Endocrine-Disrupting Chemicals and the Effects of Distorted Epigenetics on Preeclampsia: A Systematic Review
Abstract
:1. Introduction
2. Methods
2.1. Selection Criteria
2.2. Search Strategy Description
2.3. Data Collection
2.4. Data Extraction
3. Results
3.1. Study Selection and Characteristics
3.2. PE and Its Association with EDCs
3.2.1. Perfluoroalkyl Compound Exposure
3.2.2. Phthalate Exposure
3.2.3. Phenolic Compound Exposure
3.3. Epigenetic Process Linked to PE
3.3.1. DNA Methylation
3.3.2. PE and miRNA Alteration
3.3.3. Effect of EDCs and Its miRNA Alteration in PE
3.3.4. Effect of EDCs and Genomic Imprinting
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Category | Criteria |
---|---|
Population | Preeclampsia patient group |
Exposure | One of the following endocrine disrupters (“Phthalates”, “PBDE”, “bisphenol A”, “triclosan”, “TCS”, “PFOS”, “PFOA”, “PFNA”) |
Comparison | Healthy mothers with patient groups |
Outcome | Epigenetic alterations including miRNAs, DNA methylation |
Study design | Observational studies (cohort, case–control, cross-sectional) |
PubMed | PubMed Central | ScienceDirect | ProQuest | CTD | EBSCOhost | Google Scholar (Hand Search) | |
---|---|---|---|---|---|---|---|
Preeclampsia OR Pre-Eclampsia OR eclampsia OR PE OR pregnancy-induced hypertension OR PIH OR gestational hypertension OR toxaemia of pregnancy OR edema proteinuria OR hypertension gestos | 99,469 | 462,776 | 123,843 | 48,871 | 103 | 164,222 | |
Endocrine disrupting chemicals OR EDC OR EDCs OR endocrine disruptors OR EDs OR Phthalates OR polybrominated diphenyl ether OR PBDE OR bisphenol A OR BPA OR triclosan OR TCS OR per fluorinated compounds OR perfluorooctanoate OR PFOS OR per fluorinated octanoic acid OR PFOA OR perfluoroalkyl OR PFA OR perfluoro nonanoic acid OR PFNA OR xenoestrogen | 100,313 | 421,370 | 119,334 | 47,755 | 895 | 14,482 | |
DNA methylation OR microRNAs OR miRNA OR miRs OR epigenetics | 315,176 | 513,992 | 152,976 | 26,128 | 985 | 1329 | |
Preeclampsia AND endocrine disrupting chemicals AND microRNAs | 2 | 145 | 58 | 2 | 1 | 1 | 6 |
Further screening | 103 | ||||||
After duplicates removed | 51 | ||||||
Qualitative synthesis | 29 |
Selection | Comparability | Outcome | |||||||
---|---|---|---|---|---|---|---|---|---|
No. | References | Were the Inclusion and Exclusion Criteria Applied to All Groups? | Were All the Studies Performed over the Same Time Period? | Were the Sample Size of All Groups Similar? | Were the Groups Age-Matched? | Level of Adjustment (Analysis/Design) | Were All the Studies Confident in the Exposure Characterization? | Were All the Studies Confident in the Outcome Assessment? | Did Authors Report Conflicts of Interest? |
1 | [16] | + | + | − | − | + | − | + | + |
2 | [17] | + | + | − | − | + | − | + | + |
3 | [18] | + | − | − | − | + | − | − | + |
4 | [4] | + | − | − | − | + | + | + | + |
5 | [19] | NR | NR | + | − | + | + | + | + |
6 | [20] | + | − | − | − | + | + | + | + |
7 | [3] | + | − | − | − | + | + | + | + |
8 | [21] | NR | NR | + | − | NR | NR | + | NR |
9 | [11] | + | − | − | − | + | − | + | + |
10 | [2] | + | − | − | − | + | + | + | + |
11 | [22] | NR | − | − | − | + | + | + | NR |
12 | [23] | NR | − | − | − | + | + | + | − |
13 | [24] | + | − | − | − | + | + | + | + |
14 | [25] | + | + | − | − | + | + | + | + |
15 | [26] | + | − | − | − | + | + | + | + |
16 | [27] | + | − | − | − | − | + | + | NR |
17 | [28] | − | − | − | − | + | + | + | − |
18 | [29] | + | − | − | − | + | + | + | + |
19 | [30] | + | − | − | − | + | + | + | − |
20 | [10] | + | − | − | − | + | − | + | + |
21 | [31] | + | NR | − | − | + | − | + | NR |
22 | [32] | + | − | − | − | + | − | + | + |
23 | [33] | + | − | + | − | + | − | + | + |
24 | [34] | + | − | − | − | + | + | + | + |
