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. 2026 May 22;4(9):2041–2054. doi: 10.1021/envhealth.6c00171

Gestational Low-Dose Bisphenol A Exposure Enhances Susceptibility to Metabolic Disorders in Adult Offspring Mice: Role of the Gut Microbiota-SCFAs-GPRs Axis

Yun Hong †, Yujie Qiu †, Qingqing Yang †, Bingbing Sun †, Yuheng Zhang †, Zhiyuan Zhu †, Zuo Li †, Tong Shen †,‡,§,∥,*
PMCID: PMC13595394  PMID: 42775182

Abstract

Bisphenol A (BPA), frequently detected at low levels in pregnant women, has been linked to long-term metabolic disturbances in offspring. Emerging evidence indicates that maternal gut microbiota critically influence offspring susceptibility to metabolic diseases through their metabolites. This study aimed to investigate how maternal gut microbiota and short-chain fatty acids (SCFAs) mediate the increased susceptibility to high-fat-diet (HFD)-induced metabolic disorders in adult offspring following gestational low-dose BPA exposure. Pregnant mice were exposed to 0, 10, 100, and 1000 nmol/L BPA via drinking water throughout gestation, after which pups were cross-fostered by unexposed dams and fed normal chow or HFD until adulthood. Adult offspring from BPA-exposed dams exhibited aggravated HFD-induced dyslipidemia and insulin resistance. Maternal BPA exposure decreased the abundance of f_Prevotellaceae and g_Bacteroides, accompanied by reduced circulating SCFAs in both dams and offspring. Reduced SCFAs impaired embryonic pancreas and intestinal development by downregulating GPR41 and GPR43, which may predispose offspring to metabolic disorders at adulthood. Importantly, maternal high-fiber diet restored gut microbiota composition along with SCFA production, normalized embryonic GPRs expression, and subsequently alleviated offspring metabolic impairments. These findings provide key insights into BPA-induced developmental programming of metabolic disorders and offer promising strategies against metabolic dysfunction induced by endocrine-disrupting chemicals.

Keywords: Bisphenol A, maternal exposure, gut microbiota, SCFAs-GPRs axis, metabolic disorders

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1. Introduction

Global incidence and prevalence rates of metabolic disorders, including obesity, type 2 diabetes, and dyslipidemia, have raised markedly over recent decades and become major public health concerns. , It is generally believed that sedentary behavior, excessive caloric intake, and genetic predisposition are the risk factors for metabolic disorders. , Recently, growing attention has turned to the role of environmental chemicals, especially endocrine-disrupting chemicals (EDCs), in the developmental origins of metabolic disease. − Among EDCs, bisphenol A (BPA) has drawn considerable concerns due to its widespread application in plastics and epoxy resins production and pervasive presence in the environment and human tissues, including urine sample from pregnant women. − Biomonitoring studies indicate that the median urinary BPA concentrations in pregnant women typically range from 1 to 3 ng/mL. Furthermore, the estimated daily human intake of environmental BPA frequently falls below the traditional reference dose or tolerable daily intake (TDI) of 50 μg/kg/day, a benchmark previously established by the European Food Safety Authority (EFSA) and the US Environmental Protection Agency (EPA). , Despite being below these regulatory thresholds, continuous exposure to such low, environmentally relevant doses during critical developmental windows has been increasingly associated with the disruption of metabolic disorders in childhood. − Unlike postnatal exposures, which can trigger acute inflammation of adipose tissue leading to an obese phenotype, prenatal exposures may fundamentally reprogram metabolic organogenesis. ,, However, whether prenatal exposure to environmentally relevant low-dose BPA elevates susceptibility to metabolic disorders in later life, as well as the underlying mechanisms, remains to be fully investigated.

Recent studies have identified that maternal gut microbiota is a key contributor to programming fetal metabolic development through short-chain fatty acids (SCFAs). , SCFAs such as acetate, propionate, and butyrate not only serve as metabolic substrates but also activate G protein-coupled receptors (GPRs) 41/43 in the fetal intestine and pancreas, shaping long-term metabolic outcomes. A deficiency of SCFA-GPR43 signaling during embryonic development can impair insulin and glucose homeostasis and heighten susceptibility to obesity and type 2 diabetes postnatally.

