Summary
As the contamination of the environment by endocrine-disrupting chemicals (EDCs) diminishes, endocrine disruption is believed to be minimized. This statement seems not to be true in some instances. Recent studies clearly demonstrate that EDCs can leave long-lasting and heritable effects if germ cells are exposed to them during their critical stages of increased sensitivity, such as germ cell sex differentiation and spermatogenesis. Such effects can be inherited by somatic cells of the offspring if not corrected during epigenetic reprogramming of the embryo and lead to adverse health outcomes depending on where in the genome the lesions are. Here we show that bisphenol A (BPA), atrazine, ethinylestradiol (EE2), and delta-9 tetrahydrocannabinol (THC) can induce heritable effects in germ cells which leads to reproductive and metabolic disorders in subsequent unexposed generations. BPA exposure of medaka embryos for the first 12 days of life resulted in reproductive impairment in males, dysbiosis of gut microbiota, and non-alcoholic fatty liver disease in the unexposed grandchildren. Clear germline transmission of altered DNA methylation profile was observed in the paternal sperm and offspring somatic cells predicting dysregulation of transcriptional networks associated with observed phenotypes. Atrazine, EE2, and THC exposure during the same developmental period led to fertility impairment in males in the unexposed third-generation offspring, including transcriptional dysregulation in the brain predictive of increased addiction in future generations by THC exposure. These studies collectively suggest that environmental exposure effects are heritable and can persist in organisms even after the environmental contamination is mitigated. These observations also call for research to determine the health risks caused by past environmental contaminants in humans and wildlife as well susceptibility of current unexposed generation to second or third hit by the chemical contaminants of emerging concern. It also warrants strategies to mitigate transgenerational diseases in future generations before their onset in adulthood.
Brief biography
Dr. Bhandari graduated with a PhD in Comparative Endocrinology from Hokkaido University and worked as a postdoctoral fellow with Dr. Michael Skinner at Washington State University and Dr. Fred vom Saal at the University of Missouri before joining the University of North Carolina Greensboro as a tenure-track faculty. The overall goal of Dr. Bhandari’s research program is to understand how gene-environment interactions lead to adaptive or maladaptive phenotypic traits. To understand this broad question, his research group is considering chemicals and non-chemical stressors to which humans and other vertebrate organisms are exposed to as environment, epigenetic mechanisms as drivers, and altered health outcomes, mainly early embryonic development and later life reproductive and metabolic health as phenotypic traits. They take comparative, molecular, cellular, and bioinformatics approaches and utilize in vitro 3D human cell co-culture and in vivo animal models (fish and rodents) in research. They use advanced research tools, including next-generation genomic and epigenomic analysis, transgenesis, and CRISPR-mediated genome and epigenome editing to understand mechanisms underlying environmentally induced altered health conditions and inheritance of environmentally induced health effects in subsequent generations. Dr. Bhandari has been supported by funding from the National Institutes of Health, US Geological Survey, University of Missouri, and the University of North Carolina Greensboro. He has published 52 papers and additional several manuscripts are currently under review.
With the funding support of the ‘Severo Ochoa Centre of Excellence’ accreditation, of the Spanish “Ministerio de Ciencia, Innovación y Universidades”. 2020-2023 (CEX2019-000928-S).