Prenatal Exposures to Common Phthalates and Prevalent Phthalate Alternatives and Infant DNA Methylation at Birth

Abstract

Phthalates are a diverse group of chemicals used in consumer products. Because they are so widespread, exposure to these compounds is nearly unavoidable. Recently, growing scientific consensus has suggested that phthalates produce health effects in developing infants and children. These effects may be mediated through mechanisms related to the epigenome, the constellation of mitotically heritable chemical marks and small compounds that guide transcription and translation. The present study examined the relationship between prenatal, first-trimester exposure of seven phthalates and epigenetics in two pregnancy cohorts (n = 262) to investigate sex-specific alterations in infant blood DNA methylation at birth (cord blood or neonatal blood spots). Prenatal exposure to several phthalates was suggestive of association with altered DNA methylation at 4 loci in males (all related to ΣDEHP) and 4 loci in females (1 related to ΣDiNP; 2 related to BBzP; and 1 related to MCPP) at a cutoff of q < 0.2. Additionally, a subset of dyads (n = 79) was used to interrogate the relationships between two compounds increasingly used as substitutions for common phthalates (ΣDINCH and ΣDEHTP) and cord blood DNA methylation. ΣDINCH, but not ΣDEHTP, was suggestive of association with DNA methylation (q < 0.2). Together, these results demonstrate that prenatal exposure to both classically used phthalate metabolites and their newer alternatives is associated with sex-specific infant DNA methylation. Research and regulatory actions regarding this chemical class should consider the developmental health effects of these compounds and aim to avoid regrettable substitution scenarios in the present and future.

Prenatal phthalate exposure and cord blood DNA methylation

“…However, a study in Taiwan showed an inverse association between small gestational age (SGA) and maternal MnBP exposure in female neonates [43] . Sex-speci c effects of some phthalates on methylation and expression of genes in the placenta and cord blood have been reported in previous studies [13,44,45] . Moreover, phthalate exposure may adversely in uence fetal development parameters, such as gestational age reduction and preterm delivery, with a signi cant gender impact [46] .…”

“…Several of these functional categories, such as the regulation of small GTPase-mediated signal transduction and positive regulation of GTPase activity, were involved in biological processes in cord blood MEOHP. Another study demonstrated a similar function in different phthalate metabolites, such as butylbenzylphthalate (BBzP), which is related to small GTPase-mediated signal transduction only in female infants 45 . In the present study, embryonic cleavage, positive regulation of mitotic metaphase, and mitotic sister chromatid separation were highly signi cant in cord blood MnBP.…”

Prenatal phthalate exposure and cord blood DNA methylation

“…Although cohort studies in humans have shown an association between maternal phthalate exposure and DNA methylation changes in cord blood samples 13 – 20 , the results have been inconsistent, likely because of differences in epigenetic profiles according to race or ethnicity, sex, and age. More research is needed to gain, insight into the mechanisms of the effects of prenatal phthalate exposure is important for developing prevention strategies to mitigate phthalate-associated health outcomes.…”

Fetal exposure to phthalates and bisphenols and DNA methylation at birth: the Generation R Study

“…As DNA methylation is tissue- and age-specific, results of these studies are not directly comparable. Several other studies of prenatal bisphenol and phthalate exposure, using an epigenome-wide approach, have identified differential DNA methylation at multiple CpG sites in cord blood in relation to exposure to different phthalates or bisphenols [ 20 – 25 ]. In addition, one study explored the associations of prenatal exposure to phthalates with DNA methylation in peripheral blood and buccal epithelial cells during childhood [ 26 ].…”

“…In addition, one study explored the associations of prenatal exposure to phthalates with DNA methylation in peripheral blood and buccal epithelial cells during childhood [ 26 ]. When exploring the associations with DNA methylation in cord blood, only the studies by Miura et al and Petroff et al included more than 70 mother–child pairs and the studies by Chen et al and Petroff et al were the only studies that included a phthalate [ 20 , 22 , 24 , 25 ]. Most previous studies that assessed the associations of maternal phthalate or bisphenol urine concentrations with DNA methylation focused on one or a few phthalates or bisphenols and did not consider joint effects of the exposures [ 15 – 30 ].…”