In this study, we aimed to investigate whether prenatal environmentally relevant BPA exposure is associated with increased susceptibility to metabolic disorders in offspring and whether alterations in maternal gut microbiota-SCFA-GPR signaling may be involved. By combining gestational low-dose BPA exposure with an adult offspring HFD challenge to assess maternal microbiome profiles, embryonic organogenesis, and offspring metabolic susceptibility, we observed that environmentally relevant low-dose BPA exposure during pregnancy disrupted homeostasis of gut microbiota, lowered SCFA levels, and impaired development of pancreas and intestine alongside downregulated SCFAs-GPR41/GPR43 signaling in the embryo. These alterations may predispose offspring to HFD-induced metabolic disorders in adulthood. Furthermore, maternal high-fiber diet (HFiD) supplementation mitigated the enhanced susceptibility to metabolic disorders upon BPA exposure by restoring the gut microbiota-SCFAs-GPRs axis. Collectively, our findings provide novel mechanistic insights into the developmental origins of metabolic disorders caused by environmental toxicants and identify maternal dietary modulation as a promising preventive strategy.

2. Materials and Methods

2.1. Mice and Treatment

C57BL/6N wild-type (WT) mice, both male and female, aged 8 weeks (8W), were acquired from Beijing Vital River and kept in a specific pathogen-free (SPF) facility under controlled humidity (50% ± 5%), temperature (21 °C ± 2 °C), and a 12 h light/dark photoperiod. Following the 1W acclimatization period, females and males were paired at a 2:1 ratio for mating. The detection of a vaginal plug the next morning was designated as gestational day (GD) 0. From GD0 until birth, pregnant mice (n = 14/group) were exposed to 0 (vehicle control), 10, 100, or 1000 nmol/L BPA (purity 99.9%, Sinopharm, Shanghai, China) dissolved in DMSO (Sigma), administered via drinking water. The final DMSO concentration was kept below 0.1%. Based on reported daily water intake, the highest exposure level (1000 nmol/L; 10 mL/day) corresponded to approximately 45.6 μg/kg/day, which is below the reference dose set by the European Food Safety Authority (50 μg/kg/day) (https://www.efsa.europa.eu/en). Fecal samples and tail vein blood were collected from pregnant mice at GD0, GD12, and GD18 for gut microbiota analysis and SCFAs detection. On embryonic day (ED) 18.5, six pregnant mice from each group were sacrificed to collect fetal whole blood, pancreas, and intestinal tissues for SCFA measurement, histopathology, RT-qPCR and Western blotting. The remaining dams (n = 8/group) were allowed to deliver naturally. Pups were weighed at birth, and litter sizes were standardized to eight pups per litter (four males and four females). These pups were cross-fostered to unexposed foster mothers from birth until weaning at 3W. At 3W, to avoid litter effects, one male and one female pup were randomly selected from each of the eight litters per group (n = 8/sex/group) and sacrificed for the collection of whole blood, pancreas, liver, intestines, and fecal samples for further analysis. From the remaining pups in each litter, one male and one female were randomly assigned to receive a normal chow diet (NCD), while another male and female from the same litter were assigned to receive a high-fat diet (HFD) (n = 8/sex/diet group). These offspring were separated by sex and fed their respective diets until 19W, followed by euthanasia and tissue collection as described above.

To investigate whether HFiD supplementation during gestation could alleviate BPA-enhanced susceptibility to HFD-induced metabolic disturbances in offspring by modulating maternal gut microbiota dysbiosis and SCFA levels, the fiber intervention (15% inulin supplementation) was applied exclusively to pregnant dams during gestational BPA exposure. After birth, all pups were cross-fostered to unexposed mothers fed a standard diet and subsequently challenged with NCD or HFD postweaning. The detailed formulations and nutrient composition of the NCD, HFD, and the 15% inulin-supplemented diet are provided in Table S1. The subsequent procedures, including sample collection and tissue processing, were performed as described above. All of the animals were euthanized by carbon dioxide inhalation. 100% CO2 was introduced into a 6.0 L euthanasia chamber at 3.0 L/min until apnea and absence of the pedal withdrawal reflex were observed; CO2 inflow was then maintained for an additional 1–2 min, followed by cervical dislocation to ensure death. A schematic overview of the experimental design is shown in Figure . All experimental procedures are in accordance with the Laboratory Animal Code of Anhui Medical University and approved by the institution’s Laboratory Animal Ethics Committee (approval no. LLSC20200892)

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Scheme of animal experiment.

2.2. Detection of Biochemical Parameters

Serum was obtained by centrifuging blood samples at 3500 r/min for 15 min at 4 °C. Subsequently, the concentrations of total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured using commercial assay kits (Jiancheng Bioengineering Company) following the manufacturer’s instructions.

2.3. FG, FI, and HOMA-IR

Fasting glucose (FG) was measured using a Roche blood glucose meter (Roche Diagnostics), whereas fasting insulin (FI) was quantified using an ELISA kit (Calvin Company) according to the manufacturer’s instructions. HOMA-IR was used to evaluate IR with the formula HOMA-IR = FI (μU/mL) * FG (mmol/L)/22.5.

