Effects of Di-(2-ethylhexyl) Phthalate on the Hypothalamus–Uterus in Pubertal Female Rats

Abstract

Abstract:The pollution of endocrine disruptors and its impact on human reproductive system have attracted much attention. Di-(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, is widely used in food packages, containers, medical supplies and children's toys. It can cause diseases such as infertility, sexual precocity and uterine bleeding and thus arouse concerns from the society and scholars. The effect of DEHP on pubertal female reproductive system is still not well-studied. This study was to investigate the effects of DEHP on the hypothalamus-uterus in pubertal female rats, reveal the reproductive toxicity of DEHP on pubertal female rats and its mechanism, and provide scientific evidence for the evaluation of toxicity and toxic mechanism of DEHP on reproductive system. Forty-eight pubertal female rats were randomly divided into four groups and respectively administered via oral gavage 0, 250, 500, or 1000 mg/kg/d DEHP in 0.1 mL corn oil/20 g body weight for up to four weeks. Compared with control rats, the DEHP-treated rats showed: (1) higher gonadotropin-releasing hormone (GnRH) level in the hypothalamus; (2) higher protein levels of GnRH in the hypothalamus; and (3) higher mRNA and protein levels of GnRH receptor (GnRHR) in the uterus. Our data reveal that DEHP exposure may lead to a disruption in pubertal female rats and an imbalance of hypothalamus-uterus. Meanwhile, DEHP may, through the GnRH in the hypothalamus and its receptor on the uterus, lead to diseases of the uterus. DEHP may impose a negative influence on the development and functioning of the reproductive system in pubertal female rats.

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

“…For instance, Hannon et al [ 121 ], showed that the exposure to DEHP at 10 µg/mL increased the levels of Cyp19a1, Hsd17b1 and exposure to DEHP at 100 µg/mL decreased levels of those enzymes in cultured mouse antral follicles. In contrast, some studies are showing that phthalates induced linear toxicity [ 176 , 181 ]. For example, Ha et al [ 181 ] observed that with the increasing dose of DEHP in Sprague-Dawley rats, levels of testosterone, FSH and LH decreased.…”

“…Phthalates can affect the HPG axis and steroidogenesis through interaction with genes for GPCRs—receptors for GnRH on pituitary cells, receptors for FSH and LH on Leydig cells, ovarian cells—granulosa and thecal cells. Postnatal exposure to DEHP in female Wistar rats at 3000 [ 176 ] and 1000 mg/kg/day [ 131 ] increased the expression of Gnrhr [ 132 , 176 ]. A similar pattern was observed in Fshr.…”

Di-(2-ethylhexyl) Phthalate (DEHP) and Uterine Histological Characteristics

“…DEHP is agonistic to PR (Sheikh et al 2016). DEHP upregulated uterine GnRH receptors and hypothalamic GnRH in pubertal rats (Liu et al, 2016). DEHP induces inflammation mediating peroxisome proliferator-activated receptor gamma (PPARγ) in cultured primary endometrial stroma cells without epithelial-mesenchymal transition (EMT) (Huang et al, 2016).…”

Impaired follicular development and endocrine disorders in female rats by prepubertal exposure to toxic doses of cadmium

“…These findings show that prepubertal exposure to Cd in juvenile and peripubertal period would affect the onset of puberty (Figures 2(a) and 3(a) and (b)). Changes in the timing of puberty onset are affected by many factors including heredity, nutrition, systemic diseases, endocrine hormone, psycho-mental factors, heavy metals, and EDCs (Liu et al, 2016; Louis et al, 2008; Yang et al, 2015), which would delay the onset of puberty through dysregulation of the HPG axis and normal steroidogenesis. The onset of puberty is highlighted by the augmentation of pulsatile GnRH secretion, which is the initiator of the HPG axis (Urbanski and Ojeda, 1987; Yang et al, 2015).…”