Reproductive toxicology of environmental endocrine-disrupting chemicals in women: a cohort study protocol.

Introduction: Epidemiological evidence over the last few decades has consistently shown that exposure to endocrine-disrupting chemicals (EDCs) is associated with adverse reproductive health outcomes, including male and female infertility, poor-pregnancy outcomes, and increased risk of diseases in childhood and beyond. To investigate the effects of EDCs and lifestyle on all aspects of reproduction (including early oocyte development, fertilization, embryo development, embryo implantation, abortion, and preterm birth). Methods: We performed this cohort study on patients receiving in vitro fertilization (IVF) treatment. Biological samples including urine, serum, follicular fluid, semen, fetal tissue, decidua, and placenta, were obtained. Results: By studying the correlations between reproductive outcomes and environmental pollutant exposure and lifestyle, we determined the toxicological mechanisms and health effects of EDCs on female reproductive health. We found that higher concentrations of per- and polyfluoroalkyl substances were correlated with polycystic ovary syndrome (PCOS). Using specific biomarkers, we also detected the concentrations of organophosphorus flame retardants (OPFRs) in urine and found that OPFRs may disrupt hormone homeostasis. Discussion: All of these results reveal EDCs may disrupt female reproduction.

Influence of targeted nursing-guided bladder filling on embryo transfer outcomes and patient comfort: A prospective open randomized controlled study.

BACKGROUND: The success of assisted pregnancy relies heavily on the effectiveness of the embryo transfer process. Currently, embryo transfer is typically conducted with the assistance of abdominal ultrasound. OBJECTIVE: The primary aim of this study was to evaluate the influence of targeted nursing interventions on the embryo transfer procedure, its impact on pregnancy outcomes, and the level of patient comfort concerning bladder management throughout the procedure. METHODS: A total of 247 patients who underwent embryo transfer at the Reproductive Center of Peking University People's Hospital from December 2019 to August 2020 were included in this study. These patients were categorized into two groups: the control group (n= 124) and the experimental group (n= 123). Within the control group, patients received conventional preoperative education, whereas those within the experimental group were subjected to targeted nursing interventions. Furthermore, patients in the experimental group were furnished with explicit instructions pertaining to the volume and timing of water intake. Multiple factors were assessed in this study, encompassing bladder filling, the quality of uterine imaging, the utilization of assistive devices during the surgical procedure, and pregnancy outcomes. Additionally, a post-operative questionnaire was administered to both groups to gauge their comfort levels regarding urinary retention. RESULTS: Following the targeted nursing intervention, ultrasound scans indicated an increase in bladder depth (5.91 ± 1.76 vs. 5.40 ± 1.61, P= 0.02), resulting in clearer endometrial imaging (96.74% vs. 88.71%, P= 0.02). Additionally, the experimental group reported significantly higher levels of comfort with urine retention (P= 0.01) compared to the control group, and these differences held statistical significance. Furthermore, the pregnancy rate in the experimental group was greater than that in the control group (52.85% vs. 50.8%, P> 0.05). CONCLUSION: Based on the premise that pregnancy rates remain unaffected, the implementation of targeted nursing care has the potential to augment bladder filling, enhance the quality of endometrial imaging, reduce the requirement for instrument-assisted embryo transfers, and notably enhance the comfort of patients in relation to urine retention.

Effects of letrozole co-treatment on the cumulative live-birth rate among normal responders in gonadotropin-releasing hormone antagonist cycles.

