. 2023 Dec 4;131(12):126001. doi: 10.1289/EHP12956

Table 1.

Prenatal environmental exposure epigenome-wide association study literature review results. Studies ( $lowercase italic n equals 51$ ) were included if they performed replication or meta-analysis.

Reference	Cohort/consortia	$n$ ^a	Ancestry	Exposure	Exposure tissue	Epigenetic measure	Epigenetic tissue	Significant DMPs	Criteria for significance	Validation type	Replication successful yes/no
Cigarette smoking
Joubert et al.³³	PACE	6,685	Multi – primarily European	Prenatal maternal smoking	NA	450K	Cord blood	FDR – 6,073; Bonferroni - 568	Bonferroni	Meta-analysis & replication	Yes, Kolmogorov $p value < 2.2 \times 10^{- 16}$ for replication look-up in older children’s blood
Sikdar et al.³⁴	PACE	5,648	Multi – primarily European	Prenatal maternal smoking	NA	450K	Cord blood	5,547	$false discovery rate less than 0.05$	Meta-analysis	NA
Everson et al.³⁵	PACE	1,700	Multi – primarily European	Prenatal maternal smoking	NA	450K	Placenta	443	Bonferroni	Meta-analysis	NA
Hannon et al.³⁶	MINERVA	1,263	European	Prenatal maternal smoking	NA	450K	Blood spots	110	Bonferroni	Meta-analysis & replication	Yes, 102 of 110 DMPs, sign test $p < 2 \times 10^{- 323}$
Vives-Usano³⁷	HELIX	1,105	Multi – primarily European	Prenatal maternal smoking	NA	450K	Child peripheral blood	41	$false discovery rate less than 0.05$	Replication	Yes, 17 of 18 loci
Joubert et al.³⁸	MoBa	1,062	Multi – primarily European	Prenatal maternal smoking	NA	450K	Cord blood	26	Bonferroni	Replication	Yes
Rotroff et al.³⁹	MoBA	1,062	European	Prenatal maternal smoking	Maternal plasma (cotinine)	450K	Cord blood	27	Bonferroni	Replication	Mixed, 9 of 15 genes
Markunas et al.⁴⁰	Norway facial clefts study	889	European	Prenatal maternal smoking	NA	450K	Heel prick blood spots	185	$false discovery rate less than 0.05$	Replication	Mixed, 22 of 26 DMPs
Küpers et al.⁴¹	GECKO Drenthe	255	European	Prenatal maternal smoking	NA	450K	Cord blood	35	$false discovery rate less than 0.05$	Meta-analysis & replication	Mixed, 3 of 8 DMPs
Morales et al.⁴²	INMA	179	European	Prenatal maternal smoking	Survey and maternal urine cotinine	450K	Placenta	50	$false discovery rate less than 0.05$	Replication	Yes, 4 of 4 DMPs
Shorey-Kendrick et al.⁴³	NA	59	Multi – primarily European	Prenatal maternal smoking	NA	EPIC	Placenta	726	$false discovery rate less than 0.05$	Replication	Mixed, 105 of 726 DMPs
Howe et al.⁴⁴	MACHS	20	European	Prenatal maternal Smoking	NA	Whole-Genome bisulfite sequencing	Cord blood $uppercase c d 4 open parenthesis plus close parenthesis$	10,381	$false discovery rate less than 0.05$	Replication	Mixed, 4 of 9 DMRs Replicated in adult $uppercase c d 4 plus cells$
Maternal alcohol and diet
Sharp et al.⁴⁵	PACE	3,075	Multi – primarily European	Maternal alcohol	NA	450K	Cord blood	0	$false discovery rate less than 0.05$	Meta-analysis	NA
Küpers et al.⁴⁶	PACE	2,802	Multi – primarily European	Mediterranean diet	NA	450K	Cord blood	1	$false discovery rate less than 0.05$	Meta-analysis	No, 0 of 1 DMPs
Joubert et al.⁴⁷	PACE	1,988	European	Folate	NA	450K	Cord blood	48	Bonferroni	Meta-analysis	NA
Gonseth et al.⁴⁸	CCLS	343	Multi – primarily European	Folate	NA	450K	Blood spots	4	Permutation-based $P$ values test	Replication	Mixed, 3 of 4 DMPs
Amarasekera et al.⁴⁹	NA	23	European	Folate	Maternal serum in last trimester of pregnancy	450K	Cord blood ( $uppercase c d 4 open parenthesis plus close parenthesis$ T-cells & antigen-presenting cells)	No DMPs/DMPs reported, only DMR	NA	Replication	Mixed, DMR only
Suderman et al.⁵⁰	MoBa; ALSPAC	1,416	European	25-hydroxyvitamin D	Maternal plasma	450K	Cord blood	0	$false discovery rate less than 0.05$	Meta-analysis	NA
Tauebert et al.⁵¹	INMA and Generation R	1,286	European	Iron	Maternal serum; cord blood	450K	Cord blood	3	$false discovery rate less than 0.05$	Meta-analysis	NA
Størdal et al.⁵²	MoBA	1,062	European	Iron supplements	NA	450K	Cord blood	0	Bonferroni	Replication	NA
Caramaschi et al.⁵³	ALSPAC	641	European	B12	Genotype (proxy)	450K	Cord blood	3	$false discovery rate less than 0.05$	Replication	Mixed, 1 of 3 DMPs
Geraghty et al.⁵⁴	ROLO	60	European	Glycemic index diet intervention	NA	EPIC	Cord blood serum	0	$false discovery rate less than 0.05$	Replication	NA
Yan et al.⁵⁵	NA	24	Asian	Glycemic index dietary intervention	NA	450K	Placenta	365	$false discovery rate less than 0.05$	Replication	Mixed, 4 of 10 DMPs
Air pollution
Gruzieva et al.⁵⁶	PACE	1,949	Multi – primarily European	$particulate matter begin subscript 10 end subscript$	NA	450K	Cord blood	6	$false discovery rate less than 0.05$	Meta-analysis & replication	Mixed, 0 of 6 loci in newborns, 4 of 6 DMPs in older children
Isaevska et al.⁵⁷	Piccolipin	384	European	$particulate matter begin subscript 10 end subscript$	NA	EPIC	Cord blood	284	$false discovery rate less than 0.05$	Replication	Mixed, 10 of 151 DMPs tested
