Table 1.

Summary of discovery EWAS and look-up replication studies showing exposure-related DNA methylation patterns are present and can be detected long after an exposure occurred.

Exposure Domain	Timing of:		Tissue	Scale and purpose	Reference	Notes
	Exposure	DNAm measure
Behavior/Lifestyle
Smoking	Prenatal	Birth	Placenta	Genome-scale discovery	[82]
			Cord blood	EWAS discovery	[27]
				EWAS discovery	[25]
				Meta-EWAS discovery	[23]
		Infancy	Blood spots: Guthrie cards	Lookup of birth EWAS meta-results	[29]
		Birth & 18 months	Cord & peripheral blood	Candidate gene, replication & DNAm persistence	[51]	Showed longitudinal persistence of prenatal smoking DNAm marks
		Childhood	Buccal epithelium	Targeted, gene discovery	[83]
			Peripheral blood	EWAS discovery	[30]
			Peripheral blood	Lookup of birth EWAS in older children	[23, 31]
		Birth, childhood, adolescence	Cord blood, peripheral blood	EWAS discovery in cord blood, lookup results in blood collected later in life	[24]	Showed longitudinal persistence of DNAm marks at age 7, and 17 even after adjusting for postnatal and personal exposure
			Peripheral blood	Replication of adolescent EWAS results in an independent sample across 3 timepoints	[26]	Adjusted for postnatal self and parental smoking
		Adolescence	Peripheral blood	EWAS discovery in adolescent blood	[26]	Adjusted for postnatal personal and parental smoking
	Adult	Later adulthood	Buccal epithelium	EWAS discovery	[48]
			Peripheral blood	EWAS discovery	[48]
			Peripheral blood	Meta-EWAS discovery	[46]	Show methylation trajectories in former smokers do not return to non-smoker levels even after 30yrs
			Peripheral blood	EWAS discovery and replication in different Race	[47]
Alcohol	Prenatal	Birth	Cord blood	Meta-EWAS discovery	[28]
	Adult	Later adulthood	Peripheral blood	Meta-EWAS discovery, current use prediction	[49]
Nutrition & Supplementation
Folic acid	Prenatal	Adults, at age 47	Saliva	EWAS discovery	[32]	Exposure from randomized folic acid supplementation trial - 1960’s
Maternal diet	Peri-conception	Childhood	Peripheral blood	Candidate gene discovery	[33, 34]	Seasonally driven nutrition differences - The Gambia
		Infancy	Peripheral blood	Candidate gene discovery	[35, 36]	Seasonally driven nutrition differences – The Gambia
Methyl-group donor intake	Prenatal	Infancy	Buccal	Candidate gene, discovery	[37]
		Birth	Cord blood	Candidate gene, discovery	[38]
Docosahexaenoic acid (DHA)	Prenatal	Neonates	Guthrie blood cards	EWAS discovery	[39]	From DOMInO randomized controlled trial for DHA supplementation
		Childhood	Peripheral blood	Lookup at later time point for persistent changes
Short-term high fat overfeeding diet	Adulthood	Adults, 6–8 weeks later	Skeletal muscle	Targeted gene, discovery	[50]	Diet-related DNA methylation levels were still present months after returning to a normal diet
Adversity
Dietary (Famine)	Prenatal	Adults, at age 60	Peripheral blood	Candidate gene discovery	[42, 84]	Data from the Dutch Hunger Winter study
		Adulthood	Peripheral blood	Candidate gene, replication	[85]	Bangladesh sample
Stress (Maltreatment)	Childhood	Later Childhood	Saliva	Candidate gene discovery	[43]	Showed 6 month longitudinal changes in DNA methylation among 35 year olds with severe maltreatment exposure
Toxicants
Air pollutants (Nitrogen dioxide)	Prenatal	Birth	Cord blood	EWAS discovery	[40]
		Childhood	Peripheral blood	Lookup of birth EWAS results in older children	[40]	Associations with prenatal NO2 levels not explained by postnatal NO2 exposure near time of sample collection.
Lead	Cumulative Lifelong	Adulthood	Peripheral Blood	DNAm global burden (LINE-1)	[86]
Mercury	Prenatal	Birth & childhood	Cord & peripheral blood	DNAm global burden (LC-MS/MS)	[41]
Health conditions
Maternal early pregnancy BMI	Prenatal	Birth	Cord blood	Meta-EWAS discovery	[44]
	Prenatal	Adolescence	Peripheral blood	Lookup of meta- EWAS results in adolescence	[44]
Maternal Eating Disorder	Prenatal	Birth	Cord blood	Global genome DNAm burden	[45]	This could reflect dietary deficiency exposure

BMI, body mass index

DNAm, DNA methylation

EWAS, epigenome-wide association study