can result in oxidative damage to fetal brain tissue. Therefore, women who have been exposed to chemotherapy and may become pregnant should be treated with antioxidant compounds such as QR to reduce the risk of damage to fetal brain tissues.

Keywords: Chemotherapy, Cyclophosphamide, Doxorubicin, Fetal development, Quercetin

Introduction

Chemotherapy is the widely accepted standard of care for most forms of cancer. Cancers of the breast, cervix, and ovary are commonly treated with a variety of chemotherapeutic agents (Meistrich 2009).

Cyclophosphamide (CYC) and doxorubicin (DOX) are among the most effective and widely used anticancer chemotherapy drugs (Agarwal et al. 2003). The anthracycline antibiotic DOX represents the single most effective chemotherapeutic agent for the treatment of breast cancer, bone and soft tissue sarcomas, and malignant lymphomas (Bayne and Sohal 2002; Taskin and Dursun 2014a). DOX-induced toxicity stimulates the translocation of calreticulin to the cell surface in tumor cells, enhancing uptake and clearance by dendritic cells (Bines et al. 1996). Both in vitro and in vivo data support the hypothesis that a combination of the antioxidant Quercetin (QR) and DOX produces beneficial, synergistic effects in the treatment of breast cancer and leukemia (Black et al. 2002; Bolzan et al. 1997; Ceballos et al. 1992) However, exposure of pregnant women to chemotherapy results in congenital malformations in as many as 10–20 % of cases (Cevik et al. 2013).

CYC is a potent alkylating agent (Howell and Shalet 2005a). Alkylating agents are particularly gonadotoxic, producing adducts and cross-links in DNA that may result in prolonged azoospermia (Vaisheva et al. 2007). At moderate doses, recovery of normospermic conditions may occur within 1–3 years; however, increased exposure can result in extended or permanent azoospermia (Claeson et al. 2000; Cheng et al. 2002; Doganay et al. 2006; Ciftci et al. 2013; Delbes et al. 2010). Premature menopause and infertility may result from acute exposure to chemotherapy regimens including anthracycline and CYC (Du et al. 2010a; Estany et al. 2007). DOX exposure is known to increase oocyte apoptosis in cell culture based on experiments (Estany et al. 2007).

Potential chemopreventive and chemotherapeutic functions have recently been attributed to flavonoids (Bolzan et al. 1997; Fadillioğlu et al. 2002). QR (QT, 3,3′,4′,5,7-pentahydroxyflavone) is one type of naturally-occurring flavonoid. Several recent studies have demonstrated the antimicrobial, antiviral, antioxidative, and anti-inflammatory properties of QR, suggesting broad benefits to human health (Gilgun et al. 2001). The flavonoid QR is known to enhance cellular antioxidant potential through the Nrf2 pathway (Haliwel and Gutterridge 1992; Gutteridge 1995). A variety of evidence from animal tirals suggests that the antioxidant properties of QR reduce oxidative damage to the brain, heart, and other tissues during ischemic reperfusion injury and exposure to compounds that induce oxidative stress (Gutteridge 1995; Bayne and Sohal 2002).

In the present study, we evaluated the hypothesis that QR would protect against the toxic effects of chemotherapeutic agents applied prior to pregnancy.

Materials and methods

All experimental procedures were reviewed and approved (2009/32) by the local ethics committee of the Medical Sciences Experimental Search and Application Center (MSESAC) at the Inonu University.

Experimental treatments

The chemotherapeutic agents CYC (Molekula, Shaftesbury, Dorset, UK) and DOX (Sigma-Aldrich, Oakville, ON, Canada) were used for experimental induction of chemotherapeutic oxidative injury. The doses calculated for treatment of experimental animals were equivalent to typical clinical dosages. CYC was administered four times at three week intervals at the total dose 27 mg/kg. DOX was administered four times at three week intervals at the total dose 1.8 mg/kg. (Fig. 1) (Agarwal et al. 2003). The doses of the drugs administered to rats were analogous to human doses after adjustment for the differences in surface area to weight ratio.

Fig. 1.

Fig. 1

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Cyclophosphamide, Doxorubicin, and Quersetin treatment regimen

QR (Quercetin dihydrate, 97%, Alfa Aesar GmbH, Karlsruhe, Germany, CAS: 6151-25-3) was suspended in corn oil and administered at a dose of 10 mg/kg/day by oral gavage throughout the course of the study (Howell and Shalet 2005b). Control groups have received only corn oil by gavage.

Animals

A total of 53 female Wistar rats weighing approximately 250 g each were used in this study. At 2 days post-chemotherapy exposure, female rats were introduced to cages containing a male rat for the purpose of breeding. Four females were housed with a single male in a wire mesh cage and pregnancy was determined by the presence or absence of a vaginal plug. The day of plug release was considered gestation day 1. Male rats were removed from the cage following confirmation of pregnancy. Food and water were given without restriction. The animals were subjected to a schedule of 12 h of light and 12 h of darkness (lights on at 06:00), and an ambient temperature of 22 ± 2 °C was maintained at all times.