Studies have shown that letrozole cotreatment can improve clinical outcomes in high and poor responders in GnRH-antagonist protocol. However, whether letrozole is also beneficial to normal responders is not known. To investigate the clinical value of letrozole cotreatment during ovarian stimulation in vitro fertilization for normal ovarian reserve patients who were treated with the GnRH antagonist protocol, we conducted a retrospective study that based data from 1 January to 31 December 2017 for all IVF-ICSI GnRH-antagonist protocols. A total of 252 women who aged <40 years, FSH <10 IU/L on day 3 and antral follicle counting (AFC) >6 were included in the analysis (96 in the letrozole group and 156 in the no-letrozole group). The cumulative live-birth rate was calculated as the first live birth achieved after all cycles having an embryo transfer (cycles using fresh embryos and frozen-thawed embryos) among both groups. The initial gonadotropin (Gn) dosage and total Gn dosage were significantly lower and the number of days of Gn treatment was significantly fewer in the letrozole group than the non-letrozole group (p < 0.05). There were also significant between-group differences in luteinizing hormone, estradiol, and progesterone concentrations; and the number of metaphase II oocytes on the day of human chorionic gonadotropin treatment (p < 0.05). There was a significant difference in the implantation rate between the two groups that the letrozole group higher than the non-letrozole group (39.79 vs. 27.96%, p = 0.006), but there was no significant difference in the cumulative live-birth rate. The combination of letrozole with a GnRH antagonist may have no effect on the clinical pregnancy rate or cumulative live-birth rate in patients with a normal ovarian reserve. However, letrozole may increase the rate of embryo implantation and may reduce the requirement for exogenous gonadotrophins and, consequently, the cost of an IVF treatment cycle. In addition, the decreased estradiol level in the ovarian simulation by letrozole supports letrozole can be a safe solution for fertility preservation in estrogen-related cancer patients.

Exposure assessment of aryl-organophosphate esters based on specific urinary biomarkers and their associations with reproductive hormone homeostasis disruption in women of childbearing age.

The effects of aryl-organophosphate esters (aryl-OPEs) on female reproduction health are still unclear owing to the lack of specific exposure biomarkers. Here, we analyzed the hydroxylated metabolites of three aryl-OPEs (phenyl diphenyl phosphate [TPhP], 2-ethylhexyl diphenyl phosphate [EHDPP], and tricresyl phosphate [TCrP]) and diphenyl phosphate (DPhP) in urine samples from 913 women of childbearing age, and explored the association between exposure to the aryl-OPEs and reproductive hormone levels. The detection frequencies of 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), phenyl di-p-tolyl phosphate (4-OH-MDTP), and 4-hydroxyphenyl diphenyl phosphate (4-OH-TPhP) were 94.6 %, 93.3 %, and 84.2 %, respectively. Multivariate linear regression analyses revealed that the quartiles of 4-OH-TPhP were positively associated with the progesterone (P4) level (p-trend = 0.008), and the P level in the highest quartile of 5-OH-EHDPP was 7.2 % (95 % CI, 5.7 % to 8.7 %) higher than that in the lowest quartile. The 17ß-estradiol levels in the highest quartiles of 4-OH-TPhP and 5-OH-EHDPP were 15.0 % (95 % CI, 13.7 % to16.1 %) and 5.9 % (95 % CI, 15.7 % to 16.1 %) lower than those in the lowest quartiles, respectively. The anti-Müllerian hormone level linearly increased across the quartiles of 4-OH-MDTP (p-trend = 0.036), and the follicle-stimulating hormone exhibited the opposite trend (p-trend = 0.0047). These results indicate that aryl-OPEs may disrupt hormone homeostasis using their specific biomarkers and may negatively affect female reproduction.

Effect of Dual Trigger In Vitro Fertilization and Intracytoplasmic Sperm Injection During the Gonadotropin-releasing Hormone-Antagonist Cycle on Final Oocyte Maturation and Cumulative Live Birth Rate in Women with Diminished Ovarian Reserve.

