Skip to main content

Table 1 List of 43 selected articles by EDC exposures, including study design and main findings

From: Transgenerational epigenetic effects from male exposure to endocrine-disrupting compounds: a systematic review on research in mammals

EDC Administration of the exposure; animal model Samples tested Main findings Reference
Atrazine Orally, during pregnancy from E6.5 till E15.5 (100 mg/kg/day); CD1 mice F1: testes (E15.5 and E18.5)
F3: testes, liver, hypothalamus
F3 testes: decreased sperm number, meiotic defects
F1 and F3 testes: histone modifications (H3K4me3)
F3 somatic cells: RNA expression that corresponds to histone modification in F1 sperm
Hao et al. 2016 [35]
Daily ip injections, from E8 till E14 (25 mg/kg); Hsd:SD1 rats F1, F2, F3: epididymal sperm
F1, F2, F3: testis, epididymis, prostate, ovary, kidney (12 months)
F1: lean, but no diseases
F2: lean females, mammary tumors, testis diseases, early-onset puberty in males
F3: lean and similar disease risk as F2, motorhyperactivity
McBirney et al. 2017 [36]
Benzo[a]Pyrene (B[a]P) Single ip injection prior to IVF treatment (150 mg/kg); B6D2F1 mice Embryos (2-cell, 8-cell, blastocyst) Differential miRNA expression patterns in embryos by cell-stage and (B[a]P) exposure Brevik et al. 2012 [37]
Single ip injection, 4 days prior to IVF treatment (150 mg/kg); B6D2F1 mice Embryos (1-cell, 2-cell, 4-cell, 8-cell, blastocyst) Several genes were differentially expressed in response to B[a]P exposure
Functional analysis showed that paternal B[a]P exposure triggers biological processes, such as DNA transcription, DNA damage response, cell cycle regulation, chromatin modification, oxidation-reduction processes, apoptosis, and embryo development
Brevik et al. 2012 [38]
During 6 weeks (3 times per week) oral doses of B[a]P (13 mg/kg); C57BL/6 male mice crossed with Balb/c wildtype female mice F1: liver (PN21) Paternal exposure to B[a]P can regulate the male offspring's mitochondrial stress levels. Proteins involved in mitochondrial function were downregulated. This was paralleled by a reduction in mDNA copy number and reduced activity of citrate synthase and b-hydroxyacyl-CoA dehydrogenase. Both 8-oxo-dG and MDA-dG adduct levels were reduced.
miRNA-122, miRNA-129-2-5p, and miRNA-1941 were upregulated in a gender-specific manner
Godschalk et al. 2018 [39]
Bisphenol A (BPA) Orally, during pregnancy and lactation, from GD0 to PND21 (40 μg/kg/day); SD rats F1: sperm
F2: blood, liver
DNA methylation changes in F1 sperm and in F2 liver, although not similar
Hypermethylation of Gck promoter and altered gene expression in liver of F2 rats
Li et al. 2014 [40]
Orally, during pregnancy and lactation, from GD0 to PND21 (40 μg/kg/day); SD rats F1: sperm
F2: blood, pancreatic islets
Pancreatic β-cell dysfunction and glucose intolerance
Increased DNA methylation at Igf2 DMR2 in F1 sperm
Decreased Igf2 expression in F1 sperm
DNA hypermethylation of Igf2 in pancreatic islets in the F2 generation
Mao et al. 2015 [41]
Diet, 2 weeks prior to mating until weaning, 2 doses: 10 μg/kg/day and 10mg/kg/day); C57BL/6J mice F1: pancreatic islets (16–21 weeks)
F2: pancreatic islets (adult)
F1 and F2 males: impaired insulin secretion and increased levels of pro-inflammatory cytokines
Dose- and sex-specific effects in gene expression levels related to inflammation and mitochondrial function, in F1 and F2
Altered DNA methylation at Igf2 DMR1 and increased Igf2 expression in F1 and F2
Bansal et al. 2017 [42]
Diet of females supplemented with BPA (5 mg/kg), 10 days before mating until end of gestation; C57BL/6 mice (note: males were also exposed to the same diet during 2 weeks of mating)
Second model:
Oral administration of 3 doses (0.5, 20, or 50 μg/kg/day) from E11 till birth; FVB mice
