Association of prenatal acetaminophen use and acetaminophen metabolites with DNA methylation of newborns: analysis of two consecutive generations of the Isle of Wight birth cohort

Abstract

Background Acetaminophen is used by nearly two thirds of pregnant women. Although considered safe, studies have demonstrated associations of prenatal acetaminophen use and adverse health outcomes in offspring. Since DNA methylation (DNAm) at birth may act as an early indicator of later health, assessments on whether DNAm of newborns is associated with gestational acetaminophen use or its metabolites are needed. Methods Using data from three consecutive generations of the Isle of Wight cohort (F0-grandmothers, F1-mothers, and F2-offspring) we investigated associations between acetaminophen metabolites in F0 serum at delivery with epigenome-wide DNAm in F1 (Guthrie cards) and between acetaminophen use of F1 and F2-cord-serum levels with F2 cord blood DNAm. In epigenome-wide screening we eliminated non-informative DNAm sites followed by linear regression of informative sites. Based on repeated pregnancies, indication bias analyses tested whether acetaminophen indicated maternal diseases or has a risk in its own right. Considering that individuals with similar intake process acetaminophen differently, metabolites were clustered to distinguish metabolic exposures. Finally, metabolite clusters from F1-maternal and F2-cord sera were tested for their associations with newborn DNAm (F1 and F2). Results Twenty-one differential DNAm sites in cord blood were associated with reported maternal acetaminophen intake in the F2 generation. For 11 of these cytosine-phosphate-guanine (CpG) sites, an indication bias was excluded and five were replicated in F2 with metabolite clusters. In addition, metabolite clusters showed associations with 25 CpGs in the F0-F1 discovery analysis, of which five CpGs were replicated in the F2-generation. Conclusion Our results suggest that prenatal acetaminophen use, measured as metabolites, may influence DNAm in newborns.

Serum level of total histone 3, H3K4me3, and H3K27ac after non-emergent cardiac surgery suggests the persistence of smoldering inflammation at 3 months in an adult population

“…However, we found that acetaminophen intake was linked to the depressed serum of H3K4me3 changes during the acute peri-operative period. Some data suggest an effect of acetaminophen on DNA methylation [ 31 , 67 , 68 ]. DNA methylation affects histone modification.…”

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

“…However, invasive testing of the foetal compartment in human is rarely indicated, which makes data on safety during pregnancy for most substances scant. Thus, most pharmacoepigenetic studies address associations of DNAm differences in cord blood or placenta from neonates delivered at term exposed to the maternal medication during pregnancy, which is also the case for paracetamol (82)(83)(84). We have previously published a study of cord blood samples from the Norwegian Mother, Father and Child cohort (MoBa), where we found differentially methylated genes in cord blood from children with ADHD exposed to long-term maternal paracetamol use (19).…”

“…However, invasive testing of the fetal compartment in human is rarely indicated, which makes data on safety during pregnancy for most substances scant. Thus, most pharmacoepigenetic studies address associations of DNAm differences in cord blood or placenta from neonates delivered at term exposed to the maternal medication during pregnancy, which is also the case for paracetamol [83][84][85] .…”

Fucoxanthin levels in maternal serum at birth and eczema risk in offspring in early childhood: A birth cohort study

“…Maternal blood samples were collected at the child's birth (predelivery) and were analyzed to measure metabolites, nutrients, and toxins (MNTs) using a data‐independent untargeted approach based on high‐resolution mass spectrometry coupled to varied sample introduction strategies (reversed‐phase liquid chromatography, hydrophilic interaction liquid chromatography, and flow‐injection analysis). Such an approached enabled a blind molecular profiling that does not require a priori knowledge of compound identities and is suitable for detecting a wide range of substances derived from environment, food, gut microbiome, and endogenous exposures 18,19 . Fucoxanthinol 3‐arachidate (nlp16.65_955.6949m_z) was measured using negative‐ion LC/high resolution MS on a Waters Xevo G2‐XS QTof mass spectrometer as its formate adduct ([M + formate] − ) as a continuous variable generated by the Progenesis QI software.…”

“…Such an approached enabled a blind molecular profiling that does not require a priori knowledge of compound identities and is suitable for detecting a wide range of substances derived from environment, food, gut microbiome, and endogenous exposures. 18,19 Fucoxanthinol 3-arachidate (nlp16.65_955.6949m_z) was measured using negative-ion LC/high resolution MS on a Waters Xevo G2-XS QTof mass spectrometer as its formate adduct ([M + formate] − ) as a continuous variable generated by the Progenesis QI software.…”