Table 8:

Developmental phthalate exposure and the epigenome in the context of cardiovascular health

Exposure details	Window of exposure	Model	Epigenetic/molecular effect	Phenotype	Sex specificity	Reference
Maternal urinary phthalate concentrations at 13 and 26 weeks gestation	Early-mid gestation	Human	Monoethyl phthalate levels in early and mid-gestation associated with Alu repeat methylation in cord blood; association with LINE-1 methylation present but weaker; increased concentration of di-(2-ethylhexyl) phthalate metabolites mid gestation associated with reduced methylation of Alu repeats in blood at 9 years of age	Not investigated	Not reported	[223]
Maternal urinary phthalate concentrations during 3rd trimester	Late gestation	Human	Negative association between placental LINE-1 methylation and concentrations of urinary phthalate metabolites (MEHHP and sum of DEHP)	Significant positive association between concentrations of several metabolites MEHHP, MEOHP, sum of DEHP, and fetal growth restriction	Not reported	[224]
1st trimester urinary concentrations of 11 phthalate metabolites	Early gestation	Human	Significant inverse association between placental H19 methylation and the sum of phthalate metabolites and low molecular weight phthalate metabolites; concentrations of sum and low molecular weight metabolites inversely associated with methylation of IGF2DMR0 in placenta	No significant effects of DNA methylation or imprinted gene expression on birth length or weight	Yes—Altered methylation of IGF2DMR0 with phthalate exposure more likely to occur in female placenta	[227]
Maternal urinary phthalate concentrations from patients with or without gestational diabetes mellitus in 2nd trimester	Mid gestation	Human	In maternal serum, increased miR-16-5p expression with MBzP levels; increased miR-29a-3p expression with adjusted MEHP; negative association between miR-29a-3p expression and unadjusted and adjusted MBP concentration; negative association between miR-29a-3p expression and unadjusted MiBP concentration	MEHP levels higher in non-diabetic patients compared to gestational diabetes	Not reported	[230]
DEHP (5, 50, 100 µg/mL) or DMSO vehicle	5 days, followed by differentiation into cardiomyocytes	Mouse P19 embryonic carcinoma cell line	In P19 cells, increased expression of Dnmt1, Dnmt3a at higher doses; increased methylation of CpGs within Ppara and Pparg1 genes	Increased rate of differentiation; increased beat rate	Not applicable	[231]
DEHP in chow (25 mg DEHP/kg chow in 7% corn oil)	2 weeks prior to mating, through gestation and lactation	Mouse	In mouse heart, sex-specific changes in DNA methylation at hundreds of CpGs and regions at 5 months of age; several genes with differential DEHP-induced methylation were also differentially methylated in heart samples from patients with heart failure	Not investigated	Yes	[232]
DEHP (0, 1, 10, and 100 mg/kg per day) or olive oil vehicle via oral gavage	Gestation days 9-21	Rat	Increased Hdac2, Dnmt1, Dnmt3a, and Dnmt3b protein expression, increased global DNA methylation in gastrocnemius in both sexes	Elevated blood glucose, insulin resistance, reduced insulin receptor, and reduced glucose uptake and oxidation in gastrocnemius muscle at 2 months of age in both sexes	Effects observed in both sexes	[234]
DEHP or DBP (50, 250 μg/l) or acetone vehicle	Starting 1.5–1.7 h post-fertilization and lasting 4 days	Zebrafish	In embryos, hypomethylation of nppa and ctnt genes related to cardiac development and upregulation of gene expression; hypermethylation of tbx5b gene and down-regulation of expression with highest DBP dose	Increased heart rate, pericardial edema, apoptosis	Not reported	[235]