Abstract
Environmental chemicals can induce liver defects in experimental animals due to their direct and acute exposure. It is not clear whether environmental chemical exposures result in the transgenerational passage of liver defects in subsequent generations living in an uncontaminated environment. Bisphenol A (BPA), a plasticizer chemical, has been ubiquitous in the environment in the recent decade. Every organism is exposed to this chemical at some point during its lifetime. Literature suggests that direct BPA exposure can result in several metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). Despite the phasing out of BPA from several consumer goods, it is unclear whether ancestral BPA exposure causes liver health problems in the unexposed future generations. Here, we demonstrate an advanced stage of NAFLD in the grandchildren (F2 generation) of medaka fish (Oryzias latipes) due to embryonic BPA exposure in the grandparental generation (F0), which persists for five generations (F4) even in the absence of BPA. The severity of transgenerational NAFLD phenotype included steatosis together with perisinusoidal fibrosis and apoptosis of hepatocytes. Adult females developed more severe histopathological conditions in the liver than males. Genes encoding enzymes involved in lipolytic pathways were significantly decreased. The present results suggest that ancestral BPA exposure can result in transgenerational metabolic diseases that can persist for five generations and that the NAFLD trait is sexually dimorphic. Given that ancestral BPA exposure can lead to altered metabolic health outcomes in the subsequent unexposed generations, the development of the methods and strategies to mitigate the transgenerational onset of metabolic diseases seem imperative to protect future generations.