25 | [35] | + | − | + | − | + | − | + | + |
26 | [36] | + | − | + | − | + | − | + | + |
27 | [37] | + | − | − | − | + | + | + | + |
28 | [38] | + | − | − | − | + | + | + | + |
29 | [39] | + | − | + | − | + | − | + | + |
No. | Author | Sample Size | Sample/Methodology | Location | Exposure | Outcome |
---|---|---|---|---|---|---|
1 | [3] | 49/34 | Placenta/SPE-HPLC isotope dilution–tandem mass spectroscopy | USA | TP (total phthalate) concentration = 231 ng/mL. | Phthalates impact placental function by modulating the expression of critical placental genes through epigenetic regulation. |
2 | [2] | 42/644 | Plasma/LC system coupled with tandem mass spectrometry | China | Plasma concentrations of PFOA = 6.98 ng/mL, PFOS = 2.38 ng/mL, PFNA = 0.64 ng/mL, PFUA = 0.40 ng/mL, PFDA = 0.36 ng/mL, PFHxS = 0.16 ng/mL, PFDoA = 0.094 ng/mL, and PFBS = 0.047 ng/mL. | Investigates the association between prenatal PFAS exposure and hypertensive disorders of pregnancy (HDP) in humans. |
3 | [23] | 179 | Placenta/SPE-HPLC isotope dilution–tandem mass spectroscopy | United States | Phthalate metabolite concentrations: MECPP = 0.6 μg/L, MEHHP = 0.7 μg/L, MEOHP = 0.7 μg/L, MEHP = 1.2 μg/L, MCPP = 0.2 μg/L, MCOP = 0.7 μg/L, MCNP = 0.6 μg/L, MBzP = 0.3 μg/L, MiBP = 0.6 μg/L, MnBP = 0.6 μg/L, and MEP = 0.8 μg/L. Phenol concentrations: DCP = 0.2 μg/L, 2,5-DCP = 0.2 μg/L, BP-3 = 0.4 μg/L, BPA = 0.4 μg/L, BuPB = 0.2 μg/L, MePB = 1.0 μg/L, PrPB = 0.2 μg/L, and TCS = 2.3 μg/L. | miR-142-3p, miR15a-5p, and miR-185 are the three miRNAs significantly linked to phenol or phthalate levels influencing their expression in the placenta. |
4 | [25] | 73 | Serum/SPE-HPLC isotope dilution–tandem mass spectroscopy | Sweden | Serum concentrations of PFNA = 0.7 ng/mL, PFOA = 1.8 ng/mL, PFOS = 5.6 ng/mL, and PFHxS = 1.9 ng/mL. | Serum concentrations of PFNA, PFOA, and PFOS show an inverse association with kidney function; change is unrelated to parallel changes in eGFR and glomerular pore size. |
5 | [26] | 64/1155 | Placenta/SPE-HPLC isotope dilution–tandem mass spectroscopy | The Netherlands | Phthalate metabolite concentration = 0.19 ng/mL. | No consistent associations of early-pregnancy bisphenol and phthalate metabolite concentrations with maternal prenatal BP, placental hemodynamic outcomes, or gestational hypertensive disorders. |
6 | [28] | 11,737 | Serum/liquid chromatography–tandem mass spectrometry | USA | Serum concentrations of PFOA = 4 ng/mL. | No associations between estimated serum PFOA levels and adverse pregnancy outcomes other than possibly preeclampsia. |
7 | [29] | 891 | Plasma/HPLC system coupled with tandem mass spectrometry | Norway | PFOS concentration associated with cholesterol = 4.2 mg/dL. | Elevated HDL (high-density lipoprotein) is not an adverse outcome per se; elevated total cholesterol associated with PFASs during pregnancy could be of concern if causal. |
8 | [34] | 369 | Urine/isotope dilution HPLC coupled with tandem mass spectrometry | USA | Urine phthalate metabolite concentrations at 16 weeks gestation: ΣDBP (31 vs. 27 μg/g Cr), ΣDEHP (99 vs. 89 μg/g Cr), MCPP (2.5 vs. 2.7 μg/g Cr), MBzP (9.2 vs. 11.2 μg/g Cr), and MEP (139 vs. 187 μg/g Cr). | Maternal urinary (MBzP) phthalate concentrations may be associated with increased diastolic blood pressure and risk of pregnancy-induced hypertensive diseases. |
9 | [37] | 64/1709 | Serum/liquid chromatography-tandem mass spectrometry | Sweden | Serum levels of PFOS = 5.4 ng/mL, PFOA = 1.6 ng/mL, PFNA = 0.5 ng/mL, PFDA = 0.26 ng/mL, PFUnDA = 0.21 ng/mL, PFHxS = 1.32 ng/mL, PFHpA = 0.018 ng/mL (p = 0.06 for PFOS, p = 0.07 for PFOA, p = 0.25 for PFNA, p = 0.33 for PFDA, p = 0.77 for PFUnDA, p = 0.62 for PFHxS, and p = 0.83 for PFHpA). | Increasing serum levels of PFOS and PFNA during early pregnancy were associated with a clinically relevant risk of preeclampsia, adjusting for established confounders. |