2.4. GTT and ITT

For glucose tolerance test (GTT), mice were fasted for 12 h prior to receiving an intraperitoneal injection of glucose (1 mg/g body weight). Blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 min postinjection. For insulin tolerance test (ITT), mice were fasted for 4 h, followed by intraperitoneal administration of insulin (0.75 IU/kg body weight), and glucose concentrations were monitored at the same time intervals. The area under the curve (AUC) for both tests was computed by using GraphPad Prism 8.0 to quantitatively evaluate glucose metabolism and insulin sensitivity.

2.5. ELISA Assay

The contents of leptin (LEP), adiponectin (ADPN), peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) were quantified using ELISA kits (Enzyme-linked Biotechnology) according to the manufacturer’s guidelines. The results were subsequently analyzed by using ELISA Calc software.

2.6. Quantitative Analysis of SCFAs

For SCFAs detection, a 20 μL sample of mouse serum was transferred to an Eppendorf tube containing 10 μL of 5 mol/L hydrochloric acid (HCl). Subsequently, 80 μL of ddH2O and 200 μL of methyl tert-butyl ether were added sequentially, the mixture was then chilled on ice for 5 min, and centrifuged at 10000 g for 5 min to extract SCFAs. An aliquot of 200 μL from the supernatant was shifted into a new 2 mL glass vial and added to 5 μL BSTFA before incubation at 70 °C for 30 min before detection. The final serum concentration was determined using a GC-MS system (Shimadzu 2010 plus-QP2020, SHIMADZU, Japan). One microliter aliquot of the analyte was injected into a DB-5 ms column (Agilent, USA). The standard solution of acetate, propionate, butyrate (GC, purity ≥ 99.5%) was purchased from Aladdin (Shanghai, China) and acetate-D4, propionate-D6, butyrate-D8 (GC, purity ≥ 99.5%) were obtained from Sigma. The ddH2O was used as a blank sample to correct for background. According to the peak area of the standard solution, standard curves were calculated (acetate: f­(x) = 1.29*x+0.53, R 2=0.999; propionate: f­(x) = 1.02*x+0.17, R 2=0.998; butyrate: f­(x) = 2.38*x+0.79, R 2=0.999) and then used to quantify following samples.

2.7. 16S rRNA Gene Sequencing

Fresh fecal samples from mice were immediately stored at −80 °C until subsequent analysis. The PF Mag-Bind Stool DNA Kit was conducted to extract the total microbial genomic DNA of mice fecal samples. The bacterial 16S rRNA gene’s V3–V4 hypervariable region was amplified with primers 338F (5′-ACTCC­TACGG­GAGGC­AGCAG-3′) and 806R (5′-GGACT­ACHVG­GGTWT­CTAAT-3′). Amplicon sequencing was conducted on the Illumina PE300/PE250 platform (Illumina, San Diego, USA) following standard procedures provided by Majorbio Bio-Pharm Technology Co., Ltd. (Shanghai, China). Sequence data analysis was primarily conducted using QIIME2 and R packages (v3.2.0). Alpha diversity metrics, including Chao1 richness and Shannon diversity index, were calculated based on the ASV table using QIIME2 and presented as box plots. To evaluate the compositional dissimilarity of microbial communities across samples (beta diversity), Bray–Curtis distances were calculated and visualized through principal coordinate analysis (PCoA). Taxonomic differences across groups were determined using linear discriminant analysis effect size (LEfSe), applying an LDA score threshold of 4 and a significance level of P < 0.05. Microbial function was predicted using PICRUSt2, and pathway annotation was carried out based on the KEGG database (https://www.kegg.jp/).

2.8. Histopathological Analysis

Freshly harvested liver, small intestine, and pancreas tissues were fixed in 4% paraformaldehyde, embedded in paraffin, and sliced into 5 μm sections. Hematoxylin and eosin (H&E) staining was performed to evaluate histological changes under a light microscope. For lipid accumulation analysis, a portion of the fixed liver tissue was embedded in OCT, cryosectioned at 10 μm using a Leica microtome, and stained with Oil Red O. Lipid droplets in hepatic tissue were visualized microscopically.

2.9. Immunofluorescence

The proportion of insulin and glucagon-positive cells of paraffin-embedded sections were detected using a primary antibody anti-insulin (Abcam, ab181547, 1:200) and antiglucagon (Abcam, ab92571, 1:200). The secondary antibodies Goat Anti-Rabbit IgG (Elab Fluor 488/594 conjugated, Elabscience) were employed to visualize positive signals. Tissues were viewed via TissueFAXS Plus. The quantification of insulin positively stained (red) pixels and glucagon positively stained (green) pixels was determined by Image-Pro Plus.

