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

Mouat, Julia S.; Li, Xueshu; Neier, Kari; Zhu, Yihui; Mordaunt, Charles E.; Merrill, Michele A. La; Lehmler, Hans‐Joachim; Jones, Michael P.; Lein, Pamela J.; Schmidt, Rebecca J.; LaSalle, Janine M.

doi:10.1016/j.envres.2023.115227

Cited by 10 publications

(4 citation statements)

References 110 publications

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“…Unfortunately, PCB 95 is not frequently analyzed in human biomonitoring studies, partly because it has a low detection frequency. , For example, PCB 95 was detected in only one sample at a concentration of 0.1 ng/g wet weight in a study of maternal serum from the high-risk autism spectrum disorder MARBLES cohort . PCB 95 was also below the detection limit in serum collected in 2001 from Japanese women .…”

Section: Resultsmentioning

confidence: 99%

“… 53 , 54 For example, PCB 95 was detected in only one sample at a concentration of 0.1 ng/g wet weight in a study of maternal serum from the high-risk autism spectrum disorder MARBLES cohort. 53 PCB 95 was also below the detection limit in serum collected in 2001 from Japanese women. 52 The total PCB levels in the Japanese cohort ranged from 1.6 to 6.9 ng/g serum and are lower compared to the PCB 95 levels observed in animal studies.…”

Section: Resultsmentioning

confidence: 99%

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Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice

Bullert

Han

et al. 2023

Chem. Res. Toxicol.

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Polychlorinated biphenyls (PCBs) are environmental contaminants that can cause neurotoxicity. PCBs, such as PCB 95 (2,2′,3,5′,6-pentachlorobiphenyl), can be metabolized by cytochrome P450 enzymes into neurotoxic metabolites. To better understand how the metabolism of PCB 95 affects neurotoxic outcomes, we conducted a study on the disposition of PCB 95 in transgenic mouse models. The mice were given a single oral dose of PCB 95 (1.0 mg/kg) and were euthanized 24 h later for analysis. PCB 95 levels were highest in adipose tissue, followed by the liver, brain, and blood. Adipose tissue levels were significantly higher in wild-type (WT) mice than in Cyp2abfgs-null (KO) or CYP2A6-transgenic (KI) mice. We also observed genotype-dependent differences in the enrichment of aS-PCB 95 in female mice, with a less pronounced enrichment in KO than WT and KI mice. Ten hydroxylated PCB 95 metabolites were detected in blood and tissue across all exposure groups. The metabolite profiles differed across tissues, while sex and genotype-dependent differences were less pronounced. Total OH-PCB levels were highest in the blood, followed by the liver, adipose tissue, and brain. Total OH-PCB blood levels were lower in KO than in WT mice, while the opposite trend was observed in the liver. In male mice, total OH-PCB metabolite levels were significantly lower in KI than in WT mice in blood and the liver, while the opposite trend was observed in female mice. In conclusion, the study highlights the differences in the atropselective disposition of PCB 95 and its metabolites in different types of mice, demonstrating the usefulness of these transgenic mouse models for characterizing the role of PCB metabolism in PCB neurotoxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice

Bullert

Han

et al. 2023

Chem. Res. Toxicol.

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“…While adverse health outcomes have been established for many pollutants, determining their specific targets and mechanisms remains challenging. For example, the family of PCBs, legacy pollutants marked as hazardous and banned decades ago, is still subject to much research and new findings. − Moreover, the flow of new pollutants is relentless, leaving toxicologists inundated with compounds to investigate. Therefore, the ability to simultaneously evaluate large numbers of pollutants for their potential impact on biological systems is essential.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput GPCRome Screen of Pollutants Reveals the Activity of Polychlorinated Biphenyls at Melatonin and Sphingosine-1-phosphate Receptors

Wilkinson,

Lehmler,

Roman

2024

Chem. Res. Toxicol.

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Exposure to environmental pollutants is linked to numerous toxic outcomes, warranting concern about the effect of pollutants on human health. To assess the threat of pollutant exposure, it is essential to understand their biological activity. Unfortunately, gaps remain for many pollutants' specific biological activity and molecular targets. A superfamily of signaling proteins, G-protein-coupled receptors (GPCRs), has been shown as potential targets for pollutant activity. However, research investigating the pollutant activity at the GPCRome is scarce. This work explores pollutant activity across a library of human GPCRs by leveraging modern high-throughput screening techniques devised for drug discovery and pharmacology. We designed and implemented a pilot screen of eight pollutants at 314 human GPCRs and discovered specific polychlorinated biphenyl (PCB) activity at sphingosine-1-phosphate and melatonin receptors. The method utilizes open-source resources available to academic and governmental institutions to enable future campaigns that screen large numbers of pollutants. Thus, we present a novel highthroughput approach to assess the biological activity and specific targets of pollutants.

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“…2,3 In the NDD enriched-risk human prospective study "Markers of Autism Risks in Babies -Learning Early Signs" (MARBLES), concentrations of PCBs detectable in maternal blood were associated with adverse neurodevelopmental outcomes including ASD and were associated with DNA methylation changes over known ASD risk genes. [4][5][6] PCBs are present in the human brain, blood, and breast milk, and they can easily cross the placental barrier, exposing fetuses through maternal blood. Humans, including pregnant women and those of child-bearing age, encounter PCBs through inhalation and consumption of contaminated food and water.…”

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confidence: 99%

Placental-brain axis in females detected within broadly impacted metabolic gene networks protects against prenatal PCB exposure

Chau,

Neier,

Valenzuela

et al. 2024

Preprint

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BackgroundNeurodevelopmental disorders have a strong male bias that is poorly understood. Placenta is a rich source of molecular information about environmental interactions with genetics (including biological sex), that affect the developing brain. We investigated placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs).ResultsTo understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta by RNAseq, we used weighted gene correlation network analysis (WGCNA) to create correlated gene networks that could be compared across sex or tissue. WGCNA revealed that expression within most correlated gene networks was significantly and strongly associated with PCB exposures, but frequently in opposite directions between male-female and placenta-brain comparisons. In both WGCNA and differentially expressed gene analyses, male brain showed more PCB-induced transcriptional changes than male placenta, but the reverse pattern was seen in females. Furthermore, non-monotonic dose responses to PCBs were observed in most gene networks but were most prominent in male brain. The transcriptomic effects of low dose PCB exposure were significantly reversed by dietary folic acid supplementation across both sexes, but these effects were strongest in female placenta. PCB-dysregulated and folic acid-reversed gene networks were commonly enriched in functions in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipids, and O-glycan biosynthesis, as opposed to toxicant responses in male brain.ConclusionsThe female protective effect in prenatal PCB exposures appears to be mediated by dose-dependent sex differences in transcriptional modulation of metabolism in placenta.Graphical Abstract

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

Cited by 10 publications

References 110 publications

Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice

Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice

High-Throughput GPCRome Screen of Pollutants Reveals the Activity of Polychlorinated Biphenyls at Melatonin and Sphingosine-1-phosphate Receptors

Placental-brain axis in females detected within broadly impacted metabolic gene networks protects against prenatal PCB exposure

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