International Journal of Molecular Sciences

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24 pages, 13218 KiB

Open AccessArticle

Effects of Dibutylphthalate and Steroid Hormone Mixture on Human Prostate Cells

by Aldo Mileo, Teresa Chianese, Gianluca Fasciolo, Paola Venditti, Anna Capaldo, Luigi Rosati and Maria De Falco

Int. J. Mol. Sci. 2023, 24(18), 14341; https://doi.org/10.3390/ijms241814341 - 20 Sep 2023

Cited by 1 | Viewed by 1210

Abstract

Phthalates are a family of aromatic chemical compounds mainly used as plasticizers. Among phthalates, di-n-butyl phthalate (DBP) is a low-molecular-weight phthalate used as a component of many cosmetic products, such as nail polish, and other perfumed personal care products. DBP has toxic effects [...] Read more.

Phthalates are a family of aromatic chemical compounds mainly used as plasticizers. Among phthalates, di-n-butyl phthalate (DBP) is a low-molecular-weight phthalate used as a component of many cosmetic products, such as nail polish, and other perfumed personal care products. DBP has toxic effects on reproductive health, inducing testicular damage and developmental malformations. Inside the male reproductive system, the prostate gland reacts to both male and female sex steroids. For this reason, it represents an important target of endocrine-disrupting chemicals (EDCs), compounds that are able to affect the estrogen and androgen signaling pathways, thus interfering with prostate homeostasis and inducing several prostate pathologies. The aim of this project was to investigate the effects of DBP, alone and in combination with testosterone (T), 17β-estradiol (E2), and both, on the normal PNT1A human prostate cell-derived cell line, to mimic environmental contamination. We showed that DBP and all of the tested mixtures increase cell viability through activation of both estrogen receptor α (ERα) and androgen receptor (AR). DBP modulated steroid receptor levels in a nonmonotonic way, and differently to endogenous hormones. In addition, DBP translocated ERα to the nucleus over different durations and for a more prolonged time than E2, altering the normal responsiveness of prostate cells. However, DBP alone seemed not to influence AR localization, but AR was continuously and persistently activated when DBP was used in combination. Our results show that DBP alone, and in mixture, alters redox homeostasis in prostate cells, leading to a greater increase in cell oxidative susceptibility. In addition, we also demonstrate that DBP increases the migratory potential of PNT1A cells. In conclusion, our findings demonstrate that DBP, alone and in mixtures with endogenous steroid hormones, acts as an EDC, resulting in an altered prostate cell physiology and making these cells more prone to cancer transformation. Full article

(This article belongs to the Special Issue Environmental Determinants and Their Impact on Human Reproduction and Reproductive Immunology)

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31 pages, 8421 KiB

Open AccessArticle

Cocktails of NSAIDs and 17α Ethinylestradiol at Environmentally Relevant Doses in Drinking Water Alter Puberty Onset in Mice Intergenerationally

by Pascal Philibert, Stéphanie Déjardin, Mélissa Girard, Quentin Durix, Anne-Alicia Gonzalez, Xavier Mialhe, Mathieu Tardat, Francis Poulat and Brigitte Boizet-Bonhoure

Int. J. Mol. Sci. 2023, 24(6), 5890; https://doi.org/10.3390/ijms24065890 - 20 Mar 2023

Cited by 3 | Viewed by 2131

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinyl-estradiol (EE2) are among the most relevant endocrine-disrupting pharmaceuticals found in the environment, particularly in surface and drinking water due to their incomplete removal via wastewater treatment plants. Exposure of pregnant mice to NSAID therapeutic doses during the [...] Read more.

Non-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinyl-estradiol (EE2) are among the most relevant endocrine-disrupting pharmaceuticals found in the environment, particularly in surface and drinking water due to their incomplete removal via wastewater treatment plants. Exposure of pregnant mice to NSAID therapeutic doses during the sex determination period has a negative impact on gonadal development and fertility in adults; however, the effects of their chronic exposure at lower doses are unknown. In this study, we investigated the impact of chronic exposure to a mixture containing ibuprofen, 2hydroxy-ibuprofen, diclofenac, and EE2 at two environmentally relevant doses (added to the drinking water from fetal life until puberty) on the reproductive tract in F1 exposed mice and their F2 offspring. In F1 animals, exposure delayed male puberty and accelerated female puberty. In post-pubertal F1 testes and ovaries, differentiation/maturation of the different gonad cell types was altered, and some of these modifications were observed also in the non-exposed F2 generation. Transcriptomic analysis of post-pubertal testes and ovaries of F1 (exposed) and F2 animals revealed significant changes in gene expression profiles and enriched pathways, particularly the inflammasome, metabolism and extracellular matrix pathways, compared with controls (non-exposed). This suggested that exposure to these drug cocktails has an intergenerational impact. The identified Adverse Outcome Pathway (AOP) networks for NSAIDs and EE2, at doses that are relevant to everyday human exposure, will improve the AOP network of the human reproductive system development concerning endocrine disruptor chemicals. It may serve to identify other putative endocrine disruptors for mammalian species based on the expression of biomarkers. Full article