2.10. RT-qPCR Analysis

Total RNA was extracted from mouse intestine and pancreas using TRIzol reagent (Invitrogen) according to the manufacturer’s protocol. Briefly, intestine and pancreas were homogenized in prechilled TRIzol using stainless steel beads and a low-temperature tissue homogenizer. The homogenate was centrifuged at 12000 × g for 10 min at 4 °C, and the upper aqueous phase was collected after phase separation with 1-bromo-3-chloropropane. RNA was precipitated with isopropanol, washed three times with 75% ethanol, air-dried, and dissolved in DEPC water. RNA concentration and purity were assessed using a NanoDrop spectrophotometer, and all samples were adjusted to 500 ng/μL. First-strand cDNA was synthesized using the Transcriptor First Strand cDNA Synthesis Kit (Roche) with both oligo (dT)­18 and random hexamer primers. Reverse transcription was performed at 25 °C for 10 min, followed by 50 °C for 60 min, and enzyme inactivation at 85 °C for 5 min. The resulting cDNA was stored at −80 °C until further use. Quantitative PCR was conducted on a Roche LightCycler system using a 20 μL reaction mixture containing 1 μL of cDNA template, 10 μL of reaction mix, 7 μL of nuclease-free water, and 1 μL of gene-specific primers. Relative gene expression levels were determined using the 2–ΔΔCt method, with β-actin employed as the internal reference gene. Primer sequences are provided in Table S2.

2.11. Western Blotting

Fetal pancreatic and intestinal tissues were homogenized and lysed using RIPA lysis buffer (Beyotime, P0013B) supplemented with protease inhibitors (MedChemExpress, HY-K0010). Total protein extracts were collected, and the protein concentration was determined prior to denaturation. Equal amounts of protein were separated by SDS-PAGE and subsequently transferred onto polyvinylidene difluoride (PVDF) membranes. The membranes were blocked with 5% nonfat milk in TBST for 1 h at room temperature. After blocking, membranes were incubated with the primary antibodies at 4 °C overnight (GPR41, ab236654, Abcam; GPR43, 19952–1-AP, Proteintech; β-actin, AF7018, Affinity), followed by incubation with HRP-conjugated secondary antibodies for 1 h at room temperature. Protein was visualized using an enhanced chemiluminescence (ECL) detection reagent (Advansta, K-12043-D10) and captured with a chemiluminescence imaging system. The relative expression levels of target proteins were quantified by ImageJ software.

2.12. Statistical Analysis

Statistical analyses were performed using SPSS software (version 25.0, Chicago, IL, USA). Data are expressed as mean ± standard error of the mean (SEM). Differences among multiple groups were evaluated using one-way or two-way analysis of variance (ANOVA), followed by Bonferroni post hoc tests for pairwise comparisons when detecting significant differences. GraphPad Prism 8.0 and R software (version 4.3.1) were employed for graphical representation. The P value less than 0.05 was regarded as statistically significant.

3. Results

3.1. Maternal Low-Dose BPA Exposure during Pregnancy Increased Susceptibility to Metabolic Disorders Induced by HFD in Adult Offspring

No significant differences in maternal body weight gain were observed between BPA-exposed and control groups (Figure S1A). The average litter size, sex ratio, and pup survival rate did not differ significantly across the BPA exposure groups. However, the average birth weight of pups in the 1000 nmol/L BPA group was significantly lower than that of the control group, suggesting potential adverse effects of maternal BPA exposure on embryonic development (Table S3). Among 3W offspring, no significant differences were detected in body weight gain (Figure S1B), hepatic lipid droplet accumulation (Figure S1C,D), serum ALT and AST levels (Figure S1E), or lipid metabolism markers (Figure S1F,G) between BPA-exposed and control groups. After weaning, HFD-fed adult offspring from BPA-exposed dams exhibited markedly increased body weight gain (Figure S2A), pronounced hepatic lipid accumulation (Figure S2B), elevated lipid metabolism indices (Figure A-D), and higher serum ALT and AST levels (Figure E,F) compared to the NCD-fed group. Additionally, significant impairments in glucose tolerance and insulin sensitivity were observed in HFD-fed offspring relative to NCD controls (Figure G-J). Notably, adult offspring from BPA-exposed dams developed severe metabolic disorders upon HFD feeding, whereas maternal BPA exposure at different doses had no significant effects on most of these parameters in NCD-fed offspring (Figures A-J and S2A-E). Collectively, these results suggest that maternal exposure to environmentally relevant low-dose BPA during pregnancy sensitizes offspring to HFD-induced metabolic disturbances in adulthood, including lipid metabolism dysfunction, insulin resistance, and glucose intolerance.

