Abstract
BackgroundPrenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life. Placental biomarkers and outcomes at birth may offer biologic insight into these associations. This is the first study to address these associations with candidate genes from the phthalate and placenta literature, accounting for sex differences, and using absolute quantitation methods for mRNA levels.MethodsWe measured candidate mRNAs in 180 placentas sampled at birth (HSD17B1, AHR, CGA, CYP19A1, SLC27A4, PTGS2, PPARG, CYP11A1) by quantitative PCR and an absolute standard curve. We estimated associations of loge mRNA with quartiles of urinary phthalate monoesters using linear mixed models. Phthalate metabolites (N = 358) and mRNAs (N = 180) were transformed to a z-score and modeled as independent, correlated vectors in relation to large for gestational age (LGA) and gestational diabetes mellitus (GDM).ResultsCGA was associated with 4 out of 6 urinary phthalates. CGA was 2.0 loge units lower at the 3rd vs. 1st quartile of mono-n-butyl phthalate (MnBP) (95% confidence interval (CI): −3.5, −0.5) in male placentas, but 0.6 loge units higher (95% CI: −0.8, 1.9) in female placentas (sex interaction p = 0.01). There was an inverse association of MnBP with PPARG in male placentas (−1.1 loge units at highest vs. lowest quartile, 95% CI: −2.0, −0.1). CY19A1, CYP11A1, CGA were associated with one or more of the following in a sex-specific manner: monobenzyl phthalate (MBzP), MnBP, mono-iso-butyl phthalate (MiBP). These 3 mRNAs were lower by 1.4-fold (95% CI: −2.4, -1.0) in male GDM placentas vs. female and non-GDM placentas (p-value for interaction = 0.04). The metabolites MnBP/MiBP were 16% higher (95% CI: 0, 22) in GDM pregnancies.ConclusionsPrenatal concentrations of certain phthalates and outcomes at birth were modestly associated with molecular changes in fetal placental tissue during pregnancy. Associations were stronger in male vs. female placentas, and associations with MnBP and MiBP were stronger than other metabolites. Placental mRNAs are being pursued further as potential mediators of exposure-induced risks to the health of the child.
Highlights
Prenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life
Urinary phthalate concentrations in pregnant women have been associated with short-term effects on their pregnancies [8,9,10] and with long-term effects in their children [11,12,13]
To estimate differences in the other 3 phthalates (MBzP, mono-2ethylhexyl phthalate (MEHP), Monoethyl phthalate (MEP)) that originate from different phthalate diesters, we modeled them as individual metabolites
Summary
Prenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life. Consideration of the placenta can grant temporal and spatial precision to estimates of association given the placenta’s physical location between maternal circulating phthalates and the developing embryo/fetus at precisely the time when organs are developing and cells and tissues are undergoing programming. With this knowledge, we can develop better measures of the placental response to the exposure, and potentially within an early enough timeframe to alter the short-term risks to the pregnancy and the long-term risks to the child
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