F3 pups (PN4): brain 50 differentially regulated genes were identified in the F3 brain of exposed lineages. A selected imprinted gene, Meg3, was upregulated
Similar results were found in both models (C57BL/6J mice and FVB mice)
Drobna et al. 2018 [43]
Dichlorodiphenyltrichloroethane (DDT) Daily ip injections, from E8 till E14 (25 or 50 mg/kg); Hsd:SD1 rats F1-F4 (10–12 months): multiple organs (testis, epididymis, seminal vesicle, prostate, kidney, ovary and uterus) Several disorders emerged in the F3 generation, including obesity, testis disease, polycystic ovarian disease, immune abnormalities and kidney disease
DNA methylation at numerous DMRs was affected in F3 sperm
Skinner et al. 2013 [44]
Daily ip injections, from E8 till E14 (25 mg/kg); Hsd:SD rats F1, F2, F3: epididymal sperm (PN120) F1, F2: altered DNA methylation and ncRNA
F3: novel histone retention sites, compared to F1 and F2. Cellular apoptosis in testes
Skinner et al. 2018 [45]
Daily ip injections, from E8 till E14 (25 mg/kg/day); Hsd:SD rats F3: epididymal sperm (PN120) F3: induced H3 differential histone retention sites (DHRs); while a core histone retention sites were not altered. Ben Maamar et al. 2018 [46]
Daily ip injections, from E8 till E14 (25 mg/kg); Hsd:SD rats F3: prospermatogonia (E16), spermatogonia (P10); and adult pachytene spermatocytes, round spermatids, caput epididymal spermatozoa, and caudal sperm (12 months) F3: DNA methylation alterations of DMRs were identified at each stage, but the majority were found in (pro)spermatogonia. A link with metabolic and cancer related pathways was shown in all stages Ben Maamar et al. 2019 [47]
Dioxins and dioxin-like compounds    
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Daily ip injections, from E8 till E14 (100 ng/kg); Hsd:SD rats F1: testis, prostate, ovary, uterus, kidney
F3: testis, prostate, ovary, uterus, kidney, and epididymal sperm (PN120)
F1: increased prostate disease, ovarian primordial follicle loss, polycystic ovary disease
F3: increased kidney disease in males, ovarian pubertal abnormalities, primordial follicle loss, polycystic ovary disease
F3 sperm: altered DNA methylation at 50 DMRs
Manikkam et al., 2012 [48]
Orally, during pregnancy from E8 till E14 (200 or 800 ng/kg); SD rats F1, F3: hepatic tissue (PN90) F1, F3: decreased Igf2 expression, hepatic damage, increased activity of hepatic enzymes, hypermethylated ICR of Igf2, hypomethylated DMR2 near H19, changes in expression of DNMTs Ma et al. 2015 [49]
Orally, single dose during pregnancy on E15.5 (10 μg/kg); C57BL/6 mice F1, F3: male-derived placentae
F1, F3: epididymal sperm
F1, F3: >2000 differentially methylated regions in placenta, including Igf2 and Pgr; methylation and expression of the latter was also altered in F1/F3 sperm and F3 placenta Ding et al. 2018 [50]
P,p′-DDE Orally, from E8 till E15 (100 mg/kg/day); SD rats F1, F3, F3: motile sperm (swim-up), testes (E18 and PN120), pancreas (8 weeks) F1, F2, F3: modifications at DMRs of imprinted genes: IGF2/H19 and Gtl2 hypomethylation. These genes were upregulated in sperm and testis. Impaired glucose tolerance, abnormal insulin secretion and β-cell dysfunction. Pancreatic impairment and decreased sperm characteristics in offspring (F3) of exposed grandfathers (F1 in utero). DNMT1 and 3a were decreased in embryonic testis of F1 and F2 (but not in F3) Song et al. 2014 [51]
Song et al. 2017 [52]
Song et al. 2018 [53]
Methoxychlor (MXC) Daily ip injections (10 mg/kg) in adult males (8 weeks old), during 8 days
Daily ip injections, from E8 till E10 (10 mg/kg); FVB/N mice
F1, F2, F3: tail, liver, skeletal muscle, epididymal sperm (2 months) F1: decreased mean sperm concentrations, altered DNA methylation patterns at several imprinted genes in sperm
