Imprinted genes and how their interactions with environmental chemicals can affect maternal and fetal health was the focus of a talk by Martha Susiarjo, Ph.D., from the University of Rochester. She spoke March 21 as part of the NIEHS Keystone Science Lecture Seminar Series.
Imprinted genes are those in which the copy from one parent is silenced through epigenetic modifications, which are changes to DNA that affect the function of genes but not the underlying DNA sequence.
“Although imprinted genes represent a small portion of the mammalian genome, they play a critical role during early development,” said Susiarjo. “We are working to understand how epigenetic markers mediate these effects and how gene-environment interactions can reprogram development of the fetus.”
Fred Tyson, Ph.D., a program director in the NIEHS Genes Environment and Health Branch, hosted the talk. “It was exciting to learn more about Susiarjo’s innovative work as an early-stage investigator,” said Tyson. “Her research is revealing new information about how epigenetic regulation of genes contributes to early development, and how environmental chemicals may alter this process.”
Regulating genomic imprinting
Susiarjo and colleagues previously discovered that exposure to bisphenol A (BPA) disrupts genomic imprinting in mice. In pregnant mice exposed to BPA, they observed altered DNA methylation, which is a type of epigenetic marker that can silence a gene. These changes occurred in regions of DNA that encode for imprinted genes in the fetus and placenta.
The team also discovered that BPA exposure can disrupt metabolic health across multiple generations through inheritance of DNA methylation changes in a region of DNA related to growth.
“DNA methylation is the best characterized epigenetic mechanism regulating imprinting,” Susiarjo explained. “Altered DNA methylation can affect imprinted gene expression, which could potentially disrupt normal fetal and placental development.”
Delving into mechanisms
When Susiarjo and her team began investigating the mechanisms involved in the effects of BPA, they found that BPA exposure significantly increased maternal and fetal levels of tryptophan, an essential amino acid.
“More recently, we have shown that Ido1, a gene that encodes for a tryptophan catabolizing enzyme, is a maternally expressed imprinted gene,” said Susiarjo. “We have also detected evidence that altered DNA methylation at the Ido1 region may be linked to pregnancy loss in mice.”
Her ongoing studies focus on further characterizing how the Ido1 gene is regulated in mice. The Susiarjo lab is also investigating how exposure to endocrine-disrupting chemicals, including a commonly used flame retardant known as TBBPA, affects imprinting and negative pregnancy outcomes. Susiarjo is interested in whether the mechanisms occurring in mice may be similar to those in people.
“Martha uses an array of epigenetic, genetic, and metabolomic approaches to identify and explain the mechanisms involved in the impacts of endocrine disrupting chemicals on pregnancy loss,” said Tyson. “Reproductive toxicology is an important component of NIEHS grants that address high priority public health concerns. Her research linking immune system changes mediated by TBBPA to adverse pregnancy outcomes is well aligned with the NIEHS mission.”
Susiarjo M, Sasson I, Mesaros C, Bartolomei MS. 2013. Bisphenol a exposure disrupts genomic imprinting in the mouse. PLoS Genet 9(4):e1003401.
Susiarjo M, Xin F, Bansal A, Stefaniak M, Li C, Simmons RA, Bartolomei MS. 2015. Bisphenol a exposure disrupts metabolic health across multiple generations in the mouse. Endocrinology 56(6):2049–2058.
Susiarjo M, Xin F, Stefaniak M, Mesaros C, Simmons RA, Bartolomei MS. 2017. Bile acids and tryptophan metabolism are novel pathways involved in metabolic abnormalities in BPA-exposed pregnant mice and male offspring. Endocrinology 158(8):2533–2542.
(Sara Amolegbe is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)