10 | [38] | 373/125 | Placenta/GC tandem MS | China | Total PBDE (polybrominated diphenyl ether) concentration = 51.354 ng/g lw. | Changes in placental DNA methylation might be part of the underlying biological pathway between prenatal PBDE exposure and adverse fetal growth. |
11 | [24] | 18/22 | Urine/placenta | Mexico; US | Detection levels are not significant compared to normal non-diabetic women. However, phthalates and BPA urinary levels showed positive correlations between adjusted urinary MBzP levels and miR-16-5p expression levels (p < 0.05), and adjusted MEHP concentrations and miR-29a-3p expression levels (p < 0.05). | Serum levels of miRNAs associated with GDM (miR-9-5p, miR-16-5p, miR-29a-3p, and miR-330-3p) and urinary levels of phthalate metabolites (mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP), and mono(2-ethyl hexyl) phthalate (MEHP)) and bisphenol A in GDM and PE patients. |
No. | Age Group | Type of Study | Study Population | Sample Size (Case/Control) | Sample | Method | EDC | Epigenetic Mechanism | Pathway | Other Findings | References |
---|---|---|---|---|---|---|---|---|---|---|---|
a. Studies Reported on EDCs | |||||||||||
1 | Mean age of 32.2 | LifeCodes prospective birth cohort case–control study population | United States | 75/75 | Plasma | Online solid-phase extraction (SPE) coupled to high-performance liquid chromatography (HPLC) isotope dilution–tandem mass spectrometry (LC-MS-MS); angiogenic markers were analyzed. | PFOA and PFDA | - | - | PFOA and PFDA were found to be associated with late-onset preeclampsia and angiogenic biomarkers like SFlt-1 and PlGF. | [4] |
2 | 20–45 years | Cohort study | Sweden | 73 | Blood | PFASs were analyzed using LC-MS. | PFNA, PFOA, and PFOS | - | - | Serum concentration of PFNA, PFOA, and PFOS declined during pregnancy. | [25] |
3 | 28–35 years | Case–control | Sweden | 64/1709 | Blood | Serum was analyzed using LC-MS. | PFOA and PFNA | - | Toxicological pathways related to inflammation and oxidative stress. | PFOS and PFNA exposures were significantly associated with preeclampsia. | [37] |
4 | 20–45 years | Cross-sectional study | China | 42/644 | Umbilical cord blood | LC-MS. | PFBS | - | - | PFBS disrupts the regulation of estrogen levels. PFBS exposure associated with preeclampsia. | [2] |
5 | 20–44 years | Cohort study | Netherlands | 64/1155 | Urine | HPLC–T-MS analysis and sFlt-1 and PlGF concentrations were measured using an immune-electrochemoluminence assay. | Phthalates | - | - | Phthalates exposure elevate clinical associations with the sFlt-1/PlGF ratio. | [26] |
6 | 27–37 years | A nested case–control study | United States | 50/431 | Urine | BPA and phthalate concentrations were measured based on methods developed by the Centers for Disease Control (CDC). | BPA and Phthalate | - | - | Urinary BPA and phthalate concentrations are associated with preeclampsia. | [20] |
7 | 23–35 years | Cohort study | United States | 369 | Urine | The samples were analyzed by isotope dilution HPLC-T-MS. | MBzP | - | - | MBzP concentrations were associated with blood pressure-related complications. | [34] |
8 | 19–44 years | Cohort study | Norway | 891 | Blood | PFASs were analyzed using HPLC-T-MS. | PFAS | - | - | PFASs were positively associated with elevated cholesterol level. | [29] |
9 | 16–44 years | Cohort study | Norway | 466/510 | Blood | PFASs were measured using HPLC-T-MS. | PFAS | - | - | PFAS exposure was not strongly associated with preeclampsia. | [30] |
10 | 14–45 years | Cohort study | United States | 11,737 | Blood | PFOAs were analyzed using LC-T-MS. | PFOA | - | - | No associations between estimated serum PFOA levels and adverse pregnancy outcomes other than possibly preeclampsia. | [28] |