Experimental groups

The experimental rats were divided into six groups: control (CONT), QR, CYC, DOX, CYC + QR, and DOX + QR. On the 20th day of gestation, fetuses were removed by cesarian section under combination of ketamine (Ketalar® 50mg/ml Pfizer, Berlin, Germany) and xylazine (Rompun® 2%, 20 mg•ml−1, Bayer, Berlin, Germany) anaesthesia (Ketamine/Xylazine, 90/10 mg/kg body weight, i.p. injection). Subsequently, fetal brain tissues were extracted for the measurement of antioxidant parameters including malondialdehyde antioxidant (MDA), glutathione (GSH), superoxide dismutase (SOD), and carnitine acylcarnitine translocase (CAT).

Biochemical analysis

Fetal brain tissue samples were homogenized in ice-cold 0.1 M Tris–HCl buffer (pH 7.5) containing protease inhibitor, phenylmethylsulfonyl fluoride, 1 mM using a tissue homogenizer (IKA, Staufen, Germany, Ultra-Turrax T 25 basic) at 16,000 rpm for 2 min at +4 °C. These homogenates were subsequently used for measurement of biochemical analysis.

MDA and GSH

Thiobarbituric acid reactive substances including MDA were measured by the addition of thiobarbituric acid to tissue homogenates and the measurement of light absorbance at 535 and 520 nm in a spectrophotometer as previously described (Mihara and Uchiyama 1978). The results were reported as nmol/g wet tissue. Fetal brain homogenate GSH concentrations were measured using the reduced glutathione assay according to the spectrophotometric Ellman’s method (Ellman 1959). Again, results were reported as nmol/g wet tissue.

SOD assay

SOD activity was measured as the total reduction of nitroblue tetrazolium by the superoxide anion produced by xanthine and xanthine oxidase (Jolitha et al. 2006). One unit of SOD activity was defined as the quantity of protein inhibiting the rate of NBT reduction by 50 %, with the results reported as units per milligram protein. The total protein content of the brain tissue homogenate samples was determined by the method of Lowry et al. (Lenton et al.1999).

Determination of CAT activity

CAT activity was measured using Aebi’s method (Aebi 1974), the determination of the rate constant k (dimension: s-1, k) of H2O2 (initial concentration 10 mM) as indicated by absorbance at 240 nm in a spectrophotometer (Casado et al. 2001). Activity was reported as k (constant rate).

Statistical analysis

All continuously variable data were expressed as mean ± SEM. The results were analyzed using SPSS 15.0 statistical software. One-way analysis of variance (ANOVA) and the post hoc Tukey’s HSD test were used to evaluate the differences in biochemical parameters between multiple groups. For statistical significance a p value of less than 0.05 was accepted.

Results

The results of the biochemical analysis of antioxidant parameters in fetal brain tissue were provided. A significant increase in SOD activity was observed in the CYC and DOX groups relative to the control group, while SOD activity was significantly decreased in the DOX + QR treatment group compared to the group exposed to DOX alone (p < 0.05) (Fig. 2).

Fig. 2.

Fig. 2

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Bar graph indicating SOD parameters in fetal brain tissue. abcd superscript symbols within the same column indicate statistically significant differences (p < 0.05). N = 5 rats per group

A significant decrease in CAT activity was observed in the CYC and DOX groups relative to the control group (p < 0.05). CAT activity was increased in the CYC + QR group relative to the group treated with CYC alone, however this difference did not reach the level of statistical significance (p > 0.05). Similarly, differences in CAT activity in the DOX + QR group relative to the DOX treatment group were not statistically significant neither (p < 0.05) (Fig. 3).

Fig. 3.

Fig. 3

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Bar graph indicating CAT parameters in fetal brain tissue. abc superscript symbols within the same column indicate statistically significant differences (p < 0.05). N = 5 rats per group

A significant decrease in GSH levels was observed in the CYC and DOX treatment groups relative to the control group (p < 0.05), however an increase in GSH in the CYC + QR and DOX + QR treatment groups did not reach the level of statistical significance (p > 0.05) (Fig. 4).

Fig. 4.

Fig. 4

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Bar graph indicating GSH parameters in fetal brain tissue. abc superscript symbols within the same column indicate statistically significant differences (p < 0.05). N = 5 rats per group

Similar to the other antioxidant parameters measured, a statistically significant increase in MDA levels was observed in the CYC and DOX groups relative to the control group (p < 0.05), although in this case MDA was also significantly decreased in the CYC + QR treatment group relative to the group treated with CYC alone (p < 0.05). However, there was no statistically significant difference in MDA levels in the DOX + QR treatment group relative to the group treated with DOX alone (p < 0.05) (Fig. 5).

Fig. 5.

