USE OF ANTIOXIDANTS TO COUNTER THE ADVERSE EFFECTS OF BISPHENOL A IN A MOUSE MODEL

Abstract

Bisphenol A (BPA) is a compound used in the manufacturing of plastics as a hardening agent and is ubiquitous in the environment due to its widespread use. BPA is a known endocrine disruptor and evidence suggests that BPA may influence multiple endocrine-related pathways and increase oxidative stress by disturbing the prooxidant/antioxidant balance of cells. The aim of the present study was to evaluate the toxic effects of BPA in pubertal and prenatal exposed mice and if co- administration of a palm-derived tocotrienol rich fraction (TRF), an antioxidant, can prevent its deleterious effects. In the first study (pubertal exposure), mice (n = 6/group) were randomly assigned into one of four groups (Group I: control; Group II: TRF-fed, Group III: BPA-fed and Group IV: BPA+TRF fed) and orally dosed daily with 50 μg/kg body weight of BPA whilst the TRF mice received 1 mg/day of TRF, starting on post-natal day (PND) 32 until sacrifice (PND50 or PND100). In the second study (prenatal exposure), mice (F0) were randomly distributed into the same groupings (6 mice/group) as the pubertal mice. At time of breeding, the male and female mice in Groups II and IV were dosed daily with TRF at 1 mg/day, and the female pregnant mice were dosed until parturition. The F0 pregnant dams (Groups III and IV) were orally fed with BPA (50 μg/kg BW) once daily, between 1000 and 1200 hours, from gestation day 12 (GD12) till gestation day 20 (GD20). Numerous significant effects were observed in the exposed mice at adulthood including elevation in final body weight, an increase in the length of the oestrous cycle and extended oestrous cycle, simple hyperplasia of the endometrium glands, thickening of the basement membrane in the testis, increased ERα expression in the hypothalamus, an increase in oestradiol levels and a decrease in testosterone levels. There were also changes in the expression of some genes with BPA treatment, including a 2.5 fold increase in Zan and decreases in Scara5 and Cdkn1a genes. Additionally, alterations in non-reproductive behaviours of males and females including anxiety, social interaction, locomotion and activity were observed. The effects of BPA were differentially expressed in the males and females, depending on the type of exposure either pubertal or prenatal. Supplementation with TRF ameliorated the BPA-induced changes to the oestrus cycle, serum oestradiol levels, anxiety and hyperactivity. TRF supplementation also protected against the recorded pathological changes in the uterus and testis and reduced the accumulation of BPA in the liver. In conclusion, TRF can ameliorate the toxic effects of BPA by its cytotoxic and antioxidant mechanism indicating its potential use as a protective antioxidant.