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Phthalates are endocrine-disrupting chemicals (EDCs) that alter hormone functions throughout the lifespan. Growing awareness of the adverse health effects of phthalate exposure has led to regulating certain phthalates in the United States, Canada, and Europe. However, international comparisons of urinary phthalate metabolite concentrations as biomarkers of exposure are sparse, and few studies have controlled for cohort-specific variables like pregnancy. We aimed to examine trends in urinary phthalate monoester metabolite concentrations in non-occupationally exposed populations globally, excluding locations where representative data are already available at the country level. We systematically reviewed studies published between 2000 and 2023 that reported urinary phthalate monoester concentrations. We examined changes in metabolite concentrations across time, controlling for region, age, and pregnancy status, using mixed-effects meta-regression models with and without a quadratic term for time. We identified heterogeneity using Cochran's Q-statistic and I2 index, adjusting for it with the trim-and-fill method. The final analytic sample consisted of 216 studies. Significant differences in phthalate metabolite concentrations were observed across regions, age groups, and between pregnant and non-pregnant cohorts. Our meta-regression identified a significant non-linear trend with time for Mono-n-butyl phthalate and Mono-isononyl phthalate concentration internationally and in Eastern and Pacific Asia (EPA). We also observed significant non-linear associations between time and Mono(2-ethyl-5-hydroxyhexyl) phthalate, Mono(2-carboxymethylhexyl) phthalate, and Mono(3-carboxypropyl) phthalate concentration internationally and/or in EPA, along with Mono(2-ethylhexyl) phthalate, Mono-carboxy-isononyl phthalate, and Mono-ethyl phthalate. Additionally, Mono-ethyl phthalate concentration showed a significant negative linear association with time in Latin America and Africa. Heterogeneity was high, indicating potential bias in our results. Our findings indicate the need for increased awareness of phthalate exposure. Further analysis of the attributable disease burden and cost at regional and international levels, especially in low- and middle-income countries, is essential to understanding these and other EDCs impact on population health and the economy.
Phthalates are endocrine-disrupting chemicals (EDCs) that alter hormone functions throughout the lifespan. Growing awareness of the adverse health effects of phthalate exposure has led to regulating certain phthalates in the United States, Canada, and Europe. However, international comparisons of urinary phthalate metabolite concentrations as biomarkers of exposure are sparse, and few studies have controlled for cohort-specific variables like pregnancy. We aimed to examine trends in urinary phthalate monoester metabolite concentrations in non-occupationally exposed populations globally, excluding locations where representative data are already available at the country level. We systematically reviewed studies published between 2000 and 2023 that reported urinary phthalate monoester concentrations. We examined changes in metabolite concentrations across time, controlling for region, age, and pregnancy status, using mixed-effects meta-regression models with and without a quadratic term for time. We identified heterogeneity using Cochran's Q-statistic and I2 index, adjusting for it with the trim-and-fill method. The final analytic sample consisted of 216 studies. Significant differences in phthalate metabolite concentrations were observed across regions, age groups, and between pregnant and non-pregnant cohorts. Our meta-regression identified a significant non-linear trend with time for Mono-n-butyl phthalate and Mono-isononyl phthalate concentration internationally and in Eastern and Pacific Asia (EPA). We also observed significant non-linear associations between time and Mono(2-ethyl-5-hydroxyhexyl) phthalate, Mono(2-carboxymethylhexyl) phthalate, and Mono(3-carboxypropyl) phthalate concentration internationally and/or in EPA, along with Mono(2-ethylhexyl) phthalate, Mono-carboxy-isononyl phthalate, and Mono-ethyl phthalate. Additionally, Mono-ethyl phthalate concentration showed a significant negative linear association with time in Latin America and Africa. Heterogeneity was high, indicating potential bias in our results. Our findings indicate the need for increased awareness of phthalate exposure. Further analysis of the attributable disease burden and cost at regional and international levels, especially in low- and middle-income countries, is essential to understanding these and other EDCs impact on population health and the economy.
Background Exposure to environmental chemicals such as phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs) during pregnancy can increase the risk of adverse newborn outcomes. We explored the associations between maternal exposure to select environmental chemicals and DNA methylation in cord blood mononuclear cells (CBMC) and placental tissue (maternal and fetal sides) to identify potential mechanisms underlying these associations. Method This study included 75 pregnant individuals who planned to give birth at the University of Cincinnati Hospital between 2014 and 2017. Maternal urine samples during the delivery visit were collected and analyzed for 37 biomarkers of phenols (12), phthalates (13), phthalate replacements (4), and PAHs (8). Cord blood and placenta tissue (maternal and fetal sides) were also collected to measure the DNA methylation intensities using the Infinium HumanMethylation450K BeadChip. We used linear regression, adjusting for potential confounders, to assess CpG-specific methylation changes in CBMC (n = 54) and placenta [fetal (n = 67) and maternal (n = 68) sides] associated with gestational chemical exposures (29 of 37 biomarkers measured in this study). To account for multiple testing, we used a false discovery rate q-values < 0.05 and presented results by limiting results with a genomic inflation factor of 1±0.5. Additionally, gene set enrichment analysis was conducted using the Kyoto Encyclopedia of Genes and Genomics pathways. Results Among the 29 chemical biomarkers assessed for differential methylation, maternal concentrations of PAH metabolites (1-hydroxynaphthalene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 1-hydroxypyrene), monocarboxyisononyl phthalate, mono-3-carboxypropyl phthalate, and bisphenol A were associated with altered methylation in placenta (maternal or fetal side). Among exposure biomarkers associated with epigenetic changes, 1-hydroxynaphthalene, and mono-3-carboxypropyl phthalate were consistently associated with differential CpG methylation in the placenta. Gene enrichment analysis indicated that maternal 1-hydroxynaphthalene was associated with lipid metabolism and cellular processes of the placenta. Additionally, mono-3-carboxypropyl phthalate was associated with organismal systems and genetic information processing of the placenta. Conclusion Among the 29 chemical biomarkers assessed during delivery, 1-hydroxynaphthalene and mono-3-carboxypropyl phthalate were associated with DNA methylation in the placenta.
Humans are ubiquitously exposed to environmental endocrine disrupting chemicals such as phthalates. Phthalates can migrate out of products and enter the human body through ingestion, inhalation, or dermal application, can have potential estrogenic/antiestrogenic and/or androgenic/antiandrogenic activity, and are involved in many diseases. As a female reproductive organ that is regulated by hormones such as estrogen, progesterone and androgen, the uterus can develop several disorders such as leiomyoma, endometriosis and abnormal bleeding. In this review, we summarize the hormone-like activities of phthalates, in vitro studies of endometrial cells exposed to phthalates, epigenetic modifications in the uterus induced by phthalate exposure, and associations between phthalate exposure and uterine disorders such as leiomyoma and endometriosis. Moreover, we also discuss the current research gaps in understanding the relationship between phthalate exposure and uterine disorders.
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