Fig. 5

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Bar graph indicating MDA parameters in fetal brain tissue. ab superscript symbols within the same column indicate statistically significant differences (p < 0.05). N = 5 rats per group

Discussion

Oxidative stress occurs as a result of insufficient antioxidant protection, elevated free radical production, or a combination of the two processes (Lowry et al. 1951; Leyder et al. 2011). The central nervous system, possessing relatively weak endogenous and exogenous antioxidant capabilities, is particularly sensitive to oxidative stress induced by the presence of free radicals (Matouk et al. 2013). In the present study, we examined markers of oxidative stress and evaluated antioxidant capacity in fetal brain tissues following exposure of the mother to chemotherapeutic agents known to induce oxidative stress.

The catalysis of superoxide to hydrogen peroxide by SOD (Meistrich 2009) results in the inhibition of lipid peroxidation, a protective function in the presence of oxygen free radicals (Mihara and Uchiyama 1978). SOD activity is elevated in tissues with high oxygen demands. CAT is an antioxidant enzyme that is itself highly sensitive to oxidative damage, resulting in loss of antioxidant activity. CAT enzymatic activity has been demonstrated to decrease following oxidative damage (Mihara and Uchiyama 1978; Niestroy et al. 2011). In the present study, fetal brain tissues were obtained from mothers exposed to the chemotherapeutic drugs CYC and DOX just prior to pregnancy. Our results demonstrate that while fetal brain SOD activity was significantly increased by CYC or DOX exposure, CAT activity was simultaneously decreased in the same tissues. This is consistent with previous reports regarding the mechanisms contributing to oxidative damage of fetal brain tissues (Mihara and Uchiyama 1978; Niestroy et al. 2011). Recent studies have implicated oxidative stress in the pathogenesis of a variety of widely prevalent human diseases (Niestroy et al. 2011). Neurodegenerative disease (Obeid et al. 2013), cardiovascular disease (Pryzant et al. 1993), cancer (Ray et al. 2000), and infertility (Senturker et al. 2002) have all been associated with increased oxidative stress. The present study indicates that chemotherapy agents significantly increase SOD activity and that QR co-treatment with the drugs significantly ameliorates the effects of chemotherapy-induced oxidative damage. Previous studies support the therapeutic effect of QR in pathologies involving oxidative stress (Gilgun et al. 2001; Bayne and Sohal 2002).

Increased availability of GSH, the reduced form of glutathione, enhances the detoxification of free radicals. The neutralization of free radicals within the cytoplasm results in GSH depletion (Sestili et al. 1998). A significant decrease in the non-enzymatic anti-oxidant GSH was observed in fetal brain tissues exposed to chemotherapeutic agents CYC and DOX relative to the control group. The depletion of GSH in the chemotherapy-exposed tissue is a clear indicator of significant oxidative damage in the fetal brain tissue. A recent study reported that elevated oxidative stress give rise to attenuate mitochondrial functions resulting from decreased mitochondrial membrane potential and ATP production (Taskin et al. 2014b; Taskin and Dursun 2014a). Attenuation of mitochondrial function probably worsened the fetal brain damage.

Numerous reports suggest that MDA expression is enhanced by lipid peroxidation resulting from oxidative stress (Sun et al. 1988; Singh et al.2003; Shen et al. 2008; Staedler et al. 2011), while SOD activity is known to suppress lipid peroxidation (Vaisheva et al. 2007). Despite elevated SOD activity in the CYC- and DOX-exposed fetal brain tissues, increased MDA expression is a clear indicator of ongoing lipid peroxidation.

The antioxidant capacity of QR is quite strong relative to other known flavonoids (Vanhees et al. 2013). Previous studies support the notion that QR acts as a free radical scavenger and is capable of suppressing lipid peroxidation (Bines et al. 1996; Walle et al. 2007; Delbes et al. 2010; Vanhees et al. 2013). The present data demonstrate that CYC and DOX exposure increases MDA levels and SOD activity in fetal brain tissue while it decreased CAT enzymatic activity indicating oxidative damage, consistent with previous studies (Wessels et al. 2011). However, the presence of QR resulted in enhancement of the antioxidant capacity of the fetal tissues and reduction of free radical induced oxidative damage, a result supported by previous work (Tanir et al. 2005).

In conclusion, our study data suggest that the therapeutic use of CYC or DOX in pregnancy should be strongly discouraged due to the risk oxidative damage to fetal brain tissue. Metabolites resulting from CYC and DOX exposure, described in this paper, accumulate in fetal brain tissues as a result of oxidative damage. In such cases where CYC and DOX must be used, QR may be a suitable anti-oxidant capable of reducing the risk of damage to fetal neurological development. Our data demonstrate that exposure to chemotherapeutic drugs prior to pregnancy can result in significant oxidative damage to fetal brain tissues. Therefore, women who have been exposed to chemotherapy and may become pregnant should be treated with antioxidant compounds such as QR to reduce the risk of damage to fetal brain tissues.

Acknowledgments

This research was supported by Inonu University Research Fund (INU-BAP 2010/58).

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