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Maternal low-dose BPA exposure exacerbated lipid metabolic dysfunction and insulin resistance induced by HFD in adult offspring. Serum LDL-C (A), T-CHO (B), TG (C), ADPN (D) content in 19W offspring from BPA-exposed or control dams (n = 6). Serum ALT (E) and AST (F) levels in 19W offspring from BPA-exposed or control dams (n = 6). (G) GTT was performed in 19W male and female offspring (n = 6). (H) The quantification of area under curves of GTT in 19W male and female offspring (n = 6). (I) ITT was performed in 19W male and female offspring (n = 6). (J) The quantification of area under curves of ITT in 19W male and female offspring (n = 6). Data are represented as mean ± SEM, HFD group compared with the NCD group, $$ P < 0.01; NCD + BPA group compared with NCD + DMSO group or HFD + BPA group compared with HFD + DMSO group, *P < 0.05, **P < 0.01.

3.2. Maternal Low-Dose BPA Exposure during Pregnancy Impaired Pancreatic and Intestinal Function in Offspring

To investigate whether maternal BPA exposure increases susceptibility to HFD-induced metabolic disturbances through impairment of pancreatic and intestinal function, offspring tissues were examined for morphological and molecular changes. Histological analysis revealed impaired islet development in 3W offspring, accompanied by a reduction in the percentage of insulin-producing β-cells per islet area (Figures S3A and A). Consistently, expression of key β-cell transcription factors and functional genes-MafA, NeuroD, Pdx1, and Insulin-was markedly decreased (Figure S3B). These impairments persisted into adulthood under both normal and HFD conditions (Figure S3A and C), with more severe β-cell disruption observed in HFD-fed offspring from BPA-exposed dams (Figure B and C).

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Effect of maternal low-dose BPA exposure during pregnancy on islet β cell development in offspring mice. Representative immunofluorescence images (20×) of pancreas in 3W (A) and 19W fed an NCD (B) or HFD (C) offspring from BPA-exposed dams, and quantitative analysis results (n = 3). Data are represented as mean ± SEM. For the area of Glucagon, BPA group compared with DMSO group or BPA + NCD group compared with DMSO + NCD group or BPA + HFD group compared with DMSO + HFD group, # P < 0.05, ## P < 0.01; For the area of Insulin, BPA group compared with DMSO group or BPA + NCD group compared with DMSO + NCD group or BPA + HFD group compared with DMSO + HFD group, & P < 0.05, && P < 0.01.

In addition to pancreatic dysfunction, structural and functional abnormalities were observed in the intestine. At 3W, offspring from BPA-exposed dams displayed shortened and sparse villi despite conventional cross-fostering. In adulthood, offspring exhibited exacerbated villous atrophy upon HFD feeding relative to NCD-fed counterparts (Figure S4A). Furthermore, the expression of genes essential for intestinal differentiation and barrier integrity including Cdx2, Pax4, Pax6, and Tjp1 was significantly suppressed in 3W offspring (Figure S4B). Postweaning, BPA exposure further aggravated HFD-induced intestinal dysfunction in adulthood (Figure S4C). Corroborating these findings, circulating levels of the gut hormones GLP-1 and PYY, critical regulators of glucose and energy homeostasis, were significantly reduced in both 3W- and HFD-fed adult offspring from BPA-exposed dams (Figure S4D-G). Collectively, these results demonstrate that maternal exposure to low-dose BPA during pregnancy impairs pancreatic and intestinal development and function in the offspring.

3.3. Maternal Low-Dose BPA Exposure during Pregnancy Induced Gut Microbiota Dysbiosis and Reduced SCFA Levels in Dams and Offspring

Considering the critical role of maternal gut microbiota and its metabolites SCFAs in the regulation of organ development in offspring, we further explored whether maternal BPA exposure during pregnancy induced gut microbiota dysbiosis in dams and offspring. 16S rRNA gene sequencing showed that low-dose BPA exposure modestly altered the alpha diversity of the gut microbiota in dams, as reflected by changes in the Shannon and Chao1 indices (Figure A). PCoA based on Bray–Curtis distances further revealed a distinct microbial community structure in 1000 nmol/L BPA-exposed dams at GD18 (Figure S5A), therefore, we will focus on the GD18 stage of pregnancy. At GD18, across all groups, the dominant bacterial phyla were Bacteroidota, Bacillota, and Actinomycetota. However, BPA exposure led to dose-dependent shifts in their relative abundances (Figure B). LEfSe analysis identified four significantly enriched taxa in the control dams, g_Prevotellaceae_UCG_001, p_Bacteroidota, c_Bacteroidia, and o_Bacteroidales, which were markedly depleted in BPA-exposed dams at GD18 (Figure C). On the basis of the 16S rRNA gene sequencing of fecal samples collected from pregnant dams at GD18, we inferred the functional potential of the gut microbiota using PICRUSt2 and mapped predicted genes to KEGG pathways. The predicted functional profiles (Figure D) revealed that the maternal gut microbiota at GD18 was predominantly enriched for pathways related to carbohydrate, amino acid, energy, and lipid metabolism, and the differences observed between BPA-exposed dams and control dams suggested that BPA-associated microbiota shifts may perturb key metabolic processes. Notably, the relative abundances of g_Bacteroides and f_Prevotellaceae, both prominent SCFA producers, were significantly reduced in BPA-exposed dams at GD18 (Figure E,F).