OBJECTIVE: It is well known that a dual trigger treatment can improve clinical outcomes of in vitro fertilization (IVF) in high or normal ovarian responders. However, it is not clear whether dual triggering also benefits patients with diminished ovarian reserve (DOR). The aim of this study was to investigate whether a dual trigger treatment of gonadotropin-releasing hormone (GnRH) agonist combined with human chorionic gonadotropin (hCG) for final follicular maturation improves the cumulative live birth rate (CLBR) during the GnRH-antagonist cycle in patients with DOR. METHODS: This retrospective study included patients with DOR who received a GnRH-antagonist protocol during IVF and intracytoplasmic sperm injection (IVF-ICSI) cycles at Peking University People's Hospital from January 1, 2017 through December 31, 2017. Oocyte maturation was triggered by GnRH combined with hCG (n=110) or hCG alone (n=71). Embryos were transferred on the third day after oocyte retrieval or during a subsequent freeze-thaw cycle. Patients were followed up for 3 years. RESULTS: The dual trigger treatment did not affect CLBR, which is an overall determinant of the success rate of assisted reproductive technology (ART). Women in the dual trigger group had significantly higher rates of fertilization than those in the hCG group (90.1% vs. 83.9%, P=0.040). CONCLUSION: Dual trigger with GnRH agonist and hCG did not improve CLBR in patients with DOR, but did slightly improve fertilization rate, oocyte count, and embryo quality.

Screening of Organophosphate Flame Retardants with Placentation-Disrupting Effects in Human Trophoblast Organoid Model and Characterization of Adverse Pregnancy Outcomes in Mice.

BACKGROUND: Abnormal placental development may result in adverse pregnancy outcomes and metabolic diseases in adulthood; however, it remains unknown whether and how xenobiotics affect human placentation. OBJECTIVES: This study aimed to screen and identify placentation-disrupting chemicals in commonly used organophosphate flame retardants (OPFRs) and, if identified, to investigate potential adverse effects on placentation in relation to adverse pregnancy outcomes and metabolic disorder in offspring in mice. METHODS: We devised a high-throughput immunofluorescence screening assay based on human trophoblast organoids and used it to screen OPFRs that inhibit the proliferation of organoids. One identified chemical was assessed for its effects on placentation by evaluating villous cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts using immunofluorescence and a mitochondrial stress test after 2 d of exposure. A 10-d exposure study was further performed to observe the dynamic effect of the OPFR on the structure of the organoids. RNA-sequencing and western blotting experiments were performed to explore the associated pathways, and a potential binding protein was identified by immunoprecipitation and in vitro kinase activity assays. Animal studies were performed to determine whether the findings in organoids could be replicated in mice and to observe adverse pregnancy outcomes. RESULTS: The proliferation of organoids exposed to three aryl-OPFRs was significantly lower than the proliferation of control organoids. Further analysis demonstrated that one such chemical, 2-ethylhexyl-diphenyl phosphate (EHDPP), disrupted placentation in organoids. Mechanistically, EHDPP interfered with insulin-like growth factor 1 receptor (IGF1R) to inhibit aerobic respiration. Mice exposed to EHDPP at a physiological human concentrations exhibited immature and mature placental disorders, which correlated with fetal growth restriction, implantation failure, stillbirth, and impaired glucose tolerance. CONCLUSIONS: The human trophoblast organoid model showed that the commonly used OPFRs disrupted placentation via IGF1R, indicating that its use may contribute to adverse pregnancy outcomes and metabolic disorders in offspring. https://doi.org/10.1289/EHP10273.

A Premature Rise of Luteinizing Hormone Is Associated With a Reduced Cumulative Live Birth Rate in Patients ≥37 Years Old Undergoing GnRH Antagonist In Vitro Fertilization Cycles.

This is a retrospective cohort study included 1021 patients underwent a flexible GnRH antagonist IVF protocol from January 2017 to December 2017 to explore the effect of a premature rise in luteinizing hormone (LH) level on the cumulative live birth rate. All patients included received the first ovarian stimulation and finished a follow-up for 3 years. A premature rise in LH was defined as an LH level >10 IU/L or >50% rise from baseline during ovarian stimulation. The cumulative live birth rate was calculated as the number of women who achieved a live birth divided by the total number of women who had either delivered a baby or had used up all their embryos received from the first stimulated cycle. In the advanced patients (≥37 years), the cumulative live birth rate was reduced in patients with a premature rise of LH (ß: 0.20; 95% CI: 0.05-0.88; p=0.03), compared to patients (≥37 years) without the premature LH rise. The incidence of premature LH rise is associated with decreased rates of cumulative live birth rate in patients of advanced age (≥37 years) and aggravated the reduced potential of embryos produced by the advanced age, not the number of embryos.