11 | 16–49 | The Agricultural Health Study | United States | 11,274 | From self-reported data | Regression analysis was performed on agricultural and pesticide exposure activities among farmers involved in pesticide application. | Pesticides | - | - | First-trimester residential and agricultural activities with potential exposure to pesticides were associated with both PIH and PE. | [27] |
b. Studies Reported on Epigenetics | |||||||||||
1 | 29–35 years | Cohort study | Canada | 58/21 | Placenta | RNA sequencing on the Illumina Hiseq2000 platform. | - | miR-210-5p | - | miR-210-5p was downregulated and the gene targets such as APLN and C3AR1 were downregulated in placental samples. | [18] |
2 | 28–31 years | Cohort study | China | 30/30 | Placenta | “TargetScan Human Release 7.2”. | - | miR-141-5p | p-MAPK1 and ERK1/2 signaling. | miR-141-5p has the potential to regulate ATF2, promoting the expression of phosphatase DUSP1, which in turn affects p-MAPK1 and ERK1/2 signaling, contrubuting to the development of preeclampsia. | [33] |
3 | A nested case–control study | Czech Republic | PE-21, IUGR-18/control-58 | Plasma | miRNA analysis using real-time PCR. | - | miR-516b-5p, miR-517-5p, miR-520a-5p, miR-525-5p, and miR-526a | Eph/ephrin signaling, calcium influx, phosphoinositide 3 (PI3) kinase, mitogen-activated protein (MAP) kinase, Src kinase, and Rho. | Abnormal levels of extracellular fetal DNA, mRNA transcripts, and circulating C19MC microRNAs (miR-516b-5p, miR-517-5p, miR-520a-5p, miR-525-5p, and miR-526a) have been associated with pregnancy complications. | [11] | |
4 | 29–35 years | Cohort study | Taiwan | 79/60 | Blood and placenta | qRT-PCR. | - | miR-346 and miR-582-3p | - | miR-346 and miR-582-3p were associated with preeclampsia, preterm delivery (PTM), and SGA. | [10] |
5 | - | Case–control | United States | 16/16 | Placenta | Placental mi-RNAs were analyzed by qRT-PCR. | - | miR-26a and miR-155 | TGF-ß pathway. | Genes within the TGF-ß pathway displayed increases in PE placenta and Cd-treated trophoblast, and its targets miR-26a and miR-155 were found to be significantly altered. | [19] |
6 | 29–37 years | Cohort study | Russia | 05/06 | Placenta | qPCR. | - | miR-135b, miR-98, and miR-4532 | Hypoxia pathways. | miR-135b and miR-98 were downregulated and miR-4532 was upregulated in placental samples. | [31] |
7 | 19–34 years | A case–control study | China | 31/14 | Placenta | miRNA expression using qPCR. | - | miR-517a/b and miR-517c | Tumor necrosis factor super family 15 (TNFSF15) signaling pathway, NF-kB and MAPK signaling pathways. | miR-517a/b and miR-517c were dysregulated in the placenta, which increased production of anti-angiogenic cytokines such as TNFSF15 and sFLT1. Several genes of miR-517a/b/c, including HOXA5, SEMA3A, TFAP2B, and PTK2B, play a role in cell invasions. | [17] |
8 | - | Case–control study | Turkey | 20/20 | Blood/ | miRNA expression using qPCR. | - | miR-210 and miR-152 | - | miR-210 and miR-152 were found to be altered in PE. | [21] |
9 | 19–27 years | Cohort study | United States | 124/125 | Blood | Illumina Human Methylation-27 Assay. | - | DNA methylation | - | Differential methylation of POMC, AGT, CALCA, and DDAH1 genes; CpG sites associated with preeclampsia. | [36] |
10 | 23–32 years | Case–control | Netherlands | 76/76 | Placenta | MassARRAY EpiTYPER assays. | - | DNA methylation | ErbB signaling pathway, p53-pathway, type-Ⅰ diabetes mellitus pathway. | 5hmC and 5mC changes may play a vital role in the development of late-onset preeclampsia. | [39] |
