Parabens Accelerate Ovarian Dysfunction in a 4-Vinylcyclohexene Diepoxide-Induced Ovarian Failure Model.

Jae-Hwan Lee,Hee Kang,Dinh Tran,Myeongho Lee,Changhwan Ahn,Eui-Bae Jeung

doi:10.3390/ijerph14020161

Abstract

Parabens are widely used preservatives in basic necessities such as cosmetic and pharmaceutical products. In previous studies, xenoestrogenic actions of parabens were reported in an immature rat model and a rat pituitary cell line (GH3 cells). The relationship between parabens and ovarian failure has not been described. In the present study, the influence of parabens on ovarian folliculogenesis and steroidogenesis was investigated. A disruptor of ovarian small pre-antral follicles, 4-vinylcyclohexene diepoxide (VCD, 40 mg/kg), was used to induce premature ovarian failure (POF). Methylparaben (MP, 100 mg/kg), propylparaben (PP, 100 mg/kg), and butylparaben (BP, 100 mg/kg) dissolved in corn oil were treated in female 8-week-old Sprague-Dawley rat for 5 weeks. Estrus cycle status was checked daily by vaginal smear test. Ovarian follicle development and steroid synthesis were investigated through real-time PCR and histological analyses. Diestrus phases in the VCD, PP, and BP groups were longer than that in the vehicle group. VCD significantly decreased mRNA level of folliculogenesis-related genes (Foxl2, Kitl and Amh). All parabens significantly increased the Amh mRNA level but unchanged Foxl2 and Kitlg acting in primordial follicles. VCD and MP slightly increased Star and Cyp11a1 levels, which are related to an initial step in steroidogenesis. VCD and parabens induced an increase in FSH levels in serum and significantly decreased the total number of follicles. Increased FSH implies impairment in ovarian function due to VCD or parabens. These results suggest that VCD may suppress both formation and development of follicles. In particular, combined administration of VCD and parabens accelerated inhibition of the follicle-developmental process through elevated AMH level in small antral follicles.

Highlights

In humans, premature ovarian failure (POF), known as premature ovarian insufficiency [1], is characterized by amenorrhea, infertility, low estrogen levels, excess gonadotropin, and a lack of mature follicles before the age of 40 [2]
Amh mRNA level but unchanged Foxl2 and Kitlg acting in primordial follicles
During administration of vinylcyclohexene diepoxide (VCD) and parabens, estrus cycle status of 8-week-old SD rats was determined every day based on vaginal smear test results (Figure 1)

Summary

Introduction

Premature ovarian failure (POF), known as premature ovarian insufficiency [1], is characterized by amenorrhea, infertility, low estrogen levels, excess gonadotropin, and a lack of mature follicles before the age of 40 [2]. The occurrence of POF is mainly associated with the sustained reduction of the excess ovaries pool. In POF, the follicles do not develop properly. The exact mechanism producing inhibition of follicles in POF has not yet been described. The chemical 4-vinylcyclohexene diepoxide (VCD) is known to induce POF in an experimental model [3,4]. The primary structure in the ovary is the follicle, which is composed of a germ cell (oocyte) surrounded by somatic cells (granulosa and theca interna) [3,5].

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Results

Conclusion