(This article belongs to the Special Issue Environmental Determinants and Their Impact on Human Reproduction and Reproductive Immunology)

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14 pages, 3242 KiB

Open AccessArticle

Bitter Taste Receptors and Endocrine Disruptors: Cellular and Molecular Insights from an In Vitro Model of Human Granulosa Cells

by Francesca Paola Luongo, Sofia Passaponti, Alesandro Haxhiu, Maryam Raeispour, Giuseppe Belmonte, Laura Governini, Livio Casarini, Paola Piomboni and Alice Luddi

Int. J. Mol. Sci. 2022, 23(24), 15540; https://doi.org/10.3390/ijms232415540 - 8 Dec 2022

Cited by 5 | Viewed by 1780

Abstract

Endocrine disrupting chemicals (EDCs) are compounds that interfere with the synthesis, transport and binding action of hormones responsible for reproduction and homeostasis. Some EDCs compounds are activators of Taste bitter Receptors, a subclass of taste receptors expressed in many extraoral locations, including sperm [...] Read more.

Endocrine disrupting chemicals (EDCs) are compounds that interfere with the synthesis, transport and binding action of hormones responsible for reproduction and homeostasis. Some EDCs compounds are activators of Taste bitter Receptors, a subclass of taste receptors expressed in many extraoral locations, including sperm and follicular somatic cells. This makes TAS2Rs attractive molecules to study and investigate to shed light on the effect of EDCs on female reproduction and fertility. This study aims to assess the effect of selected EDCs [namely Biochanin A (BCA), caffeine, Daidzein, Genistein and Isoflavone] on hGL5, an immortalized cell line exhibiting characteristics coherent with primary follicular granulosa cells. After demonstrating that this model expresses all the TAS2Rs (TAS2R3, TAS2R4, TAS2R14, TAS2R19, TAS2R43) specifically expressed by the primary human granulosa cells, we demonstrated that BCA and caffeine significantly affect mitochondrial footprint and intracellular lipid content, indicating their contribution in steroidogenesis. Our results showed that bitter taste receptors may be involved in steroidogenesis, thus suggesting an appealing mechanism by which these compounds affect the female reproductive system. Full article

(This article belongs to the Special Issue Environmental Determinants and Their Impact on Human Reproduction and Reproductive Immunology)

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9 pages, 984 KiB

Open AccessArticle

Increased Arterial Responsiveness to Angiotensin II in Mice Conceived by Assisted Reproductive Technologies

by Theo Arthur Meister, Rodrigo Soria, Afzal Dogar, Franz H. Messerli, Ariane Paoloni-Giacobino, Ludwig Stenz, Urs Scherrer, Claudio Sartori and Emrush Rexhaj

Int. J. Mol. Sci. 2022, 23(21), 13357; https://doi.org/10.3390/ijms232113357 - 1 Nov 2022

Cited by 5 | Viewed by 1385

Abstract

Since the first report in 1978, the number of individuals conceived by Assisted Reproductive Technologies (ART) has grown incessantly. In parallel, with the recent emergence of possible underlying mechanisms of ART-induced epigenetic changes in the renin-angiotensin system, the cardiovascular repercussions of ART in [...] Read more.

Since the first report in 1978, the number of individuals conceived by Assisted Reproductive Technologies (ART) has grown incessantly. In parallel, with the recent emergence of possible underlying mechanisms of ART-induced epigenetic changes in the renin-angiotensin system, the cardiovascular repercussions of ART in mice and human offspring (including arterial hypertension, vascular dysfunction, and cardiac remodeling) have become increasingly recognized. Here, we hypothesized that ART may increase arterial responsiveness to angiotensin II (ANG II) by epigenetically modifying the expression of its receptors. To test this hypothesis, we assessed the vasoconstrictor responsiveness to ANG II in isolated aortas from ART and control mice. We also examined ANG II receptor (ATR) type 1 and 2 expression and the promoter methylation of the At1aR, At1bR and At2R genes. We found that the vasoconstrictor response to ANG II was markedly increased in ART mice compared to controls. This exaggerated vasoconstrictor responsiveness in ART mice correlated with a significant increase in the ANG II receptor (ATR) type 1 to ATR type 2 protein expression ratio in the aorta; this was mainly driven by an increase in AT1R expression, and by hypomethylation of two CpG sites located in the At1bR gene promoter leading to increased transcription of the gene. We conclude that in mice, ART increase the vasoconstrictor response to ANG II in the aorta by epigenetically causing an imbalance between the expression of vasoconstrictor (AT1R) and vasodilator (AT2R) ANG II receptors. Unbalanced expression of AT1R and AT2R receptors seems to be a novel mechanism contributing to ART-induced arterial hypertension in mice. Full article

