The impact of phthalate on reproductive function in women with endometriosis

Abstract

Background: Endometriosis is a common gynecological condition in which stromal or glandular epithelium is implanted in extrauterine locations. Endometriosis causes detrimental effects on the granulosa cells, and phthalate interferes with the biological and reproductive function of endometrial cells at a molecular level.

Methods: This article retrospectively reviewed the studies on phthalate exposure and its relationship with endometriosis. A literature search was performed for scientific articles using the keywords "phthalate and endometriosis," "endometriosis and granulosa cells," "phthalate and granulosa cells," and "phthalates and endometrial cells."

Results: Endometriosis can affect cytokine production, steroidogenesis, cell cycle progression, expression of estrogen receptor-α (ER-α)/progesterone receptor (PR), and cause endoplasmic reticulum stress, senescence, apoptosis, autophagy, and oxidative stress in the granulosa cells. Mono-n-butyl phthalate (MnBP) alters the expression of cytokines, cell cycle-associated genes, ovarian stimulation, steroidogenesis, and progesterone production. Several in vitro studies have demonstrated that phthalate caused inflammation, invasion, change in cytokines, increased oxidative stress, viability, resistance to hydrogen peroxide, and proliferation of endometrial cells.

Conclusion: This might provide new insights about the impact of phthalate on the pathogenesis of endometriosis and its consequences on the ovarian function.

Keywords: endometrial cells; endometriosis; granulosa cells; phthalate; reproductive function.

FIGURE 1

The potential effects of endometriosis on granulosa cells. Endometriosis might affect steroidogenesis (aromatase, StAR, 3β‐HSD), cytokine production (IL6, IL‐8, IL‐12, TNF‐ α), cell cycle progression, ER‐α/ PR, oxidative stress, ER stress, apoptosis, senescence, and autophagy in granulosa cells. The granulosa cells in women with endometriosis showed increased oxidative stress, which induced DNA damage, and decreased the mitochondrial membrane potential and ATP production and induced apoptosis. The increased TNF‐α activated NF‐κβ to decrease the telomerase activity and hTERT. TNF‐α also induced extrinsic and intrinsic apoptosis pathway and decreased survivin expression. The increased oxidative stress in the granulosa cells in women with endometriosis stimulated senescence and apoptosis through ER stress. StAR, steroidogenic acute regulatory protein; 3β‐HSD, 3β‐hydroxysteroid dehydrogenase; IL‐6, interleukin‐6; IL‐8, interleukin‐8; IL‐12, interleukin‐12; TNF‐α, tumor necrosis factor α; ER‐α, estrogen receptor‐ α ; PR, progesterone receptor; NF‐κB, nuclear factor‐κB.; hTERT, human telomerase reverse transcriptase, ER stress, endoplasmic reticulum stress; BECN1, beclin‐1. This figure was created with BioRender.com

FIGURE 2

Potential mechanisms of MnBP on human granulosa cells. A high dose of MnBP, it stimulates IL‐1β and TNF‐α cytokine expression. MnBP also affects the G2/M phase of mitosis and spindle assembly checkpoint, including BIRC5, BUB1, CDC20, and cyclin B1 gene expression. These changes cause decrease in AMH, inhibin B, StAR, and P450scc, which affect ovarian stimulation and steroidogenesis. The affected gene expressions result in poor health of the cells. A low dose of MnBP stimulated NF‐κB binding to vimentin promoter and induced progesterone production. MnBP, Mono‐n‐butyl phthalate; IL‐1β, interleukin‐1β; TNF‐α, tumor necrosis factor α; BIRC5, baculoviral inhibitor of apoptosis repeat‐containing 5; BUB1B, budding uninhibited by benzimidazoles 1 homolog beta, mitotic checkpoint serine/threonine kinase beta; CDC20, cell division cycle 20; AMH, anti‐Mullerian hormone; StAR, steroidogenic acute regulatory protein; P450ssc, cytochrome cholesterol side‐chain cleavage enzyme; NF‐κB, nuclear factor‐κB. This figure was created with BioRender.com

FIGURE 3

The effect of phthalates on endometrial cells. After phthalate stimulation, the endometrial cells showed inflammation, invasion, change of cytokines, increased oxidative stress, cell viability, resistance to hydrogen peroxide, and proliferation. The inflammatory effects stimulated the secretion of PGF2‐α, Pak‐4, PPARγ, ICAM‐1, COX2, cytokine (IL‐1β and IL‐8), and inhibited the secretion of PGE2. Phthalate also increased ROS generation and decreased the expression of SOD, GPX, HO, and CAT. In DEHP‐treated mice, the endometrial cell might show increased migration through MMP‐2 and MMP‐9. Increased ER‐α/PR activated p‐ERK/p‐p38 and NF‐κB. Exposure to phthalate induced endometrial cell viability, resistance to hydrogen peroxide and proliferation. PGF2‐α, prostaglandin F2‐α; IL‐1β, interleukin‐1β; IL‐8, interleukin‐8; Pak‐4, p21‐acticvated kinase‐4; PPARγ, peroxisome proliferator‐activated receptor‐γ; ICAM‐1, intercellular cell adhesion molecule‐1; COX2, cyclooxygenase‐2; prostaglandin E2, PGE2. ROS, reactive oxygen species; SOD, superoxide dismutase, GPX, glutathione peroxidase; HO, heme oxygenase; CAT, catalase; MMP2, matrix metalloproteinase‐2; MMP9, matrix metalloproteinase‐9; ER‐α, estrogen receptor‐α; PR, progesterone receptor; NF‐κB, nuclear factor‐κB. This figure was created with BioRender.com