Gruzieva et al.⁵⁶	PACE	1,551	Multi – primarily European	$particulate matter begin subscript 2.5 end subscript$	NA	450K	Cord blood	14	$false discovery rate less than 0.05$	Meta-analysis & replication	No, 0 of 14 DMPs
Plusquin et al.⁵⁸	ALSPAC and EXPOsOMICS (ENVIRONAGE, INMA, Piccolipiù and Rhea)	850	Multi – primarily European	PM	NA	450K	Cord blood; peripheral blood	0 – cross-sectional; 1 – longitudinal	$false discovery rate less than 0.05$	Meta-analysis	NA
Breton et al.⁵⁹	NA	240	Multi – primarily European	Air pollution PM	NA	450K	Blood spots	31	$false discovery rate less than 0.15$	Replication	Mixed, 1 of 2 DMPs
Gruzieva et al.⁶⁰	PACE	1,508	Multi – primarily European	${NO}_{2}$	NA	450K	Cord blood	3	$false discovery rate less than 0.05$	Meta-analysis & replication	Mixed, 1 of 3 DMPs
Peng et al.⁶¹	Project Viva	482	Multi – primarily European	Proximity to roadways	NA	450K	Cord blood	4	$false discovery rate less than 0.05$	Replication	No, 0 of 4 DMPs
Metals and other elements
Lozano et al.⁶²	PACE	1,462	Multi – primarily European	Methylmercury	Maternal blood; cord blood; maternal hair	450K and EPIC	Cord blood; childhood peripheral blood	2	$false discovery rate less than 0.10$	Meta-analysis	No, 0 of 2 DMPs
Bakulski et al.⁶³	Baltimore THREE	141	Multi – primarily African	Mercury	Cord blood	CHARM 2.0	Cord blood	0	$false discovery rate less than 0.10$	Replication	Yes, 1 of 1 DMR region replicated
Tian et al.⁶⁴	NHBCS and RICHS	484	Multi – primarily European	Selenium	Placenta	450K	Placenta	5	$false discovery rate less than 0.05$	Meta-analysis	NA
Everson et al.⁶⁵	NHBCS and RICHS	484	Multi – primarily European	Cadmium	Placenta	450K	Placenta	3	$false discovery rate less than 0.05$	Meta-analysis	NA
Park et al.⁶⁶	MOCEH	384	Asian	Cadmium	Maternal venous blood; cord blood	EPIC	Cord blood	2	$false discovery rate less than 0.05$	Meta-analysis	NA
Gliga et al.⁶⁷	NA	71	Asian	Cadmium	Maternal blood and child urine (age 9 y)	450K	PBMCs – cord blood and peripheral blood	Cord blood – 458; child blood age 9–6 y	$false discovery rate less than 0.05$	Replication	Yes, 1 of 1 DMR tested
Kennedy et al.⁶⁸	NA	447	European	Copper	Placenta	450K	Placenta	0	Bonferroni	Meta-analysis	NA
Park et al.⁶⁹	NA	364	Asian	Lead	Maternal blood and cord blood	EPIC	Cord blood	0 (111 in male-only analysis)	$false discovery rate less than 0.05$	Meta-analysis	NA
Wu et al.⁷⁰	Project Viva	268	Multi – primarily European	Lead	Maternal blood	450K	Cord blood	4	$false discovery rate less than 0.05$	Replication	No
Bozack et al.⁷¹	NA	120	Asian & admixed/Latino	Arsenic	Natural experiment and water samples	EPIC & 450K	Blood; buccal cells	PBMCs – 1; PBMCs & buccal cells – 3	$false discovery rate less than 0.05$	Meta-analysis	NA
Kaushal et al.⁷²	NA	64	Asian	Arsenic	Maternal urine	450K	Cord blood	579	$false discovery rate less than 0.05$	Replication	No, 0 of 553 DMPs tested
Bozack et al.⁷³	NA	44	Asian	Arsenic	Drinking water; maternal toenails	450K	Cord blood	380	$lowercase italic p less than 1 times 10 begin superscript 6 end superscript$	Replication	Mixed, 2 of 3 genes tested using pyrosequencing
Zeng et al.⁷⁴	NA	24	Asian	E-waste exposure (heavy metals)	Prenatal maternal blood (validate heavy metal exposure)	450K	Cord blood	125	$lowercase italic p less than 0.05$	Replication	Yes, 2 of 2 DMPs
Other chemicals
Liu et al.⁷⁵	HOME	266	Multi – primarily European	PFAS	Maternal serum	EPIC	Cord blood; peripheral blood at 12 y of age	2 DMPs for PFOS, 12 for PFOA, 8 for PFHxS, and 413 for PFNA	$false discovery rate less than 0.05$	Replication	Mixed, 6 of 315 DMPs
Miura et al.⁷⁶	Hokkaido study	190	Asian	PFAS	Maternal blood	450K	Cord blood	4	$false discovery rate less than 0.05$	Replication	No, 0 of 4 DMPs
Miura et al.⁷⁷	Hokkaido study	203	Asian	di-2-ethylhexyl phthalate	Maternal blood	450K	Cord blood	2	$false discovery rate less than 0.05$	Replication	No, 0 of 2 DMPs
Vilahur et al.⁷⁸	NA	181	European	Xenoestrogens	Placenta	450K	Placenta	0	$false discovery rate less than 0.05$	Replication	No, 0 of 2 DMPs
Miura et al.⁷⁹	Hokkaido study	Male – 123; female – 154	Asian	BPA	Cord blood	450K	Cord blood	Male – 27; female – 16	$false discovery rate less than 0.05$	Replication	No, 0 of 14 DMPs in females, 0 of 26 in males
McCabe et al.⁸⁰	MMIP	69	Multi – primarily European	BPA	Maternal urine	EPIC	Umbilical cord blood leukocytes	38	$false discovery rate less than 0.05$	Replication	No, non-significant and slight correlation between effect estimates of DMPSs in independent study
Yu et al.⁸¹	NA	24	Asian	DDT pesticide	Cord blood	450K	Cord blood	1,131	$lowercase italic p less than 0.05$	Replication	Yes, 2 of 2 DMPs
Social stressors
Alfano et al.⁸²	ALSPAC	973	European	Socio-economic position	NA	450K	Cord blood; whole blood	Birth:4/childhood:0/adolescence:20	$false discovery rate less than 0.05$	Replication	No, 0 of 4 DMPs
Other exposures
Caramaschi et al.⁸³	ALSPAC and MoBa	2,644	European	Medically assisted reproduction	NA	450K	Cord blood	5	$false discovery rate less than 0.05$	Meta-analysis	No, 0 of 5 DMPs