F2-F3: transference of defects through the male germ line, but methylation defects were limited to a few genes
Stouder et al. 2011 [54]
Daily ip injections, from E8 till E14 (200 mg/kg); Hsd:SD1 rats F1, F3, F4: kidney, ovary, uterus, testis, prostate, epididymal sperm (10-12 months) F1, F3: increased incidence of kidney disease, ovary disease, obesity and multiple diseases
F3: sperm "epimutations"
F4: increased disease incidence through the female germ line
Manikkam et al. 2014 [55]
Phthalates Daily ip injections, from E7 till E19 (750 mg/kg); SD rats F1, F2, F3, F4: testis, epididymal sperm (PN80) F1: cryptorchidism incidence 30%, conception rate 50%, atrophy of seminiferous epithelium with few spermatogenic cells
F2: cryptorchidism incidence 12.5%, conception rate 75%
F3, F4: no cryptorchidism, conception rate 100%, normal sperm cells
From F1 to F4: increased Dnmt levels, differentially methylated DNA sequences
Chen et al. 2015 [56]
Orally, from E8 till E14 (500 mg/kg/day); SD rats F1, F2, F3: testis, epididymal sperm (PN60) F1 - F3: decreased sperm count, increased betaine levels, lowered expression of BHMT and global DNA hypomethylation Yuan et al. 2017 [57]
Vinclozolin Daily ip injections, from E8 till E14 (100 mg/kg/day); Hsd:SD rats F1, F2, F3: testes at E16 F1, F2: changes in testis transcriptome, altered expression of methyltransferases
F3: similar as F1 and F2, but most methyltransferases returned to the control generation levels
Anway et al. 2008 [58]
F3: epididymal sperm F3: differential DNA methylation in at least 16 promoter regions Guerrero-Bosagna et al. 2010 [59]
F3: pathologies of testis, seminal vesicle, prostate, liver, kidney, ovary, heart, ovary, uterus (PN120) F3: unique tissue transcriptome, but common cellular pathways were identified between tissues; a number of identified gene clusters corresponded to the epimutations previously found in sperm that transmit epigenetic transgenerational inheritance of disease phenotypes Skinner et al. 2012 [60]
F3: fetal testis (E13 and E16) F3: altered germ line transcriptome and epigenome, distinct in E13 germ cells (onset of gonadal sex determination) and E16 germ cells (after cord formation in the testis) Skinner et al. 2013 [61]
F3: testis and Sertoli cells (PN20) F3: Increased spermatogenic cell apoptosis, 417 differentially expressed genes in Sertoli cells that have been linked with 22 pathways (incl. pyruvate/lactate metabolism pathway), > 100 promoter regions were differentially methylated in Sertoli cells Guerrero-Bosagna et al. 2013 [62]
F3: Sertoli cells (E13) F3: altered SRY binding sites Skinner et al. 2015 [63]
F3: epididymal sperm (12 months) F3: > 200 differentially expressed sncRNAs and associations with differentially methylated regions Schuster et al. 2016 [64]
F1, F3: epididymal sperm F1: 290 altered DMRs
F3: 981 altered DMRs
No overlap between these DMR sets
Beck et al. 2017 [65]
F1, F2, F3: pathologies (12 months)
F3: epididymal sperm
F1, F2: few abnormalities
F3: increased testis, prostate and kidney disease, changes in puberty onset in males, increased obesity rate in females; most of these diseases were linked to DMRs in sperm
Nilsson et al. 2018 [66]
F1, F2, F3: epididymal sperm (12 months) F1, F2, F3: altered DNA methylation and ncRNAs, distinct between direct versus transgenerational exposure
F3: high numbers of differential histone retention sites
Ben Maamar et al., 2018 [67]
F3: prostate (PN19-21 and 12 months) F3: increased prostate abnormalities, changes in gene expression, ncRNA expression and DNA methylation Klukovich et al. 2019 [68]
Daily ip injections, from E7 till E13 (100 and 200 mg/kg/day); CD1 mice
Daily ip injections, from E7 till E13 (100 mg/kg/day); inbred 129-mice (pathology analyses only)