11 | 20–35 years | A prospective case–control study | United States | 31/14 | Placenta | DNA methylation using genome-wide Illumina Infinium Methylation 450 Bead Chip array. | - | DNA methylation | Placental gene pathways | Changes in CDH11, COL5A1, NCAM1, and TNF gene expression were associated with alteration in methylation which contributed to changes in the placenta. | [16] |
12 | 25–30 years | Case–control | United States | 14/14 | Blood | Illumina Human Methylation-27 Assay. | - | DNA methylation | Neuropeptide signaling pathway | Methylation changes were detected in the genes of maternal leukocyte DNA in preeclamptic pregnancies at the time of delivery. | [35] |
13 | 28–41 years | Cohort study | China | 30/32 | Placenta | Illumina Infinium HumanMethylation450 (450k) Bead Chip. | - | DNA methylation | - | Hypomethylated in the placental DNA methylome may lead to impaired function of de novo DNA methyltransferases, disrupting trophoblast turnover and potentially contributing to the development of PE. | [32] |
c. Studies Reported on EDCs and Epigenetic Changes | |||||||||||
1 | 22–32 years | Case–control | China | 124/125 | Umbilical cord | Serum was analyzed using liquid chromatography–tandem mass spectrometry. | PBDE | DNA methylation | - | HSD11B2/IGF2 methylation due to PBDE exposure was associated with the development of fetal growth retardation. | [38] |
2 | 24–45 years | Case–control study | Mexico City, Mexico | 18/22 | Urine | Urinary phthalate metabolites were analyzed using UPLC-MS/MS. miRNA expression was analyzed by qRT-PCR. | phthalate metabolites MBP, MiBP, MEHP, MBzP, and BPA | miR-9-5p, miR-16-5p, miR-29a-3p, and miR-330-3p | MAPK, insulin, TGF-β, and mTOR signaling pathways, glycolytic pathways. | Serum levels of miRNAs (miR-9-5p, miR-16-5p, miR-29a-3p, and miR-330-3p) were associated with GDM and PE. Urinary levels of the phthalate metabolites MBP, MiBP, MEHP, MBzP, and BPA were analyzed in GDM and PE patients. | [24] |
3 | 19–49 years | Cohort study | United States | 49/34 | Urine/placenta | Urinary phthalate metabolite concentrations using SPE-HPLC-T-MS. Placenta methylation using Illumina’s Infinium Human Methylation 850k BeadChip. | Phthalate | DNA methylation | ErB signaling pathway. | Phthalate exposure was associated with first-trimester DNA methylation changes associated with EGFR. | [3] |
4 | 27–37 years | Cohort study | United States | 179 | Placenta | Placental miRNAs were analyzed by qRT-PCR. | Phthalate and phenol | miR-185, miR-142-3p, miR15a-5p | Protein serine/threonine kinase, positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway, IGFR signaling pathway, PlGFR signaling pathway. | Urinary phthalate and phenol exposure were associated with alteration of miRNA (miR-185, miR-142-3p, miR15a-5p) expression. | [23] |
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Rani, B.U.; Vasantharekha, R.; Santosh, W.; Swarnalingam, T.; Barathi, S. Endocrine-Disrupting Chemicals and the Effects of Distorted Epigenetics on Preeclampsia: A Systematic Review. Cells 2025, 14, 493. https://doi.org/10.3390/cells14070493
Rani BU, Vasantharekha R, Santosh W, Swarnalingam T, Barathi S. Endocrine-Disrupting Chemicals and the Effects of Distorted Epigenetics on Preeclampsia: A Systematic Review. Cells. 2025; 14(7):493. https://doi.org/10.3390/cells14070493
Chicago/Turabian StyleRani, Balu Usha, Ramasamy Vasantharekha, Winkins Santosh, Thangavelu Swarnalingam, and Seetharaman Barathi. 2025. "Endocrine-Disrupting Chemicals and the Effects of Distorted Epigenetics on Preeclampsia: A Systematic Review" Cells 14, no. 7: 493. https://doi.org/10.3390/cells14070493
APA StyleRani, B. U., Vasantharekha, R., Santosh, W., Swarnalingam, T., & Barathi, S. (2025). Endocrine-Disrupting Chemicals and the Effects of Distorted Epigenetics on Preeclampsia: A Systematic Review. Cells, 14(7), 493. https://doi.org/10.3390/cells14070493