Interactions between prenatal obesogen exposure and Total Western diet lead to a transgenerational thrifty phenotype: functional and epigenomic analysis of effects in fat and liver

PROJECT SUMMARY
Obesity is a serious public health concern, largely because obesity and related disorders (e.g., cardiovascular
disease, type II diabetes, hypertension, cancers, etc.) add more than $200 billion annually to US health care
costs. The current clinical paradigm for obesity is one of energy intake versus energy expenditure, with clinical
management focused on diet and exercise. Diet and exercise are important factors in obesity, particularly the
energy dense Western dietary pattern, but they do not fully account for the obesity epidemic. US adults were
2.3 kg/m2 higher in BMI in 2006 than in 1988, even at comparable caloric intake and energy expenditure.
Emerging evidence supports an important role for exposure to endocrine disrupting chemicals (EDCs)in
obesity. We identified tributyltin (TBT) as an environmental “obesogen” - a chemical that leads to weight gain,
in vivo. In utero exposure to environmentally-relevant levels of TBT increased fat depot weight, reprogrammed
mesenchymal stem cells to favor the adipogenic fate and caused non alcoholic fatty liver disease in F1-F4
male offspring. We reproduced these transgenerational phenotypes in two independent experiments and found
that male F4 descendents of F0 TBT-treated animals became obese when dietary fat was increased. This fat
persisted after the animals were returned to normal low fat chow. TBT-treated animals and their descendents
were resistant to fasting-induced fat loss, indicating that these animals do not mobilize fat to the same extent
as controls during fasting. We found that fat in F4 male descendants of TBT treated dams showed persistent
DNA hypomethylation in regions encompassing important metabolic genes such as the Lep gene, increased
leptin mRNA expression, elevated plasma leptin levels, and that these hypomethylated regions in fat were less
accessible in sperm chromatin of F3/F4 males. We proposed that these animals exhibited a transgenerational
"thrifty phenotype" caused by altered chromatin structure and accessibility. We hypothesize that TBT exposure
modifies the epigenome across multiple generations, sensitizing animals to weight gain and that this “thrifty
phenotype” is revealed or exacerbated by increased dietary fat. Two specific aims are proposed: 1) How does
TBT exposure exacerbate the effects of “Total Western Diet” leading to weight gain?, and 2) How does TBT
exposure make animals resistant to fat loss? Answering these key questions will address knowledge gaps in
the field that are relevant to human health. The proposed research will reveal which molecular mechanisms
may underlie the effects of obesogens and how a Western dietary pattern interacts with obesogen exposure to
predispose toward fat gain and promote the transgenerational programming of obesity. This will greatly inform
the thinking of clinicians and the public in understanding individual susceptibility to obesity and how best it may
be treated and prevented in individuals. The successful completion of this research will illuminate the molecular
mechanisms underlying the role of xenobiotic chemicals on obesity, and may provide insights into how the
obesity epidemic can be curtailed.

Grant Number: 5R01ES031139-05
NIH Institute/Center: NIH
Principal Investigator: BRUCE BLUMBERG