Association between Low House Cleaning Frequency, Cough and Risk of Miscarriage: A Case Control Study in China.

This study investigated the association between house cleaning frequency and the risk of miscarriage in a case control sample of Chinese population. We recruited 59 pregnant women with clinical pregnancy loss as cases and 122 women who chose to conduct induced abortion as controls. All participants were aged 20~40 years and completed a questionnaire of lifestyle exposure with a trained nurse. The effect of frequency of cleaning up on risk of miscarriage was estimated using multivariable logistic regressions, adjusting for potential confounders. In the present study, it was shown that house cleaning of less than twice per week was significantly associated with cough during day or night with odds ratio (OR) of 2.97 (95% CI: 1.36~6.75, p = 0.007), and cough during day or night was significantly associated with risk of miscarriage with OR of 2.69 (95% CI: 1.22~6.02, p = 0.014). Thus, house cleaning of less than twice per week was statistically significantly associated with miscarriage with OR of 3.05 (95% CI: 1.51~6.31, p = 0.002). We found that females who have their house cleaned less than twice per week are at elevated risk for miscarriage. Therefore, the home of pregnant woman should be cleaned at least twice per week in order to avoid miscarriage.

Effect of a "Dual Trigger" Using a GnRH Agonist and hCG on the Cumulative Live-Birth Rate for Normal Responders in GnRH-Antagonist Cycles.

"Dual triggering" for final oocyte maturation using a combination of a gonadotropin-releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG) can improve clinical outcomes in high responders during in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) GnRH-antagonist cycles. However, whether this dual trigger is also beneficial to normal responders is not known. We retrospectively analyzed the data generated from 469 normal responders from 1 January to 31 December 2017. The final oocyte maturation was undertaken with a dual trigger with a GnRHa combined with hCG (n = 270) or hCG alone (n = 199). Patients were followed up for 3 years. The cumulative live-birth rate was calculated as the first live birth achieved after all cycles having an embryo transfer (cycles using fresh embryos and frozen-thawed embryos) among both groups. Women in the dual-trigger group achieved a slightly higher number of oocytes retrieved (11.24 vs. 10.24), higher number of two-pronuclear (2PN) embryos (8.37 vs. 7.67) and a higher number of embryos available (4.45 vs. 4.03). However, the cumulative live-birth rate and the all-inclusive success rate for assisted reproductive technology was similar between the two groups (54.07 vs. 59.30%). We showed that a dual trigger was not superior to a hCG-alone trigger for normal responders in GnRH-antagonist cycles in terms of the cumulative live-birth rate.

Association between phthalate exposure and risk of spontaneous pregnancy loss: A systematic review and meta-analysis.

Numerous studies suggested that phthalates might be associated with increased risk of spontaneous pregnancy loss. However, these results were conflicting and inconclusive. Thus we performed this systematic review and meta-analysis to assess the relationship between phthalate exposure and risk of pregnancy loss. We searched PubMed, EMBASE, Web of Science and major Chinese literature databases for studies investigating phthalates and spontaneous pregnancy loss. Pooled odds ratio (OR) with 95% confident interval (CI) were calculated for risk estimate. A total of 8 studies involving 4713 participants (including 651 cases and 4062 controls) were enrolled in the present meta-analysis. Our pooled results showed that spontaneous pregnancy loss was associated with higher urinary levels of monobutyl phthalate (MBP) (OR: 1.34, 95% CI: 1.04-1.72), mono(2-ethylhexyl) phthalate (MEHP) (OR: 1.57, 95% CI: 1.29-1.90), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (OR: 1.59, 95% CI: 1.23-2.07) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) (OR: 1.47, 95% CI: 1.15-1.89). Indirect estimate of di-2-ethylhexyl phthalate (DEHP) levels, which were pooled from molar sum of urinary DEHP metabolites and hair DEHP, were also correlated with elevated risk of spontaneous pregnancy loss (OR: 1.79, 95% CI: 1.27-2.53). No significant association was found regarding urinary concentrations of monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP) or mono(2-ethyl-5-carboxypentyl) phthalate (MECPP). Our findings indicate that phthalate exposure might be a risk factor for spontaneous pregnancy loss. Given indirect estimate of phthalate exposure by evaluating its metabolite levels, our results should be interpreted with caution.

