Perinatal Bisphenol AP Exposure Induces Multigenerational Cardiometabolic Dysfunction via Dysregulation of...

The use of BPA alternatives in consumer products has increased substantially, yet their long-term metabolic safety remains poorly understood. This study investigated the effects of perinatal exposure to bisphenol AP (BP-AP) on multigenerational metabolic and cardiovascular outcomes, with particular emphasis on cholesterol homeostasis in hepatic and cardiac tissues and the potential association between hepatic and cardiac alterations. F0 dams were exposed to BP-AP during gestation and lactation, and metabolic phenotypes were evaluated in F1 and F2 offspring. Oral glucose tolerance and insulin tolerance tests were performed to assess glucose homeostasis, while echocardiography was used to evaluate cardiac structure and function. Histopathology, serum lipid profiling, urine metabolomics, oxidative stress assessments, and gene and protein expression analyses were conducted to investigate molecular and metabolic alterations associated with BP-AP exposure. Both F1 and F2 male offspring exhibited impaired glucose homeostasis and progressive cardiac dysfunction, characterised by increased left ventricular mass, reduced ejection fraction, and myocardial histopathological abnormalities. Urine metabolomics revealed elevated hydroxycholesterol species, consistent with altered cholesterol turnover. Hepatic and cardiac tissues showed increased cholesterol accumulation, accompanied by altered estrogen receptor signalling and activation of the SREBP2-HMGCR cholesterol biosynthetic pathway. Genes involved in cholesterol uptake, transport, and reabsorption, including LDLR, SR-B1, NPC1L1, APOA1, and APOB, were dysregulated, together with compensatory changes in cholesterol efflux transporters. BP-AP exposure also induced persistent oxidative stress, as evidenced by increased oxidative damage biomarkers and cardiac malondialdehyde levels, together with reduced glutathione and catalase activities. These molecular alterations were more pronounced in males and persisted across generations. In conclusion, perinatal BP-AP exposure was associated with multigenerational, sex-specific disruption of cholesterol homeostasis in hepatic and cardiac tissues, oxidative stress, and cardiometabolic dysfunction. The coordinated hepatic and cardiac alterations suggest a potential association between disrupted hepatic cholesterol metabolism and cardiac dysfunction. These findings support further investigation of the long-term, multigenerational, and sex-specific biological effects of BPA substitutes.