Note: ALSPAC, Avon Longitudinal Study of Parents And Children; BPA, bisphenol A; CCLS, California Childhood Leukemia Study; DDT, dichlorodiphenyltrichloroethane; DMP, differentially methylated position; DMR, differentially methylated region; ENVIRONAGE, ENVIRonmental influence ON early AGEing; FDR, false discovery rate; HOME, Health Outcomes and Measures of the Environment; GECKO, Groningen Expert Center for Kids with Obesity; HELIX, Human Early Life Exposome; HOME, Health Outcomes and Measures of the Environment; INMA, INfancia y Medio Ambiente; MACHS, Moderate Alcohol and Cardiovascular Health; MINERVA, MINimizE Right Ventricular pacing to prevent Atrial fibrillation and heart failure; MMIP, Michigan Mother and Infant Pairs Cohort; MoBa, The Norwegian Mother & Child Cohort Study; MOCEH, Mothers and Children’s Environmental Health; NHBCS, New Hampshire Birth Cohort Study; NA, Not Applicable; PACE, Pregnancy And Childhood Epigenetics consortium; PBMCs, peripheral blood mononuclear cell; PFAS, perfluoroalkyl substances; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoate; PFOA, perfluorooctanoate; PFOS, perfluorooctane sulfonate; PM, particulate matter; RICHS, Rhode Island Child Health Study; ROLO, Randomised cOntrol trial of LOw glycaemic index diet to prevent macrosomia; THREE, Tracking Health Related to Environmental Exposures.

^{^a}

Largest $n$ reported when multiple exposure tissues, sum of all study $n$ for meta-analyses.