Nontargeted identification of per- and polyfluoroalkyl substances in human follicular fluid and their blood-follicle transfer.

The female reproductive toxicity of per- and polyfluoroalkyl substances (PFAS) has raised concerns, but knowledge about their human preconception exposure is limited. In this study, 15 emerging PFAS were identified in follicular fluid samples from healthy women by using high-resolution mass spectrometry, and Cl-substituted perfluoroalkyl ether sulfonates (Cl-PFESAs) including 4:2, 5:2, 6:2, and 8:2 Cl-PFESAs, 4:4 C8 perfluoroalkyl ether sulfonate (PFESA), C8 perfluoroalkyl ether carboxylate (PFECA), and C8 polyether PFECA (Po-PFECA) were detected in over 50% of 28 follicular fluid samples. Ten legacy PFAS were also detected, and the geometric mean concentration of PFOS was the highest (4.82 ng/mL), followed by PFOA (4.60 ng/mL), 6:2 Cl-PFESA (1.09 ng/mL), PFHxS (0.515 ng/mL), PFNA (0.498 ng/mL), and C8 PFECA (0.367 ng/mL). The blood-follicle transfer efficiencies for PFCAs decreased with increasing chain length (0.96 for PFHpA, 0.56 for PFTriDA), and the transfer efficiencies of C8 PFECA (0.78) was significantly higher than that of PFOA (0.76). The transfer efficiencies of 4:2 Cl-PFESA (0.73), 6:2 Cl-PFESA (0.75) and 8:2 Cl-PFESA (0.91) were significantly higher than that (0.70) of PFOS (p = 0.028, 0.026 and 0.002, respectively). This study constitutes the first report of the human oocyte exposure to emerging PFAS and their blood-follicle transfer abilities.

Organophosphorus Flame Retardants in Pregnant Women and Their Transfer to Chorionic Villi.

The potential for prenatal exposure has recently raised concerns over the health risks of endocrine disruptors; however, knowledge about human prenatal exposure to organophosphorus flame retardants (OPFRs) is lacking. In this study, 2-ethylhexyl diphenyl phosphate (EHDPP), tributyl phosphate (TBP), triphenyl phosphate (TPHP), and tris(2-chloroethyl) phosphate (TCEP) were detected in the majority of chorionic villus samples, with median concentrations of 13.6, 18.8, 11.1, and 0.51 ng/g of dry weight (dw), respectively, significantly higher than those in the matching maternal decidua samples (5.96, 10.8, 1.44, and 0.26 ng/g of dw, respectively). The ratios of concentrations in chorionic villi (containing embryos) to those in maternal deciduae (CMRs) were 4.17, 3.82, 2.81, and 2.00 for EHDPP, TPHP, TBP, and TCEP, respectively, which correlated with their log Kow values (p = 0.003). The results of transthyretin (TTR) binding assays indicated that the stronger the binding ability to TTR, the higher the CMRs. The median concentrations of the metabolites diphenyl phosphate (DPHP), dibutyl phosphate (DBP), and bis(2-chloroethyl) phosphate (BCEP) were 4.11, 429, and 157 ng/g of dw in chorionic villi, higher than those in deciduae (1.64, 181, and 25.4 ng/g of dw, respectively). The ratios of DPHP/TPHP and DPHP/EHDPP were 0.20 and 0.43 in chorionic villi and 1.24 and 2.03 in deciduae, respectively, much lower than those of DBP/TBP and BCEP/TCEP (20.9 and 165.6 in chorionic villi and 13.1 and 35.3 in deciduae, respectively), suggesting that the difference in metabolism between the deciduae and chorionic villi would affect their maternal transfer.

Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast invasion via the PPARγ pathway.

Concerns over the adverse reproductive outcomes in human have been raised, more evidence including the underlying mechanism are required. Since extravillous trophoblast (EVT) invasion is an important physiological step during early development, the effects of mono-2-ethylhexyl phthalate (MEHP), the bioactive metabolite of DEHP, on EVT invasion were investigated using Matrigel-coated transwell chambers and cell line HTR-8/SVneo. In the transwell-based invasive assay, MEHP exposure inhibited EVT invasion as judged by decreased invasion index. Further analysis showed that MEHP exposure significantly inhibited the activity of matrix metalloproteinase-9 (MMP-9), which is an important positive regulator of EVT invasion. Meanwhile, the protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), one key negative regulator of EVT invasion, were upregulated by MEHP treatment. Finally, inactivation of PPARγ pathway by either PPARγ inhibitors or PPARγ shRNA knockdown rescued the MEHP-induced inhibited invasion of HTR-8/SVneo cells, which is accompanied by the recovery of inhibited MMP-9 expression. The present study provides the evidence that MEHP exposure inhibits trophoblast invasion via PPARγ at concentrations comparable to those found in humans, which provides an insight in understanding the mechanisms of DEHP-associated early pregnancy loss.

Activation of Peroxisome Proliferator-Activated Receptor Gamma and Disruption of Progesterone Synthesis of 2-Ethylhexyl Diphenyl Phosphate in Human Placental Choriocarcinoma Cells: Comparison with Triphenyl Phosphate.

2-Ethylhexyl diphenyl phosphate (EHDPP), an organophosphate flame retardant (OPFR), is frequently detected in human blood. In this study, the sensitive dual-luciferase reporter gene assay and molecular docking were used to investigate the activation of EHDPP to human peroxisome proliferator-activated receptor gamma (PPARG). Results show that EHDPP exhibited stronger PPARG activation (EC20: 2.04 µM) than triphenyl phosphate (TPhP) (EC20: 2.78 µM). EHDPP upregulated the gene expression of 3ß-hydroxysteroid dehydrogenase type 1 (3ß-HSD1) in human placental choriocarcinoma cells in a dose-dependent manner, and the lowest observable effective concentration was 10 µM, lower than that of TPhP (20 µM). EHDPP significantly altered progesterone secretion at a lower concentration (10 µM) than that of TPhP (20 µM), and both EHDPP and TPhP significantly promoted human chorionic gonadotropin (hCG) production at 20 µM. Furthermore, inactivation of PPARG by either a pharmacological inhibitor (GW9662) or small interfering RNA (siRNA) abolished the change in progesterone secretion and gene expression in the cells exposed to EHDPP, suggesting that the PPARG signaling pathway plays a role in the upregulation of progesterone by the two OPFRs. This is the first report to show that OPFRs can alter the biosynthesis of progesterone in the placenta, which could affect female reproduction and fetal development.

Folic acid-conjugated superparamagnetic iron oxide nanoparticles for tumor-targeting MR imaging.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been the subject of extensive research due to their potential biomedical applications. In the present investigation, superparamagnetic FA-PEI-Fe3O4 were successfully prepared and evaluated as a targeted MRI contrast agent. FTIR characteristics, TGA, VSM, and MR imaging confirmed the composition and magnetic properties of the synthesized nanoparticles. TEM showed that FA-PEI-Fe3O4 were spherical in shape and well dispersed. The nanoparticles were superparamagnetic at room temperature with a saturation magnetization value of 67.1 emu/g. The nanoparticles showed higher uptake efficiency due to receptor-mediated endocytosis. Moreover, specificity of FA-PEI-Fe3O4 to target tumor cells was demonstrated by the increased nanoparticle uptake and significant contrast enhancement of KB cells over MCF7 cells. The competitive inhibition of FA-PEI-Fe3O4 by free FA further confirmed the specific interaction of this conjugate with FA receptors. In vivo MR imaging studies showed a decreased signal intensity and enhanced tumor contrast post-injection of FA-PEI-Fe3O4. These results indicate that FA-PEI-Fe3O4 can be used as a promising tumor-targeting agent as well as a T2 negative-contrast agent in MR imaging applications.