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Maternal low-dose BPA exposure disrupted gut microbiota homeostasis and reduced SCFA levels in both pregnant dams and embryos. (A) Alpha diversity of the Shannon index, Chao index in pregnant dams (n = 6). (B) Relative abundance of predominant microbiota at phylum level in pregnant dams at GD18 (n = 6). (C) Discriminative species in pregnant dams at GD18 were identified by LEfSe analysis, the LDA score was 4, P < 0.05. (D) PICRUSt2 combined with the KEGG database to predict the function of bacterial microbiota in dams at GD18. The relative abundance of g_Bacteroides (E) and f_Prevotellaceae (F) at GD18 dams (n = 6). Levels of acetate (G), propionate (H), and butyrate (I) in pregnant dams at GD0, GD12, GD18 (n = 6). (J) Levels of acetate, propionate, and butyrate in ED18.5 embryos (n = 6). (K) Correlations between the concentration of maternal SCFAs and embryonic SCFAs. Pearson’s coefficients (R) and P values are shown. The lines and gray zones show the fitted linear regression lines with 95% confidence intervals. The correlation analysis incorporated paired maternal and embryonic samples across all experimental groups (DMSO, 10, 100, and 1000 nmol/L BPA). Data are represented as mean ± SEM, BPA group compared with DMSO group, *P < 0.01, **P < 0.01.

The maternal gut microbiota can be vertically transmitted to the offspring, shaping the development of the offspring’s gut microbiome. As shown in Figure A, Shannon and Chao1 indices were significantly increased in 3W female offspring. After weaning, among NCD-fed offspring from BPA-exposed dams, only mild changes in alpha diversity were observed. In contrast, HFD-fed female offspring from BPA-exposed dams exhibited a pronounced decrease in the Shannon and Chao1 indices (Figure B). PCoA revealed that offspring from BPA-exposed dams had distinct bacterial compositions (Figure S5B). Notably, across all exposure groups, the significant enrichment of f_Erysipelotrichaceae was exclusively observed in the highest dose group (1000 nmol/L BPA) in both male and female HFD-fed offspring (Figures C,D and S5C), a family previously associated with host lipid metabolism dysregulation. While a downward trend in the relative abundance of f_Prevotellaceae and g_Bacteroides was observed in 3W offspring (data not shown), these SCFA-producing bacteria were significantly depleted in both NCD- and HFD-fed 19W offspring from BPA-exposed dams (Figure E,F).

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Maternal low-dose BPA exposure induced gut microbiota dysbiosis and decreased the SCFA concentrations in offspring. Alpha diversity of the Shannon index, Chao index in 3W offspring (A) and 19W fed with NCD or HFD offspring (B) from BPA-exposed or control dams (n = 4). Discriminative species in 19W male (C) and female (D) offspring fed with HFD from BPA-exposed or control dams were identified by LEfSe analysis, the LDA score was 4, P < 0.05. The relative abundance of f_Prevotellaceae (E) or g_Bacteroides (F) in 19W offspring fed with NCD or HFD from BPA-exposed or control dams (n = 4). (G) Concentration of acetate, propionate, and butyrate in 3W offspring from BPA-exposed or control dams (n = 6). (H) Concentration of acetate, propionate, and butyrate in 19W offspring fed with NCD or HFD from BPA-exposed or control dams (n = 6). Data are represented as mean ± SEM, BPA group compared with DMSO group, *P < 0.01, **P < 0.01, ***P < 0.001.