F3: testis, prostate, kidney and ovary, epididymal sperm, isolated sperm heads (PN60-90 and 13–15 months) F3: abnormalities in testis, prostate and kidney, polycystic ovarian disease, and spermatogenic cell defects (higher in low dose exposure than in high dose exposure); these effects were mainly seen in CD1 mice
F3 (sperm heads of CD1 mice and lowest dose only): differential DNA methylated regions
Guerrero-Bosagna et al. 2012 [69]
Daily ip injections, from E8 till E14 (100 mg/kg/day); Big Blue rats carrying lacl mutation-reporter transgene F1, F3: kidney, epididymal sperm (< 1 year of age) F1: no changes in mutation frequency in kidney and sperm
F3: higher frequency of point mutations in kidney and sperm from control and in VCZ lineages, compared to F1; a subset of F3 animals showed a significantly higher mutation frequency in VCZ-exposed lineages, compared to F3 controls
McCarrey et al. 2016 [70]
Daily ip injections, from E8 till E15 (100 mg/kg/day); Hsd:SD rats F1, F2: testis (PN6)
F1, F2: epididymal sperm, testis, prostate, seminal vesicle (13 weeks old)
F1, F2: no effect on spermatogenesis and fertility, no changes in methylation status Inawaka et al. 2009 [71]
Daily ip injections, from E10 till E18 (50 mg/kg/day); FVB/N mice F1, F2, F3: epididymal sperm, tail, liver, skeletal muscle F1: decreased DNA methylation at H19 and Gtl2 and increased DNA methylation at Peg1, Snrpn, Peg3; decreased motile sperm fraction
F2, F3: the F1 effects decreased gradually
Stouder et al. 2010 [72]
Orally, during pregnancy (1 and 100 mg/kg/day); CD1 mice F1, F2, F3: testis (E13.5 and adult) F1: male fertility rate reduces gradually by increasing dose, decreased number of PGCs, increased apoptosis in adult testis
F2: fertility rate was recovered (in low dose lineage only), but still increments in apoptosis in adult testis of both high and low dose lineages
F3: decreased fertility rate (both doses), recovery of number of PGCs (both doses), increased number of apoptotic cells in adult testis
F1, F2, F3: deregulation of several microRNAs in PGCs
Brieno-Enriquez et al. 2015 [73]
Daily ip injections, from E8 till E158 (1 mg/kg); SD rats F1, F3: sperm, brain (hippocampal CA3 and central amygdala) (PN120) F1, F3: hypermethylation, intergenic CpG islands proximal to pRNA were affected; fewer DMRs were found in brain compared to sperm, and in between tissue overlap of related genes was small Gillette et al. 2018 [74]
EDC mixtures Daily ip injections, from E8 till E14 (Permithrin: 150 mg/kg, DEET: 40 mg/kg, BPA: 50 mg/kg, DEHP: 750 mg/kg, DBP: 66 mg/kg, TCDD: 100 ng/kg, Jet fuel: 500 mg/kg); Hsd:SD rats F1, F2, F3: blood, ovary, testis, epididymis, isolated sperm heads (PN90-120) F3: plastics, dioxin and jet fuel were found to promote early-onset female puberty, decreased ovarian primordial follicle pool size, and spermatogenic cell apoptosis
F3 (sperm heads): differential DNA methylated regions, specific to the exposure group
Manikkam et al. 2012 [75]
Daily ip injections, from E8 till E14 (BPA 50 mg/kg, DEHP 750 mg/kg, DBP 66 mg/kg); Hsd:SD rats F1, F3: kidney, ovary, uterus, testis, epididymis, prostate, seminal vesicle, (12 months)
F3: epididymal sperm, isolated sperm heads
F1: increased kidney and prostate disease
F3: Increased pubertal anomalies, testis disease, obesity, ovarian disease
F3: differential DNA methylation regions in gene promoters of sperm
Manikkam et al. 2013 [76]
Daily ip injections, from E8 till E158 (A1221: 1 mg/kg); SD rats F1, F3: sperm, brain (hippocampal CA3 and central amygdala) (PN120) F1, F3: hypermethylation, intergenic CpG islands proximal to pRNA were affected; fewer DMRs were found in brain compared to sperm, small overlap of related genes between sperm and brain Gillette et al. 2018 [74]