Prenatal bisphenol a and phthalate exposure are risk factors for male reproductive system development and cord blood sex hormone levels

Sunman, Birce; Yurdakök, Kadriye; Koçer-Gümüşel, Belma; Özyüncü, Özgür; Akbıyık, Filiz; Balcı, Aylin; Özkemahlı, Gizem; Erkekoğlu, Pınar; Yurdakök, Murat

doi:10.1016/j.reprotox.2019.05.065

Cited by 45 publications

(18 citation statements)

References 73 publications

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“…Among them, DEHP is widely distributed in the environment. DEHP and its metabolite MEHP have been classified as reproductive toxicants (Brehm, Rattan, Gao, & Flaws, 2018; Sunman et al, 2019). In this study, we proposed that exposure to MEHP could promote apoptosis and pyroptosis of HEMECs, which was required by the NLRP3 inflammasome.…”

Section: Discussionmentioning

confidence: 99%

“…Its metabolites are mainly mono (2‐ethylhexyl) phthalate (MEHP) (Kalo et al, 2019). A number of studies have shown that MEHP is closely related to various diseases like the immune (Stermer et al, 2017), respiratory (Rafael‐Vázquez, García‐Trejo, Aztatzi‐Aguilar, Bazán‐Perkins, & Quintanilla‐Vega, 2018), and reproductive systems (Sunman et al, 2019). Evidence from epidemiological studies suggests that females have unique exposure to MEHP due to the frequent application of various beauty products (such as perfume, lotion, and nail polish) (Al‐Saleh et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Exposure to mono (2‐ethylhexyl) phthalate facilitates apoptosis and pyroptosis of human endometrial microvascular endothelial cells through NLRP3 inflammasome

2020

J of Applied Toxicology

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Mono (2‐ethylhexyl) phthalate (MEHP) is a major metabolite of di (2‐ethylhexyl) phthalate (DEHP). This study aimed to observe the toxic effect of MEHP on human endometrial microvascular endothelial cells (HEMECs) and its potential molecular mechanism. HEMECs were exposed to different concentrations of MEHP (0, 50, 100, and 200 nM). Cell viability and apoptosis were assessed by cell counting kit‐8 (CCK‐8) and flow cytometry assays. Western blot was performed to examine the expression of apoptosis‐related proteins (Bcl‐2, Bax, and Caspase‐3). Moreover, the expression of pyroptosis‐related Caspase‐1 was detected by western blot and immunofluorescence assays. Lactate dehydrogenase (LDH) release levels were evaluated in HEMECs treated with MEHP and/or Caspase‐1 inhibitor Ac‐YVAD‐CHO. After exposure to MEHP, NLRP3 expression was examined by reverse transcription quantitative polymerase chain reaction (RT‐qPCR) and western blot. LDH release and apoptosis levels were tested in HEMECs induced by MEHP and/or siNLRP3. MEHP significantly induced cell viability and inhibited apoptosis for HEMECs, with a concentration‐dependent manner. Furthermore, Bcl‐2/Bax ratio was distinctly reduced and Caspase‐3 expression was increased in HEMECs after exposure to MEHP. Western blot and immunofluorescence results confirmed that MEHP markedly augmented Caspase‐1 expression in HEMECs. Furthermore, LDH release levels were fortified in HEMECs treated with MEHP, which were improved following cotreatment with Ac‐YVAD‐CHO. At the mRNA and protein levels, NLRP3 expression was prominently increased in HEMECs exposed to MEHP. NLRP3 knockdown markedly ameliorated the increase in LDH release and apoptosis induced by MEHP exposure in HEMECs. Our findings suggested that exposure to MEHP facilitates apoptosis and pyroptosis of HEMECs through NLRP3 inflammasome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exposure to mono (2‐ethylhexyl) phthalate facilitates apoptosis and pyroptosis of human endometrial microvascular endothelial cells through NLRP3 inflammasome

2020

J of Applied Toxicology

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“…In the Chinese study on anogenital distance, maternal urine BPA levels showed negative associations with boys' cord blood T levels and T/estradiol (E2) -ratio (83). In the Turkish study on anogenital distance in boys, cord blood levels of BPA, phthalates and reproductive hormones were studied (79). BPA levels were positively associated with E2 levels in cord blood, but no other significant associations between chemical and reproductive hormone levels were observed (79).…”

Section: Association Between Edc Exposure and Hormone Levels In Early Lifementioning

confidence: 99%

“…Some of the above mentioned studies on cryptorchidism or anogenital distance have suggested association between EDC exposure levels and reproductive hormone levels of boys in amniotic fluid, cord blood or in serum samples taken at 3 months of age (79,83,103,106,107,110,114,115,126,128,129). In Danish case-control studies on cryptorchidism, amniotic fluid DEHP and DiNP metabolite and PFOS levels associated positively with amniotic fluid testosterone (T) levels and negatively with amniotic fluid Insulin-like peptide 3 (INSL3) levels (114,115,128).…”

