Table 2:

Generational effects of environment on cardiovascular health

Environmental factor	Window of exposure	Model	Epigenetic/molecular effect	Phenotype	Sex specificity	Reference
Nutrient and calorie restriction	Gestation	Rat	Not investigated	High blood pressure and impaired vasodilation (F1, F2, and F3) at 16 weeks of age	Only male offspring were evaluated	[74]
High-fat and high-sucrose diet	Gestation and lactation	Mouse	Not investigated	Increased left ventricular mass in male (F1, F2, and F3) and female (F1 and F2) offspring, cardiac mitochondrial abnormalities in both sexes (F1, F2, and F3) at 8 weeks of age	Yes	[16]
Bisphenol A (100 and 2000 μg/l)	Spermatogenesis	Zebrafish	No changes in global DNA methylation in testicular cells or spermatozoa	Cardiac edema and malformations (defects in both heart chambers) in high dose exposed 7 dpf larvae (F1 and F2)	Not reported	[75]
Food availability	Slow growth period (before pre-pubertal peak in growth velocity) in males	Human	Not investigated	Increased risk of death from diabetes mellitus in grandchildren of men exposed to abundant food during the slow growth period; decreased risk of death from CVD among grandchildren of men exposed to famine during the slow growth period	Not reported	[76]
Food availability	Period prior to puberty in females	Human	Not investigated	Increased risk of cardiovascular mortality in daughters of the sons from women exposed to sharp changes in food supply before puberty	Yes	[77]
Famine	Gestation	Human	Not investigated	Increased risk of hyperglycemia (F1 and F2) in adulthood	Not reported	[78]
BPA, DEHP, and DBP at two doses: BPA 50 mg/kg BW/day, DEHP 750 mg/kg BW/day and DBP 66 mg/kg/BW/day and a second group with half of those doses via intraperitoneal injection	Gestation days 8–14	Rat	Differential DNA methylation in 197 regions in sperm of F3 generation	Obesity and pubertal abnormalities (primarily delayed puberty onset) in F3 males and females	Effects observed in both males and females	[82]
Methoxychlor (200 mg/kg BW/day)	Gestation days 8–14	Rat	Differential DNA methylation in sperm of F3 generation	Pubertal abnormalities in F1 males and females; obesity in F3 males and females, with a greater incidence in males; obesity in F4 generation males (transmitted through female)	Yes	[83]
A pesticide mixture (permethrin 150 mg/kg and DEET 40 mg/kg), a plastic mixture (bisphenol A 50 mg/kg, DBP 66 mg/kg, and DEHP 750 mg/kg), dioxin (TCDD 100 ng/kg) and a hydrocarbon mixture (jet fuel, JP8 500 mg/kg) or sesame oil control by intraperitoneal injection	Gestation days 8 to 14	Rat	Differentially methylated regions in the sperm of males from all exposure lineages	Early onset puberty in F3 females with exposure to plastics, dioxin and jet fuel; reduced number of ovarian follicles in F3 females with all exposures; increased sperm apoptosis in F3 males exposed to jet fuel	Yes	[84]
Vinclozolin (100  or 200 mg/kg) or DMSO in sesame oil control	Gestation days 7–13	Mouse	Differential DNA methylation in F3 sperm	Increased testis, prostate and kidney disease in F3 males; increase sperm apoptosis in F1, F2, and F3 males; increased ovarian cysts in F1, F2, and F3 females	Yes	[85]
Jet fuel (25% the oral LD50 dose) or DMSO in sesame oil by intraperitoneal injection	Gestation days 8 to 14	Rat	Differential DNA methylation at 33 regions in F3 sperm	Renal abnormalities in F1 males and females; prostate and altered puberty timing in F1 males; loss of ovarian follicles and polycystic ovarian disease in F1 and F3 females; obesity in F3 males and females	Yes	[86]
Glyphosate (25 mg/kg body weight daily)	Gestation days 8–14	Rat	Differential DNA methylation in sperm of F1 (264 regions), F2 (174 regions), and F3 (378 regions) generations	Delayed puberty in F1 and F2 males and F2 females; obesity in F2 and F3 males and females at 1 year of age	Yes	[87]
Tributyltin (50 nM in drinking water)	Gestation and lactation	Mouse	Changes in global DNA methylation in white adipose tissue from F4 males; changes in chromatin accessibility in F3 and F4 sperm	Increased obesity in response to a high-fat diet in F4 males	Yes	[6]
Tributyltin (5.42, 54.2, or 542 nM in drinking water)	7 days prior to mating, through gestation	Mouse	Not investigated	Increased white adipose tissue and depots and adipocyte size and number in F1, F2, and F3 males and F1 and F2 females	Effects observed in both males and females	[88]
Maternal high-fat diet	6 weeks prior to mating, through gestation and lactation	Mouse	Not investigated	Increased body weight in F3 females and improved glucose tolerance in F3 males	Yes	[89]