Occurrence and Maternal Transfer of Chlorinated Bisphenol A and Nonylphenol in Pregnant Women and Their Matching Embryos.

Prenatal exposure has recently raised concerns over the health risks of endocrine disruptors; however, little is known about their extent and the mechanisms of maternal transfer in the embryo stage. In this study, bisphenol A (BPA), nonylphenol (NP), and their six chlorinated derivatives were quantified in decidua samples from 25 pregnant women and their matching embryos, which were collected as chorionic villi samples. Monochloro-BPA (MCBPA), dichloro-BPA (DCBPA), monochloro-NP (MCNP), and dichloro-NP (DCNP) were detected in over 70% of the decidua or chorionic villi samples, while BPA, NP, trichloro-BPA (TCBPA), and tetrachloro-BPA (TeCBPA) were detected in less than half. The geometric mean (GM) concentrations of MCBPA, DCBPA, NP, MCNP, and DCNP in chorionic villi samples were 0.13, 0.17, 5.33, 4.52, and 2.44 ng/g dw, respectively, higher than those in maternal decidua samples, which were 0.10, 0.12, 3.27, 1.85, and 0.74 ng/g dw, respectively, while the GM concentration of BPA was lower in chorionic villi samples (0.09 ng/g dw) than in maternal decidua (0.10 ng/g dw). The ratios of the average lipid-normalized concentrations of chemicals in chorionic villi to those in maternal decidua (EMR) were calculated to be 1.53 for MCNP and 2.38 for DCNP, while those of BPA, MCBPA, DCBPA, and NP were lower than 1 (0.39-0.97). Such obvious difference in maternal transfer is probably due to their different affinities to plasma proteins, as exemplified by the correlation between EMR and the binding affinities to T4 transport proteins (TTR). This is the first report on the occurrence and maternal transfer of chlorinated derivatives of BPA and NP in human embryos and decidua.

Levels of Phthalate Metabolites in Urine of Pregnant Women and Risk of Clinical Pregnancy Loss.

Toxicological studies have shown that phthalate esters (PAEs), a class of widely used and environmentally prevalent chemicals, can increase the abortion rate in animals, but epidemiological evidence is scarce. This study aimed to explore the relationship between the urinary concentration of phthalate metabolites and the risk of clinical pregnancy loss. A total of 132 women who underwent clinical pregnancy loss (cases) and 172 healthy pregnant women (controls) were recruited from Beijing, China. Eight phthalate metabolites in urine were determined by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Five phthalate metabolites, monomethyl phthalate (MMP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono(2-ethlyhexyl) phthalate (MEHP), were detected in at least 95% of the urine samples, with the highest median concentration of 51.0 µg/g of creatinine for MnBP of all participants. The differences in urinary concentrations of phthalate metabolites between cases and controls were evaluated using the Mann-Whitney U test. The concentrations of MEP (median of 18.7 µg/g of creatinine), MiBP (23.3 µg/g of creatinine), and MnBP (58.2 µg/g of creatinine) detected in the cases were significantly higher than those (15.7 µg/g of creatinine for MEP, 19.4 µg/g of creatinine for MiBP, and 43.9 µg/g of creatinine for MnBP) in the controls (p < 0.05). Increasing risks of clinical pregnancy loss were observed from the first to fourth quartiles of the MEP, MiBP, and MnBP concentrations (p < 0.05 for trend). We concluded that exposure to MEP, MiBP, and MnBP was associated with an increased risk of clinical pregnancy loss.