Elsevier

Life Sciences

Volume 74, Issue 24, 30 April 2004, Pages 2931-2940
Life Sciences

Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice

https://doi.org/10.1016/j.lfs.2003.07.060Get rights and content

Abstract

We investigated the modifications in endogenous antioxidant capacity and oxidative damage in the brain, liver, kidney and testis in mice exposed to bisphenol A (BPA), an environmental endocrine disrupter. Mice were exposed to BPA throughout embryonic/fetal life and during lactation by feeding their pregnant/lactating mothers BPA at 5 or 10 μg per milliliter of drinking water. At the age of four weeks, male mice were sacrificed. Exposure to BPA increased the activity of catalase and glutathione peroxidase in the liver and kidney, respectively. It also increased thiobarbituric acid-reactive substances in the brain, kidney and testis, and decreased the wet weight of the brain, kidney and testis. Our results suggest that exposure to BPA throughout embryonic/fetal life and during infancy induces tissue oxidative stress and peroxidation, ultimately leading to underdevelopment of the brain, kidney and testis.

Introduction

Although oxygen is required for many important aerobic cellular reactions, it may undergo electron transfer reactions, which generate highly reactive membrane-toxic intermediates, such as superoxide, hydrogen peroxide or hydroxyl radicals. These reactive species inflict significant oxidative damage of membrane lipids and cause lipid peroxidation. Oxidative stress is considered to be an important pathophysiological process, promoting cell death in a variety of disorders. Various mechanisms are invoked to protect cells against damage caused by oxidative free radicals, including scavenging enzyme systems such as superoxide dismutase (SOD, EC:1.15.1.1), catalase (EC:1.11.16), and glutathione peroxidase (GPx, EC:1.11.1.9). Glutathione is a non-specific free radical scavenger and a substrate for GPx, and is reduced in the tissues by oxidative stress Sian et al., 1994, Melchiorri et al., 1996. L-ascorbic acid is also a non-specific free radical scavenger.

Bisphenol A (BPA; 2,2-bis-(4-hydroxyphenyl)-propane) is a monomer used in the manufacture of resins with a wide range of applications, for example, plastic coatings in the food packaging industry. BPA has a weak estrogenic activity (Roy et al., 1997) and has been implicated as an endocrine disrupter. In rats and mice, oral administration of BPA may be associated with adverse effects on the reproductive system (Morrissey et al., 1987). BPA itself, a diphenyl compound containing two hydroxyl groups in para positions, acts chemically as a radical scavenger because it inhibits the polymerization of methacrylate (Kadoma and Fujisawa, 2000). Redox status regulates numerous cellular processes, such as transcription factor activation and binding, protein folding, and calcium sequestration. It is feasible that BPA might affect biological metabolic processes by disturbing redox control systems.

In the present study, we administered BPA to mice throughout pregnancy and lactation. BPA is known to be transferred to the fetus via the placenta Shin et al., 2002, Takahashi and Oishi, 2000 and to the neonate via milk (Yoo et al., 2001). Thus, in our experiments, mice born of and raised by the BPA-treated mice were exposed to BPA throughout the embryonic/fetal life and infancy, via the placenta and milk. At the age of four weeks, the male mice were sacrificed. We measured the wet weight and concentration of BPA in the mouse brain, liver, kidney and testis, and investigated the effects of BPA on a biogenic macromolecular peroxidation indicator (thiobarbituric acid-reactive substance [TBARS]), antioxidants (glutathione [GSH] and L-ascorbic acid), and reactive oxygen species regulating enzymes (SOD, GPx and catalase).

Section snippets

Animals and experimental protocol

ICR mice (Charles River, Japan Inc., Japan) were used in all experiments. They were provided ad libitum with water and a standard laboratory diet containing 24% protein (MF, Oriental Yeast Co., Tokyo, Japan), and housed in an air-conditioned room set at 25 °C with a 12-h light and 12-h dark cycle (lights on, 06:00–18:00). The experimental protocol was approved by the Ethics Review Committee for Animal Experimentation of Kagawa Prefectural College of Health Sciences.

After a housing

BPA concentrations in the brain, kidney, liver and testis

We could not detect BPC in the brain, kidney liver and testis of the control mice. The BPA concentrations in the tissues of the BPA(10 μg/mL)-treated mice were shown in Fig. 1.

Weight of the body, brain, kidney, liver and testis

There was no difference of birth number per one mother among the control and BPA (5 μg/mL, 10 μg/m) administrated groups, and no obvious behavioral changes among the groups were observed apparently. BPA administration did not alter body weight (Table 1). The wet weight of the brain of BPA (5 μg/mL)-treated mice was

Discussion

BPA is known to be transferred to the fetus and neonate via placenta and milk, respectively, when it is administered to rats Shin et al., 2002, Takahashi and Oishi, 2000, Yoo et al., 2001. Takai et al. (2001) reported that prenatal exposure to BPA affected the early embryonic and postnatal development in mice. They reported that pups treated with BPA during the preimplantation period were significantly heavier than controls at postnatal day 21. In our study, mice ingested BPA with drinking

Conclusion

When BPA was administered throughout the embryonic/fetal life and during infancy via the placenta and milk, reactive oxygen species were induced in the organs. Although GPx and catalase activities were up-regulated, peroxidation of the brain, testis and kidney was induced, and ultimately resulting in underdevelopment of the brain, kidney and testis.

Acknowledgements

This study was supported by a grant from the Kagawa Prefectural College of Health Sciences.

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