Table 7:
developmental phthalate exposure and cardiovascular health
| Exposure details | Window of exposure | Model | Epigenetic/molecular effect | Phenotype | Sex specificity | Reference |
|---|---|---|---|---|---|---|
| Exposure to DEHP (500 mg/kg) during pregnancy | Embryonic days 6.5–14.5 | Mouse | Not investigated | Reduced fetal weight, increased septal defects, and ventricular myocardium noncompaction | Not reported | [202] |
| DEHP (0.02 pg) injected into the yolk sac of the embryo | 1–4 days post-fertilization | Zebrafish | Not investigated | Increased mortality at 2 and 3 days post-fertilization; reduced heart rate at 3 and 4 days post-fertilization; pericardial edema and heart looping disorder 3 days post-fertilization | Not reported | [203] |
| Benzyl butyl phthalate (0, 0.3, 1.9, and 3.8 μM) in petri dish water | 4–72 h post-fertilization | Zebrafish | Not investigated | Dose-dependent cardiac malformations (pericardial edema, elongated and string-shaped heart, looping abnormalities), reduced heart rate | Not reported | [204] |
| Dibutyl phthalate (0, 0.36, 1.8, and 3.6 μM) in petri dish water | 4–72 h post-fertilization | Zebrafish | Not investigated | Dose-dependent increase in pericardial edema, structural abnormalities; reduced heart rate at highest dose | Not reported | [205] |
| DEHP administered to dams (0, 1, 10, and 100 mg/kg/day via oral gavage) | Lactation—postpartum days 1–21 | Rat | Not investigated | Dose-dependent increased fasting blood glucose; decreased insulin receptor expression and insulin receptor substrate phosphorylation in female hearts at postnatal day 60 | Only females were evaluated | [206] |
| DEHP administered to dams (1, 10, and 100 mg/kg/day) or olive oil control by oral gavage | Lactation—postpartum days 1–21 | Rat | Not investigated | Increased blood glucose, decreased glucose uptake and oxidation, and decreased insulin receptor expression in male hearts at post-natal day 22 | Only males were evaluated | [207] |
| DEHP (1, 10, 100, and 300 mg/kg) administered intragastric under anesthesia | 5–6 weeks of age, for a period of 35 days | Mouse | Not investigated | Inhibition of fatty acid beta oxidation and TCA cycle; increased glycolysis; inhibition of synthesis and transport of fatty acids in hearts of male mice | Only males were evaluated | [208] |
| DEHP (50 and 100 μg/mL) or DMSO vehicle in culture medium | 72 h | Neonatal rat cardiomyocytes from 1-day-old rats | Not investigated | Increase in cardiomyocyte fatty acid transport and beta oxidation; increased expression of genes associated with fatty acid transport and beta oxidation | Not reported | [209] |
| DEHP (300 mg/kg/day) by oral gavage | Gestational day 14 until birth | Rat | Not investigated | Decreased activity in post-natal day 60 offspring; decreased activity and blood pressure in post-natal day 200 offspring | Only males were evaluated | [210] |
| Phthalate exposure estimated via job exposure matrix | Reported occupational exposure during periconceptional period | Human | Not investigated | Maternal phthalate exposure associated with perimembranous ventricular septal defect, patent ductus arteriosus, secundum atrial septal defect, and pulmonary valve stenosis; paternal exposures associated with perimembranous ventricular septal defect and pulmonary valve stenosis | Not reported | [215] |
| Phthalate exposure estimated via job exposure matrix | Reported occupational exposure during periconceptional period | Human | Not investigated | Paternal phthalate exposure associated with increased incidence of congenital heart defects; no significant associations observed for maternal exposures | Not reported | [216] |
| Maternal urinary phthalate metabolites in 1st, 2nd, and 3rd trimester | Gestation | Human | Not investigated | Increased phthalic acid in 1st trimester associated with increased pericardial fat index at 10 years of age | Effects observed in both sexes | [217] |
| Maternal urinary phthalates in 1st, 2nd, and 3rd trimester | Human | Not investigated | 3rd trimester high molecular weight phthalates associated with lower systolic and diastolic blood pressure in girls (mean age 9.7 years); no associations observed for boys | Yes | [46] | |
| Urinary phthalate metabolites in children 6–8 years of age | Childhood | Human | Not investigated | Significant positive association between several phthalate metabolites and blood pressure z-score, pulse pressure, mean arterial pressure; monomethyl phthalate associated with increased risk of high blood pressure | Not reported | [218] |
| Urinary metabolite concentrations of three phthalates (low molecular weight, high molecular weight, and DEHP) | Childhood, adolescence—ages 6–19 | Human | Not investigated | Positive association between metabolites of DEHP and systolic blood pressure | Not reported | [219] |
| Maternal urinary phthalate concentrations in 1st, 2nd, and 3rd trimester | Gestation | Human | Blood leukocyte DNA methylation at H19 or HSD11B2 do not mediate association between phthalate exposure and adiposity | 1st and 2nd trimester phthalate metabolites positively (MBP and MIBP) or negatively (MBzP) associated with adiposity in adolescent girls; 2nd trimester MBzP associated with increased BMI and waist circumference in boys | Yes | [220] |
| Maternal urinary phthalate metabolites at 13 and 26 weeks gestation | Early-mid gestation | Human | Not investigated | Early gestational phthalate metabolites (monobenzyl, monocarboxyoctyl, and monocarboxynonyl phthalate) negatively associated with 8-isoprostane at 9 years of age; early gestational mono(2-ethylhexyl) and mono(2-ethyl-5-carboxypentyl) phthalate positively associated with 8-isoprostane at 14 years of age | Not reported | [221] |