Maternal High-Fat Diet Combined With BPA Exposure Sex-Specifically Exacerbates Metabolic Disorders F1and F2 Generation

Background:Maternal obesity is transmitted to offspring in a sex-specific manner and affects the metabolism of the offspring.High-fat diet?HFD?and environmental endocrine disruptor bisphenol A?BPA?can induce maternal metabolic damage and lead to metabolic disorders in the offspring,but the combined effects of maternal exposure to HFD and BPA on the metabolic effects of offspring and sex-specific changes in the offspring are still not Very clear.In this study,female ICR mice were used as mothers?F0?to simultaneously expose LFD,BPA,HFD and HFD+BPA,and to generate intergenerational transmission mouse models of the first generation?F1?and second generation?F2?.To explore the gender difference effects of maternal combined exposure to HFD and BPA on the metabolism of F1 and F2 generations.Methods:Six-week-old female ICR mice were selected and fed into the SPF environment for 1 week.They were randomly divided into LFD,BPA,HFD and HFD+BPA,and HFD or BPA intervention continued until F1weaning.Mice can drink water and eat freely.BPA was dissolved in PBS solution and given to F0 mice by intragastric administration at a dose of500?g/kg/day.F0 mice were mated with normal male ICR mice at 17weeks of age to produce F1 generation mice.After F1 weaning,female and male mice were separated and feed on a normal diet until 12 weeks to mate with normal heterosexual ICR mice to produce F2 generations.F2generation mice were fed on a LFD after weaning to 13 weeks and then exposed to HFD to 21 weeks.The body weight changes of F0,F1 and F2generation mice were monitored every week,and glucose tolerance test?GTT?was conducted.HE staining was used to detect liver changes in F0,F1 and F2 mice.In addition,indirect calorimetry was used to determine the energy metabolism characteristics of F2 generation mice.Result:Maternal high-fat diet combined with BPA exposure accelerated the weight gain of maternal mice,although similar to the body weight of female mice exposed to HFD.The GTT test results showed that F0 mice exposed to HFD+BPA had a tendency to exacerbate impaired glucose tolerance,but there was no significant difference compared with other groups of mice.And the combined exposure to HFD+BPA increased liver lipid accumulation and hepatic steatosis in F0 mice.In F1 mice,body weight results from weaning to 12 weeks showed that the weight of male offspring O₁-BPAm,O₁-HFDm,O₁-HFD+BPAm mice increased significantly,but there was no significant difference between the three groups.However,there was no significant difference in body weight of female offspring mice,only O₁-BPAf mice gained weight.The results of the F1 generation GTT test showed that there was no significant difference in glucose tolerance both the male and female mice.F1 liver HE staining results showed that male O₁-BPAm and O1-HFDm mice had mild lipid accumulation,and O₁-HFD+BPAm mice had increased liver lipid accumulation,but female mice had not obvious lipid metabolism disorder.In F2 generation mice,we found that all F2 generation mice had no significant difference in body weight and glucose tolerance during LFD feeding.After HFD intervention,H-O₂-HFD+BPAmf mice in F2 female offspring whose F1 male mice were fathers significantly increased weight gain and impaired glucose tolerance,but there was no significant difference in body weight and glucose tolerance of F2 male offspring.F2 generation mice whose F1 generation female mice were mothers found similar results.The body weight of male H-O₂-HFD+BPAfm mice increased rapidly compared with H-O₂-LFDfm and H-O₂-HFDfm mice.Moreover,the body weight of H-O₂-BPAfm mice increased rapidly and there was a significant difference between H-O₂-LFDfm mice.However,there was no difference in body weight of F2 female mice.The GTT test results showed that the glucose tolerance level of male H-O₂-BPAfm,H-O₂-HFDfm,H-O₂-HFD+BPAfm mice was similar to that of H-O₂-LFDfm mice.However,there was no significant difference in the glucose tolerance of female mice.Furthermore,maternal high-fat diet combined with BPA exposure exacerbated liver lipid accumulation in F2 female offspring of F1 males and F2 male offspring of F1 females.In addition,H-O₂-HFD+BPAmf and H-O₂-HFD+BPAfm mice also significantly reduced O₂ consumption,CO₂exhalation,and energy expenditure.Conclusions:Maternal compound exposure to HFD+BPA exacerbates maternal glucose tolerance and liver metabolic disorders,and affects the metabolism of the first and second generations.Maternal compound exposure to HFD+BPA specifically exacerbates the metabolic disorder in the male generation of offspring rather than the female generation of offspring.Maternal compound exposure to HFD+BPA differentially changes the metabolic phenotype of the second-generation HFD-exposed children,specifically exacerbating the second-generation female mice of the first-generation male mice as fathers and the second-generation male mice of the second-generation female mice as mother Of metabolic disorders.