(This article belongs to the Special Issue Environmental Determinants and Their Impact on Human Reproduction and Reproductive Immunology)

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12 pages, 1368 KiB

Open AccessArticle

Endometrial Cells Acutely Exposed to Phthalates In Vitro Do Not Phenocopy Endometriosis

by Roberto Gonzalez-Martin, Andrea Palomar, Yassmin Medina-Laver, Alicia Quiñonero and Francisco Domínguez

Int. J. Mol. Sci. 2022, 23(19), 11041; https://doi.org/10.3390/ijms231911041 - 20 Sep 2022

Cited by 2 | Viewed by 1682

Abstract

Environmental factors that have been linked to an increased endometriosis risk include exposure to di-(2-ethylhexyl)-phthalate (DEHP), an endocrine disruptor. This study aims to investigate whether DEHP in vitro exposure in primary endometrial stromal cells (EnSC), primary endometrial epithelial cells (EnEC), and the human [...] Read more.

Environmental factors that have been linked to an increased endometriosis risk include exposure to di-(2-ethylhexyl)-phthalate (DEHP), an endocrine disruptor. This study aims to investigate whether DEHP in vitro exposure in primary endometrial stromal cells (EnSC), primary endometrial epithelial cells (EnEC), and the human endometrial adenocarcinoma cell line Ishikawa properly mimics alterations described in the eutopic endometrium of women with endometriosis. Primary EnSC and EnEC, isolated from six fertile egg donors, and Ishikawa cells were exposed to DEHP (0.1, 1, and 10 µM) and were assessed for viability, endometriosis markers (IL-6, VEGF-A, HOXA10, EZH2, and LSD1), steroid receptor gene expressions (ER-1, ER-2, PR-T, PR-B, and PGRMC1), and invasive capacity. Viability after 72 h of DEHP exposure was not significantly affected. None of the endometriosis markers studied were altered after acute DEHP exposure, nor was the expression of steroid receptors. The invasive capacity of EnSC was significantly increased after 10 µM of DEHP exposure. In conclusion, acute DEHP exposure in primary endometrial cells does not fully phenocopy the changes in the viability, expression of markers, or steroidal receptors described in endometriosis. However, the significant increase in EnSC invasiveness observed after DEHP exposure could be a link between DEHP exposure and increased endometriosis likelihood. Full article

(This article belongs to the Special Issue Environmental Determinants and Their Impact on Human Reproduction and Reproductive Immunology)

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26 pages, 4772 KiB

Open AccessArticle

Di-(2-ethylhexyl) Phthalate Triggers Proliferation, Migration, Stemness, and Epithelial–Mesenchymal Transition in Human Endometrial and Endometriotic Epithelial Cells via the Transforming Growth Factor-β/Smad Signaling Pathway

by Hwi Gon Kim, Ye Seon Lim, Seonyeong Hwang, Hye-Yoon Kim, Yuseok Moon, Yong Jung Song, Yong-Jin Na and Sik Yoon

Int. J. Mol. Sci. 2022, 23(7), 3938; https://doi.org/10.3390/ijms23073938 - 1 Apr 2022

Cited by 12 | Viewed by 2675

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is a frequently used plasticizer that may be linked to the development of endometriosis, a common gynecological disorder with a profound impact on quality of life. Despite its prevalence, vital access to treatment has often been hampered by a lack [...] Read more.

