SUN-651 Transgenerational Obesity Induced By Prenatal Tributyltin Exposure Is Exacerbated By Diet And Associated With Reduced Thermogenic Activity

Abstract Disclosure: Y. Huang: None. R. Chang: None. K. To: None. R.S. Whitlock: None. K.U. Nguyen: None. M.C. Joemon: None. M.C. Joemon: None. M. Lopez: None. K.G. Deeprompt: None. B. Blumberg: None. T. Shioda: None. Obesity is a critical public health concern, not only causing impaired metabolism due to over-accumulated fat content but also contributes to disorders such as cardiovascular disease, type II diabetes, and cancers. Our previous studies used mouse models to demonstrate that direct or ancestral exposure to the obesogen tributyltin (TBT) led to a transgenerational predisposition to obesity that was exacerbated by a modest increase in dietary fat intake. Until now, there were no studies that tested the effects of a human-relevant diet in a transgenerational obesity animal model. We hypothesized that a high-fat human-relevant diet would mimic the effects of increased fat rodent chow, exacerbating obesity in TBT-treated mice and their male offspring. Using a diet that modeled the 50th percentile of US dietary macronutrient and micronutrient intake (the Total Western diet, TWD), we found that mice were insulin-resistant and obese when fed TWD, and that this was exacerbated in the TBT group males compared to the control group and females. This research sheds light on how the Western dietary pattern may exacerbate obesity in TBT-exposed mice, providing insights into the mechanisms through which obesogens contribute to obesity. Moreover, we observed certain changes in both beige and brown adipose tissues consistent with impaired thermogenic gene expression in TWD-fed mice that was exacerbated by TBT exposure. This led us to hypothesize that obesogens also alter thermogenic activity and energy metabolism that contributes to obesity in directly exposed mice and their unexposed descendants. These findings could provide novel insights into the developmental and heritable basis of obesity, with implications for prevention and therapeutic intervention. Presentation: Sunday, July 13, 2025