Effects of Soy-Based Infant Formula on Weight Gain and Neurodevelopment in an Autism Mouse Model

Abstract

Mice fed soy-based diets exhibit increased weight gain compared to mice fed casein-based diets, and the effects are more pronounced in a model of fragile X syndrome (FXS; Fmr1KO). FXS is a neurodevelopmental disability characterized by intellectual impairment, seizures, autistic behavior, anxiety, and obesity. Here, we analyzed body weight as a function of mouse age, diet, and genotype to determine the effect of diet (soy, casein, and grain-based) on weight gain. We also assessed plasma protein biomarker expression and behavior in response to diet. Juvenile Fmr1KO mice fed a soy protein-based rodent chow throughout gestation and postnatal development exhibit increased weight gain compared to mice fed a casein-based purified ingredient diet or grain-based, low phytoestrogen chow. Adolescent and adult Fmr1KO mice fed a soy-based infant formula diet exhibited increased weight gain compared to reference diets. Increased body mass was due to increased lean mass. Wild-type male mice fed soy-based infant formula exhibited increased learning in a passive avoidance paradigm, and Fmr1KO male mice had a deficit in nest building. Thus, at the systems level, consumption of soy-based diets increases weight gain and affects behavior. At the molecular level, a soy-based infant formula diet was associated with altered expression of numerous plasma proteins, including the adipose hormone leptin and the β-amyloid degrading enzyme neprilysin. In conclusion, single-source, soy-based diets may contribute to the development of obesity and the exacerbation of neurological phenotypes in developmental disabilities, such as FXS.

On-Tissue Spatial Proteomics Integrating MALDI-MS Imaging with Shotgun Proteomics Reveals Soy Consumption-Induced Protein Changes in a Fragile X Syndrome Mouse Model

“…Consumption of single-source, soy-based diets is associated with increased seizures, body weight, and autistic behaviors in neurodevelopmental disability models. 5,34,52 This study provides the first proteomic analysis of potential FXS protein biomarkers in response to specific diets. In this study, state-ofthe-art spatially resolved proteomic MALDI-MS imaging was employed, and LC-ESI MS/MS quantitative proteomics was integrated to systematically evaluate the spatial and dynamic changes of potential protein and peptide markers induced by the consumption of a soy protein-based diet by KO mice.…”

Improving Reproducibility to Enhance Scientific Rigor through Consideration of Mouse Diet

“…The fat content of AIN-76A at 5.1% was about half of the chows at 9–11%, but higher fat alone is not sufficient to induce weight gain as a ketogenic diet with 8.6% protein, 75% fat, 3.2% carbohydrate and an energy density of 7.24 kcal/g significantly reduces weight gain in C57BL/6J male mice [ 12 ]. Likewise, powdered human Enfamil casein- and soy protein isolate-based infant formula diets formulated into pellets and fed to mice contain significantly less protein and higher fat than standard rodent diets, but are associated with reduced and equivalent growth curves, respectively, compared to Teklad 2019 [ 6 ]. Carbohydrate content alone is likely not sufficient to cause the reduced body weight in male C57BL/6J mice because AIN-76A has the highest and ketogenic diet has the lowest carbohydrate content and both are associated with reduced body weight.…”

“…Since both test chows elicit increased weight gain in wild type C57BL/6J male mice, the causal factor here is not soybean meal, which is specific to Purina 5015. A prior study comparing casein protein- and soy protein isolate-based diets formulated from powdered human infant formulas to Teklad 2019 indicates that growth curves for the soy cohorts mirror Teklad 2019 whereas the casein-based diet resulted in drastically reduced body weight despite significantly reduced protein and increased fat content in both infant formula diets [ 6 ]. Overall, these published and new data suggest that the type of protein or feed additives or contaminants in the diet affect weight gain.…”

“…The researchers in our laboratory have found that standard grain/soy-based vivarium chows, in comparison to purified ingredient diets, alter behavior and increase weight gain in mice, and more so in developmental disability models [ 4 , 5 , 6 ]. These original findings have been followed up in humans through retrospective analysis of medical records with findings that children with autism who were fed soy-based infant formula were more likely to exhibit seizures and other comorbidities [ 7 , 8 , 9 ].…”

Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice

“…A PubMed search of the term “fragile X” returned over 9000 entries whereas the search terms “fragile X” AND “diet” returned only 39 papers. These publications include research on development and obesity [ 8 , 9 , 10 , 11 ], fatty acids [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], carbohydrate [ 22 ], proteins [ 23 , 24 , 25 , 26 ], dehydroepiandrosterone (DHEA) [ 27 ], folate [ 28 , 29 , 30 , 31 ], ethanol [ 32 ], lithium [ 33 ], exposome factors including bisphenol A (BPA) and polychlorinated biphenyls (PCB) [ 34 , 35 , 36 , 37 , 38 ], and the gut microbiome [ 21 , 39 , 40 ].…”