Perinatal exposure to environmentally relevant doses of bisphenol-A (BPA) during a period comparable to that of human fetal development causes a complex syndrome in our CD-1 mouse model that includes alterations in fertility, behavior, body composition, glucose homeostasis, metabolic profiles and increased propensity to mammary cancer. These effects were attributed to direct action of BPA on target organs; however, indirect effects may result from BPA-induced alterations in the mother, including changes in her behavior, circulating hormone levels and gut microbiome. In a pilot study, the fecal microbiota in adult females exposed perinatally to BPA revealed a decrease in beneficial bacteria and differences in bacteria associated with intestinal pathology, suggesting that these alterations may contribute to some effects of BPA exposure. Also, the metabolomic profiles of these mice differ from controls at all time-points studied. Because the gut microbiome affects the metabolome, we will explore the potential link between BPA exposure, gut microbiome changes and the serum metabolome. Metabolomic profiling will be used as an independent marker of microbiome status. We hypothesize that: 1) perinatal BPA alters the gut microbiome of exposed offspring and their mothers; and 2) the metabolomic profiles of the BPA exposed offspring will reflect changes in the gut microbiota and provide a marker of BPA exposure and gut microbiome composition.
Specific Aim 1 : explores the hypothesis that BPA exposure alters the gut microbiota of female and male offspring exposed perinatally to BPA. The microbiome will be analyzed in fecal extracts of male and female offspring at PND 15, PND 28, and at 3 months of age. Additionally, fecal extracts from their mothers will be analyzed at the end of gestation and during lactation (LD15) to examine maternal effects that may be transmitted to the offspring. Sequencing data will be analyzed to identify differentially abundant features in BPA exposed and control animals.
Specific Aim 2 explores the hypothesis that metabolomics profiling provides a biomarker of microbiome health and early BPA exposure. NMR metabolic fingerprints will be used to correlate microbiome and metabolome changes in the offspring studied in Specific Aim 1. First, we will discriminate between groups. Next, NMR and HRMS metabolomic profiles will be used to reconstruct ?metabolic networks? of mice from different treatment groups. Finally, we will identify sub-networks of biological significance e.g. the metabolic pathways that may be shifted due to effects of BPA exposure on the gut microbiota (short chain fatty acids, serotonin, butyrate, etc). These exploratory studies will delineate the effects of perinatal BPA exposure on the gut microbiota to determine whether changes in microbiota composition may contribute to some adverse effects of BPA including the altered metabolomic profiles consistently observed in our animals. These findings may identify a new target of BPA action as well as reliable metabolomics markers to guide and evaluate future therapeutic interventions (e.g. administration of pro-biotics,etc.) to ameliorate components of the BPA syndrome.

Public Health Relevance

Perinatal exposure to BPA induces deleterious effects in rodents including pathologies that have increased in human populations such as obesity, metabolic disease, infertility and mammary neoplasms suggesting a link between BPA and these outcomes. The proposed studies ask whether perinatal BPA exposure affects the gut microbiota which in turn could mediate some deleterious effects, and whether microbiome changes contribute to the altered metabolomics profile consistently found in BPA exposed animals. Understanding the potential role of the gut microbiome in the deleterious effects of perinatal BPA exposure and the relationship between the gut microbiota and the metabolome will provide guidance for future interventions (e.g. administration of pro-biotics, fecal transplants) to ameliorate some components of the perinatal BPA syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES026283-02
Application #
9321988
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Chadwick, Lisa
Project Start
2016-08-01
Project End
2018-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Tufts University
Department
Physiology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111