Sex- and Dose-Specific Effects of Maternal Bisphenol A Exposure on Pancreatic Islets of First- and Second-Generation Adult Mice Offspring

Abstract

Background:Exposure to the environmental endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with the increased risk of diabetes and obesity. However, the underlying mechanisms remain unknown. We recently demonstrated that perinatal BPA exposure is associated with higher body fat, impaired glucose tolerance, and reduced insulin secretion in first- (F1) and second-generation (F2) C57BL/6J male mice offspring.Objective:We sought to determine the multigenerational effects of maternal bisphenol A exposure on mouse pancreatic islets.Methods:Cellular and molecular mechanisms underlying these persistent changes were determined in F1 and F2 adult offspring of F0 mothers exposed to two relevant human exposure levels of BPA (10μg/kg/d-LowerB and 10mg/kg/d-UpperB).Results:Both doses of BPA significantly impaired insulin secretion in male but not female F1 and F2 offspring. Surprisingly, LowerB and UpperB induced islet inflammation in male F1 offspring that persisted into the next generation. We also observed dose-specific effects of BPA on islets in males. UpperB exposure impaired mitochondrial function, whereas LowerB exposure significantly reduced β-cell mass and increased β-cell death that persisted in the F2 generation. Transcriptome analyses supported these physiologic findings and there were significant dose-specific changes in the expression of genes regulating inflammation and mitochondrial function. Previously we observed increased expression of the critically important β-cell gene, Igf2 in whole F1 embryos. Surprisingly, increased Igf2 expression persisted in the islets of male F1 and F2 offspring and was associated with altered DNA methylation.Conclusion:These findings demonstrate that maternal BPA exposure has dose- and sex-specific effects on pancreatic islets of adult F1 and F2 mice offspring. The transmission of these changes across multiple generations may involve either mitochondrial dysfunction and/or epigenetic modifications. https://doi.org/10.1289/EHP1674

Alleviating impact of hydroethanolicMurraya koenigiileaves extract on bisphenol A instigated testicular lethality and apoptosis in mice

“…BPA is used as a coating for the inside of food cans, water bottles, baby bottles and some dental fillings (Calafat, Ye, Wong, Reidy, & Needham, ; Takahashi & Oishi, ). It has been reported that BPA is leached from food and beverage containers, and some dental sealants and composites (Howe & Borodinsky, ; Yamamoto & Yasuhara, ) which has been linked with onset of various health disorders such as diabetes, obesity, cardiovascular diseases or carcinogenesis (Adoamnei et al, ; Bansal et al, ; Fénichel & Chevalier, ; Lombó et al, ; Manfo, Jubendradass, Nantia, Moundipa, & Mathur,; Rubin, ). BPA has also been involved in impairing fertility in both men and women as evident by recurrent miscarriages or premature births in women (Rubin, ) or decrease in semen quality and DNA damage of spermatozoa in men (Li et al, , ).…”

Potential Health Risks Linked to Emerging Contaminants in Major Rivers and Treated Waters

“…BPA exposure can also lead to disruptions in DNA methylation and histone acetylation patterns [144]. Also, as was shown with atrazine exposure, a potential epigenetic transgenerational effect (on insulin production in this case) has been reported in F1 and F2 mouse offspring after maternal BPA exposure [145]. Additionally, this effect may be linked with changes in germ line cells affecting the animal's fertility (see Chianese et al, 2017 for review [146]).…”

The Effect of Ketogenic-Diet on Health

“…Conclusions also suggest that ketogenic-diet is better only through the overall calorie consumption is matched [22]. In one research [18], people on keto lose 2.2 times further fat than that on small-calorie, small-fat diets. The amounts of triglyceride, as well as HDL lipids, have also increased.…”

“…Recent research [18] provides strong evidence of a greater weight loss in people on a ketogenic or extremely low caloric intake relative to those on a somewhat more conventional reduced-fat diet or Caribbean diet. Nevertheless, the disparity in losing weight tends to vanish over the period.…”

“…• Reduced-fat maintenance: some research shows [18] that ketogenic-diets can minimize fatty acid oxidation, the process of changing glucose to lipid. • Improved fat incinerating: ketogenic-diets easily increase the number of fats that consume during rest, everyday life & workout [24].…”