Section: Association Between Edc Exposure and Hormone Levels In Early Lifementioning

confidence: 99%

Endocrine Disrupting Chemicals and Reproductive Health in Boys and Men

2021

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Male reproductive health has declined as indicated by increasing rates of cryptorchidism, i.e., undescended testis, poor semen quality, low serum testosterone level, and testicular cancer. Exposure to endocrine disrupting chemicals (EDCs) has been proposed to have a role in this finding. In utero exposure to antiandrogenic EDCs, particularly at a sensitive period of fetal testicular development, the so-called ‘masculinization programming window (MPW)’, can disturb testicular development and function. Low androgen effect during the MPW can cause both short- and long-term reproductive disorders. A concurrent exposure to EDCs may also affect testicular function or damage testicular cells. Evidence from animal studies supports the role of endocrine disrupting chemicals in development of male reproductive disorders. However, evidence from epidemiological studies is relatively mixed. In this article, we review the current literature that evaluated relationship between prenatal EDC exposures and anogenital distance, cryptorchidism, and congenital penile abnormality called hypospadias. We review also studies on the association between early life and postnatal EDC exposure and semen quality, hypothalamic-pituitary-gonadal axis hormone levels and testicular cancer.

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“…7,8 Under certain conditions, DHP can migrate from plastic packaging materials to foods and drinking water, and dietary intake is the main source of human exposure to DHP. 9,10 Phthalates and phthalate metabolites have been detected in human blood, urine and semen, [11][12][13] and there is a growing concern about the possibility of phthalates harming human health. A number of epidemiological studies have shown that phthalates can cause endocrine disorders when they enter the body, they may also contribute to allergies, metabolic syndrome, and cardiovascular disease, all of which are associated with induction of oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Combining metabolomics with bioanalysis methods to investigate the potential toxicity of dihexyl phthalate

Song

Holck

et al. 2020

Environmental Toxicology

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Dihexyl phthalate (DHP) is one of the most commonly used phthalate esters in various plastic and consumer products. Human are inevitably exposed to DHPs. Although several animal and human experiments have revealed that DHP can cause multiple toxicities, few studies have previously assessed the effects of DHP exposure by liquid chromatography mass spectrometry (LC‐MS) analysis combine with molecular biology methods on human cells. Therefore, the purpose of our study was to investigate the effect of DHP on human cell metabolism by systems biology methods. In this study, U2OS cancer cells were treated with 10 μM DHP for metabolomics analysis and apoptosis analysis at indicate time. Metabolomic study of the metabolic changes caused by DHP in U2OS cells was performed for the first time using integrative liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry (LC‐Q‐TOF‐MS). To investigate the possible reason of fatty acids level altered by DHP, we measured some key fatty acid synthesis and oxidation‐related enzyme expression levels by quantitative real‐time PCR (Q‐PCR). Apoptotic cells were analyzed by flow cytometry and apoptosis‐related gene expressions were measured by Q‐PCR. 2′,7′‐Dichlorofluorescein diacetate (DCFH‐DA) staining was used to evaluate ROS content. Partial least squares‐discriminate analysis (PLS‐DA) clearly showed that significant differences in metabolic profiles were observed in U2OS cells exposed to DHP compared with controls. A total of 58 putative metabolites in electrospray ionization source (ESI) + mode and 32 putative metabolites in ESI‐mode were detected, the majority of the differential metabolites being lipids and lipid‐like molecules. Among them, the altered fatty acids level corresponded to expression levels of genes encoding enzymes related to fatty acids synthesis and oxidation. Moreover, DHP induced reactive oxygen species (ROS) accumulation, promoted cell apoptosis and inflammation, and resulted in a significant increase in apoptosis and inflammation‐related gene expression levels compared with controls. In summary, our results suggested that metabolomics combined with molecular bioanalysis methods could be an efficient tool to assess toxic effects, which contribute to explore the possible cytotoxicity mechanisms of DHP, and provide a basis for further research.

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Prenatal bisphenol a and phthalate exposure are risk factors for male reproductive system development and cord blood sex hormone levels

Cited by 45 publications

References 73 publications

Exposure to mono (2‐ethylhexyl) phthalate facilitates apoptosis and pyroptosis of human endometrial microvascular endothelial cells through NLRP3 inflammasome

Exposure to mono (2‐ethylhexyl) phthalate facilitates apoptosis and pyroptosis of human endometrial microvascular endothelial cells through NLRP3 inflammasome

Endocrine Disrupting Chemicals and Reproductive Health in Boys and Men

Combining metabolomics with bioanalysis methods to investigate the potential toxicity of dihexyl phthalate

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