Di-(2-ethylhexyl) phthalate (DEHP) is a frequently used plasticizer that may be linked to the development of endometriosis, a common gynecological disorder with a profound impact on quality of life. Despite its prevalence, vital access to treatment has often been hampered by a lack of understanding of its pathogenesis as well as reliable disease models. Recently, epithelial–mesenchymal transition (EMT) has been suggested to have a significant role in endometriosis pathophysiology. In this study, we found that DEHP treatment enhanced proliferation, migration, and inflammatory responses, along with EMT and stemness induction in human endometrial and endometriotic cells. The selective transforming growth factor-β (TGF-β) receptor type 1/2 inhibitor LY2109761 reversed the DEHP-induced cell proliferation and migration enhancement as well as the increased expression of crucial molecules involved in inflammation, EMT, and stemness, indicating that DEHP-triggered phenomena occur via the TGF-β/Smad signaling pathway. Our study clearly defines the role of DEHP in the etiology and pathophysiological mechanisms of endometriosis and establishes an efficient disease model for endometriosis using a biomimetic 3D cell culture technique. Altogether, our data provide novel etiological and mechanistic insights into the role of DEHP in endometriosis pathogenesis, opening avenues for developing novel preventive and therapeutic strategies for endometriosis. Full article

(This article belongs to the Special Issue Environmental Determinants and Their Impact on Human Reproduction and Reproductive Immunology)

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Review

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24 pages, 1190 KiB

Open AccessReview

Estrogenic and Non-Estrogenic Disruptor Effect of Zearalenone on Male Reproduction: A Review

by András Balló, Kinga Busznyákné Székvári, Péter Czétány, László Márk, Attila Török, Árpád Szántó and Gábor Máté

Int. J. Mol. Sci. 2023, 24(2), 1578; https://doi.org/10.3390/ijms24021578 - 13 Jan 2023

Cited by 16 | Viewed by 2703

Abstract

According to some estimates, at least 70% of feedstuffs and finished feeds are contaminated with one or more mycotoxins and, due to its significant prevalence, both animals and humans are highly likely to be exposed to these toxins. In addition to health risks, [...] Read more.

According to some estimates, at least 70% of feedstuffs and finished feeds are contaminated with one or more mycotoxins and, due to its significant prevalence, both animals and humans are highly likely to be exposed to these toxins. In addition to health risks, they also cause economic issues. From a healthcare point of view, zearalenone (ZEA) and its derivatives have been shown to exert many negative effects. Specifically, ZEA has hepatotoxicity, immunotoxicity, genotoxicity, carcinogenicity, intestinal toxicity, reproductive toxicity and endocrine disruption effects. Of these effects, male reproductive deterioration and processes that lead to this have been reviewed in this study. Papers are reviewed that demonstrate estrogenic effects of ZEA due to its analogy to estradiol and how these effects may influence male reproductive cells such as spermatozoa, Sertoli cells and Leydig cells. Data that employ epigenetic effects of ZEA are also discussed. We discuss literature data demonstrating that reactive oxygen species formation in ZEA-exposed cells plays a crucial role in diminished spermatogenesis; reduced sperm motility, viability and mitochondrial membrane potential; altered intracellular antioxidant enzyme activities; and increased rates of apoptosis and DNA fragmentation; thereby resulting in reduced pregnancy. Full article

(This article belongs to the Special Issue Environmental Determinants and Their Impact on Human Reproduction and Reproductive Immunology)

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17 pages, 763 KiB

Open AccessReview

Iron Metabolism and Ferroptosis in Physiological and Pathological Pregnancy

by Yijun Zhang, Yun Lu and Liping Jin

Int. J. Mol. Sci. 2022, 23(16), 9395; https://doi.org/10.3390/ijms23169395 - 20 Aug 2022

Cited by 21 | Viewed by 5810

Abstract

Iron is a vital element in nearly every living organism. During pregnancy, optimal iron concentration is essential for both maternal health and fetal development. As the barrier between the mother and fetus, placenta plays a pivotal role in mediating and regulating iron transport. [...] Read more.

Iron is a vital element in nearly every living organism. During pregnancy, optimal iron concentration is essential for both maternal health and fetal development. As the barrier between the mother and fetus, placenta plays a pivotal role in mediating and regulating iron transport. Imbalances in iron metabolism correlate with severe adverse pregnancy outcomes. Like most other nutrients, iron exhibits a U-shaped risk curve. Apart from iron deficiency, iron overload is also dangerous since labile iron can generate reactive oxygen species, which leads to oxidative stress and activates ferroptosis. In this review, we summarized the molecular mechanism and regulation signals of placental iron trafficking under physiological conditions. In addition, we revealed the role of iron metabolism and ferroptosis in the view of preeclampsia and gestational diabetes mellitus, which may bring new insight to the pathogenesis and treatment of pregnancy-related diseases. Full article

(This article belongs to the Special Issue Environmental Determinants and Their Impact on Human Reproduction and Reproductive Immunology)

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