Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB exposure

Laufer, Benjamin I.; Neier, Kari; Valenzuela, Anthony; Yasui, Dag H.; Schmidt, Rebecca Jean; Lein, Pamela J.; LaSalle, Janine M.

doi:10.1016/j.celrep.2022.110442

Cited by 43 publications

(37 citation statements)

References 121 publications

(146 reference statements)

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Section: Resultsmentioning

confidence: 99%

“…In both modules, the methylation change associated with elevated maternal serum PCB levels appears to be in the opposite direction as ASD in the child, which is the inverse of our hypothesis but accompanies our finding that ASD diagnosis was non-significantly negatively correlated with PCBs 153+168, 170, 180+193, and 187 (Figure 3B). A previous study using a mouse model of prenatal PCB exposure identified DMRs that mapped to CSMD1 as well as AUTS2 in male and female placentas and fetal brains (Figure 5C) (Laufer et al, 2022). Several DMRs mapped to each gene for both sexes and tissues and were inconsistent in the direction of differential methylation, indicating that PCB exposure may dysregulate DNA methylation at CSMD1 and AUTS2 in variable ways.…”

Section: Placental Dna Co-methylation Modules Are Correlated With Mat...mentioning

confidence: 86%

“…C) Modules annotated to genes using the hg38 genome. Black boxes indicate genes that were identified as fetal brain and placenta differentially methylated regions in both sexes in a mouse study of gestational PCB exposure (Laufer et al, 2022) The GALC Salmon module negatively correlated with ASD diagnosis (P < 0.01), as well as ADOS comparison score (P < 0.05), but positively correlated with Mullen Score (P < 0.05). The Salmon module also positively correlated with maternal education (P < 0.05), indicating that increased placental DNA methylation at Salmon loci (GALC gene) correlates with more typical development (and less ASD diagnosis) in the offspring and higher maternal education levels.…”

Section: B Cmentioning

confidence: 99%

“…Recently, differential DNA methylation has been identified in human placenta and umbilical cord blood of individuals later diagnosed with ASD (Mordaunt et al, 2020; Zhu et al, 2022). Moreover, maternal PCB levels have been associated with altered DNA methylation in human placenta (Ouidir et al, 2020) and in mouse placenta and fetal brain (Laufer et al, 2022). Both Ouidir et al and Laufer et al found enrichment for pathways related to neurodevelopment and neuronal/brain functions.…”

Section: Introductionmentioning

confidence: 99%

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Networks of placental DNA methylation correlate with maternal serum PCB concentrations and child neurodevelopment

Mouat

Neier

et al. 2022

Preprint

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Background: Gestational exposure to polychlorinated biphenyls (PCBs) has been associated with elevated risk for neurodevelopmental disorders. The mechanism of risk is unclear but may involve placental epigenetics. Prior studies have associated differential placental DNA methylation with maternal PCB exposure or with increased risk of autism spectrum disorder (ASD). However, sequencing-based placental methylomes have not previously been tested for simultaneous associations with maternal PCB levels and child neurodevelopmental outcomes. Objectives: We aimed to identify placental DNA methylation patterns associated with maternal PCB levels and child neurodevelopmental outcomes in the high-risk ASD MARBLES cohort. Methods: We measured 209 PCB congeners in 104 maternal serum samples collected at delivery. We identified networks of DNA methylation from 147 placenta samples using the Comethyl R package, which performs weighted gene correlation network analysis for whole genome bisulfite sequencing data. We tested placental DNA methylation modules for association with maternal serum PCB levels, child neurodevelopment, and other participant traits. Results: PCBs 153 + 168, 170, 180 + 193, and 187 were detected in over 50% of maternal serum samples and were highly correlated with one another. Consistent with previous findings, maternal age was the strongest predictor of serum PCB levels, alongside year of sample collection, pre-pregnancy BMI, and polyunsaturated fatty acid levels. Twenty seven modules of placental DNA methylation were identified, including five which significantly correlated with one or more PCBs, and four which correlated with child neurodevelopment. Two modules associated with maternal PCB levels as well as child neurodevelopment, and mapped to CSMD1 and AUTS2, genes previously implicated in ASD and identified as differentially methylated regions in mouse brain and placenta following gestational PCB exposure. Conclusions: Placental DNA co-methylation modules were associated with maternal PCBs and child neurodevelopment. Methylation of CSMD1 and AUTS2 could potentially be mechanistically involved in ASD risk following maternal PCB exposure.

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Section: Resultsmentioning

confidence: 99%

Section: Placental Dna Co-methylation Modules Are Correlated With Mat...mentioning

confidence: 86%

Section: B Cmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Networks of placental DNA methylation correlate with maternal serum PCB concentrations and child neurodevelopment

Mouat

Neier

et al. 2022

Preprint

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“…To explore the etiology of FASD we have collected placental samples from PAE and control newborns at birth. Placenta is an accessible human tissue and a promising implement for identifying the effects of intra-uterine environment on embryonic development, including neuronal development 9,10 . Here, by performing genome-wide DNA methylation (DNAm) analysis of placenta, we discovered a candidate gene developmental pluripotency associated factor 4 ( DPPA4 ), which was hypomethylated particularly in the early alcohol-exposed placentas.…”

Section: Introductionmentioning

confidence: 99%

Chromatin remodeler developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders

Auvinen

Vehviläinen

Marjonen

et al. 2022

Preprint

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Alcohol affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. To explore the etiology of FASD, we performed the first genome-wide DNA methylation and gene expression analyses of 80 severely alcohol-exposed and 68 control human placentas. DPPA4, FOXP2, and TACR3 with significantly decreased DNA methylation were discovered - particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When human embryonic stem cells (hESCs) were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNA methylation similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNA methylation changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development. Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.

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Polychlorinated biphenyls (PCBs)

Katsikantami¹,

Iatrou²,

Tzatzarakis³

et al. 2024

Encyclopedia of Toxicology

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Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB exposure

Cited by 43 publications

References 121 publications

Networks of placental DNA methylation correlate with maternal serum PCB concentrations and child neurodevelopment

Networks of placental DNA methylation correlate with maternal serum PCB concentrations and child neurodevelopment

Chromatin remodeler developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders

Polychlorinated biphenyls (PCBs)

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