METABOLIC DYSFUNCTION INDUCED BY PRENATAL EXPOSURE TO BISPHENOL‐A AND DIETHYL HEXYL PHTHALATE: EXACERBATION BY HIGH FAT DIET
Authors: Hahn‐Townsend Coral Kristine , Varde Pratibha A , MohanKumar Puliyur S , MohanKumar Sheba M 
Published: November 2023

Despite ongoing medical and scientific efforts, the incidence of obesity and metabolic disease continues to rise in the United States and shows an upward trend world‐wide. Many epidemiological studies suggest that exposure to endocrine disrupting chemicals (EDCs) could be associated with an increased risk of obesity and metabolic dysfunction. It has been shown that EDCs such as Bisphenol‐A (BPA) and diethylhexyl phthalate (DEHP) can cross the placenta and affect the developing fetus. Since the fetus is exceptionally sensitive to changes in hormones and altered endocrine signaling, it is highly likely that prenatal EDC exposure programs the fetus leading to metabolic dysfunction in adulthood. Most humans are exposed to levels of BPA and DEHP far below the reference doses for these chemicals, which is considered to be a safe level of exposure. However, studies examining the effects of prenatal exposures to low levels of EDCs are limited. Therefore, we hypothesized that prenatal exposures to low levels of BPA and DEHP will affect metabolic functions in the offspring and that this effect will be exacerbated when offspring are challenged with a high fat diet (HFD). Pregnant Sprague Dawley rats were dosed once a day by oral gavage with either saline (n=5), 5μg/kg BW of BPA (n=4), or 7.5 mg/kg BW of DEHP (n=5) from gestational day 6 to day 21. Male offspring were allowed to reach 3 to 4 months of age and were then challenged with either a HFD or normal rat chow for 2 weeks. Glucose tolerance test was conducted before the HFD challenge, and after week 1 and week 2 of HFD treatment. At the end of 2 weeks, the rats were sacrificed and tissues were collected at necropsy. Serum was stored for hormone analysis and brains were frozen at −80°C for neurotransmitter analysis. During the pretreatment period, blood glucose levels increased significantly in control animals by 30 min, remained elevated at 60 min and decreased quickly to pretreatment levels by 120 min. In contrast, prenatal EDC exposure caused the blood glucose levels to drop slowly after peaking at 60 min with levels remaining high at 120 min. After 1 week of HFD, the effect was more pronounced in the BPA, BPA+HFD and DEHP+HFD groups and after 2 weeks, the effect persisted in the BPA+HFD and DEHP+HFD groups (p<0.01). There was a significant increase in adipose tissue:BW ratio in BPA and DEHP groups treated with HFD compared to controls (p<0.01). There was a marked increase in liver weights in the BPA and DEHP groups treated with chow and HFD. These results indicate that prenatal exposure to EDCs at a dose far below their reference dose for safety disrupts metabolic function. This effect is exacerbated when EDC‐exposed offspring are challenged with a HFD in adult life. We are currently analyzing differences in insulin and C‐peptide levels in these animals and are studying the involvement of hypothalamic neurotransmitters in this phenomenon.

Support or Funding Information

Supported by MSU Ag Bioresearch and UGA foundation.