Consistent with alteration in the abundance of SCFA-producing bacteria, serum concentrations of acetate, propionate, and butyrate in pregnant dams progressively declined with increasing BPA exposure duration (Figure G-I). Meanwhile, maternal BPA exposure significantly reduced serum concentrations of SCFAs (acetate, propionate, and butyrate) in offspring at both 3W and 19W. Notably, this reduction was more severe in HFD-fed offspring compared to the NCD group (Figure G,H), aligning with the diminished abundance of SCFA-producing bacteria. Given that embryos primarily acquire nutrients from the mother via blood circulation, we next quantified serum SCFA levels in ED18.5 embryos. The concentrations of acetate, propionate, and butyrate in embryos from BPA-exposed dams were significantly reduced compared with controls (Figure J). Pearson correlation analysis revealed a strong positive association between maternal (GD18) and embryonic SCFA levels (Figure K). These results suggest that maternal low-dose BPA exposure disrupts gut microbiota composition and reduces SCFA concentrations in both pregnant dams and offspring. Furthermore, HFD-fed offspring from BPA-exposed dams appear to be more vulnerable to these abnormalities.

3.4. Maternal Low-Dose BPA Exposure during Pregnancy Altered Embryonic Pancreatic and Intestinal Development along with Disrupted SCFAs-GPRs Axis

To investigate whether SCFAs derived from maternal gut microbiota influence the development of the embryonic metabolic system by sensing GPR41 and GPR43 in the pancreas and intestine, we next assessed SCFA receptor GPR41 and GPR43 expression in embryonic pancreatic and intestinal tissues. RT-qPCR and Western blotting analysis revealed significant downregulation of both receptors in ED18.5 embryonic pancreas and intestine from BPA-exposed dams (Figure A,B). This downregulation persisted postnatally in pancreatic tissues of 3W and 19W offspring (Figure C-E). Histological evaluation of ED18.5 embryonic pancreas revealed BPA dose-dependent abnormalities, including a disrupted exocrine structure, poorly organized pancreatic architecture, and reduced islet size (Figure F). Consistently, mRNA expression of key pancreatic development and function genes, Foxo1, Pdx1, MafA, and Insulin, was significantly decreased in embryos from BPA-exposed dams (Figure H). Furthermore, BPA exposure led to shortened villi and reduced villus density in the embryonic intestines (Figure G). Correspondingly, transcription of genes involved in intestinal differentiation and barrier function, including Pax4, Pax6, Cdx2, and Tjp1, was markedly suppressed in the BPA-exposed groups (Figure I). These results demonstrate that maternal exposure to low-dose BPA during pregnancy disrupts embryonic pancreas and intestinal development, likely via SCFAs-GPR41/43 signaling.

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Maternal low-dose BPA exposure impaired the embryonic pancreas and intestine development. (A) Relative Gpr41 and Gpr43 genes were normalized to β-actin mRNA in the embryonic pancreas and intestine at ED18.5 (n = 6). (B) Protein levels of GPR41 and GPR43 in the embryonic pancreas and intestine at ED18.5 were detected by Western blotting (n = 3). (C) Relative Gpr41 and Gpr43 genes were normalized to β-actin mRNA in 3W offspring pancreas (n = 6). The relative Gpr41 (D) and Gpr43 (E) genes were normalized to β-actin mRNA in 19W fed an NCD or HFD offspring pancreas (n = 6). (F) Representative H&E images (20×) of pancreas in ED18.5 embryos. (G) Representative H&E images (20×) of intestine pancreas in ED18.5 embryos. (H) Relative mRNA expression of MafA, FOXo1, Pdx1, Insulin was normalized to β-actin mRNA in the embryonic pancreas at ED18.5 (n = 6). (I) Relative mRNA expression of Cdx2, Pax4, Pax6, Tjp-1 were normalized to β-actin mRNA in the embryonic intestine at ED18.5 (n = 6). Data are represented as mean ± SEM, BPA group compared with DMSO group, *P < 0.01, **P < 0.01.

3.5. Maternal High-Fiber Diet Intake during Pregnancy Alleviated BPA-Enhanced Susceptibility to Metabolic Disorders in Adult Offspring

As a recognized prebiotic, dietary fiber promotes the growth of beneficial gut bacteria. To verify the role of the maternal gut microbiota and its metabolites in BPA-evoked susceptibility to HFD-induced metabolic disorders in adult offspring, we conducted a dietary intervention in which pregnant dams were fed an HFiD during gestational BPA exposure. Maternal HFiD intake significantly improved weight gain (Figure S6A), serum lipid metabolism abnormalities, including LDL-C, HDL-C, TG, T-CHO, ADPN, LEP (Figure A-F), the liver lipid deposition, and exacerbated injury in HFD-fed offspring from BPA-exposed dams (Figure S6B-D). In parallel, maternal HFiD intake during gestation mitigated BPA-enhanced impairments in glucose homeostasis and insulin sensitivity in offspring fed with HFD, as evidenced by improved GTT and ITT (Figures G-J and S6E-G).

