Transgenerational effects of gestational exposure to a real-life environmental chemical mixture on adult cardiac function

Globally, cardiovascular diseases (CVD) persist to be the leading cause of death with an increased incidence of CVD related mortality and morbidity in men compared to women. It is increasingly recognized that adverse exposures during early development can result in adult onset of diseases including CVD. While traditional CVD risk factors including diabetes, obesity, hypertension and lack of physical activity are well-known, exposure to anthropogenic environmental chemicals (ECs) during critical period of development may also present a risk factor in the emergence of CVD in later life. Using a sheep model of translational value, the current research investigated sex-specific cardiac effects of developmental exposure to mixture of low-level chemicals by allowing pregnant sheep to graze on either inorganic fertilizer (C) or pastures treated with biosolids (B). At adult age, in-vivo cardiovascular studies followed by histological and molecular investigations were conducted in male and female offspring in the first (F1) and second generation (F2). Findings revealed sexually dimorphic changes in adult cardiovascular functioning. EC-exposed males in F1 exhibited increased left ventricular dimensions, higher diastolic, systolic and stroke volumes, and a higher cardiac output, suggestive of an eccentric left ventricular hypertrophy. In contrast to males, EC-exposed females in F1 displayed autonomic imbalance in the form of higher sympathetic dominance as indicated by an apparent pattern of lower heart rate variability metrics, including root mean square of successive differences (RMSSD) and standard deviation of normal-to-normal intervals (SDNN). Subsequent histological and molecular investigations identified an increased level of interstitial, perivascular and replacement fibrosis complimented by an increased mRNA expression of apoptosis (CASP3), inflammation (DYA, DRB1) and insulin signalling (IGF1, IGF1-R) in EC-exposed males but not in females. Males in the F2 presented increased wall thicknesses without an enlargement in ventricular dimensions and had increased mRNA expression of markers related to fibrosis, inflammation, and hypertrophy, indicative of concentric remodelling, while females exhibited an increase in COL1A1, a marker for fibrosis. Taken together, these findings suggest sexually dimorphic impacts of gestational EC mixture exposure on adult cardiac functioning with intergenerational consequences.