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HFiD supplementation during pregnancy alleviated the BPA-aggravated metabolic disorders in adult offspring fed with HFD. Levels of serum LDL-C (A), HDL-C (B), TG (C), T-CHO (D), ADPN (E), LEP (F) in 19W offspring mice (n = 6). (G) GTT was performed in 19W male and female offspring (n = 6). (H) The quantification of area under curves of GTT in 19W male and female offspring (n = 6). (I) ITT was performed in 19W male and female offspring (n = 6). (J) Quantification of area under the curve of ITT in 19W male and female offspring (n = 6). Data are represented as mean ± SEM, HFD group compared with the NCD group, $ P < 0.05; 1000 nmol/L BPA vs DMSO group, *P < 0.05, **P < 0.01; 1000 nmol/L BPA + HFiD vs 1000 nmol/L BPA group, # P < 0.05, ## P < 0.01.

Notably, maternal HFiD supplementation reshaped the gut microbial composition in both pregnant dams and HFD-fed offspring (Figure S7A,B). Specifically, the relative abundance of SCFA-producing taxa, including f_Prevotellaceae and g_Bacteroides, was markedly increased in dams at GD18 and HFD-fed offspring from BPA-exposed dams at 19W (Figure S8A,B), along with reversed decline in serum SCFA levels (acetate, propionate, and butyrate) in pregnant dams at GD18, ED18.5 embryos, and offspring at both 3W and 19W (Figure S8C−E). Furthermore, maternal HFiD significantly upregulated the mRNA expression of SCFA receptors Gpr41 and Gpr43 in both ED18.5 embryonic tissues and partially restored their expression in HFD-fed adult offspring (Figure S8F,G). Importantly, HFiD supplementation during gestation also mitigated developmental abnormalities of the pancreas and intestine in ED18.5 embryos from BPA-exposed dams (Figure S8H,I). Together, these findings indicate that SCFAs, produced through microbial fermentation of dietary fiber, not only support the development of pancreas and intestine in embryo but also confer long-lasting metabolic benefits to the offspring.

4. Discussion

Previous studies have primarily focused on the association between postnatal BPA exposure and an increased risk of metabolic disorders in adulthood. , However, accumulating evidence indicates that prenatal exposure to EDCs may induce programmed long-term disease susceptibility independent of genetic and immunological determinants. − Nevertheless, the specific impacts and mechanisms of prenatal BPA exposure on long-term metabolic health remain incompletely understood. In this study, we established a mouse model to evaluate the effects of maternal exposure to environmentally relevant low-dose BPA throughout gestation on susceptibility to HFD-induced metabolic disorders in adult offspring. Our results demonstrate that maternal BPA exposure significantly increases the susceptibility of adult offspring to HFD-induced metabolic disturbances. Mechanistically, such exposure is accompanied by impaired development of metabolic organs in the embryo and disruptions in the maternal gut microbiota-SCFAs-embryonic GPR41/GPR43 signaling axis, which may predispose the offspring to glucose and lipid dysregulation in adulthood. This study provides new insights into the mechanisms by which maternal exposure to the environmental endocrine disruptor BPA during pregnancy contributes to the offspring’s susceptibility to metabolic disorders in adulthood.

Earlier research indicated that maternal BPA exposure elevated lipid peroxidation and induced oxidative damage in the livers of male offspring. , Additionally, BPA has been linked to lipid accumulation in both male and female offspring livers in several studies. , It is well-established that HFD consumption disrupts lipid homeostasis, leading to hepatic lipid deposition and exacerbating lipid metabolic disorders in male mice. , Although our data indicated that maternal low-dose BPA exposure had minimal effects on lipid metabolism during lactation, we observed significant increases in LDL-C, T-CHO, TG, and adiponectin levels in HFD-fed adult offspring, alongside elevated fasting glucose and insulin levels, indicating impaired glucose tolerance and insulin resistance. Notably, maternal low-dose BPA exposure further exacerbated hepatic lipid accumulation, as evidenced by Oil Red O staining, and caused liver injury, indicated by elevated serum ALT and AST levels in the HFD-fed offspring. Thus, these findings highlight that maternal low-dose BPA exposure during gestation worsens HFD-induced glucose and lipid metabolism disturbances in the adult offspring.

The gut microbiome plays a crucial role in the host digestion, immunity, and metabolism. Gut microbial imbalances, or dysbiosis, are strongly implicated in metabolic diseases. − Maternal exposure to environmentally relevant concentrations of BPA has been shown to alter gut microbiota composition in both exposed dams and their unexposed offspring. , In this study, we found that maternal BPA exposure during pregnancy disrupted gut microbiota at different time points. Specifically, it significantly altered microbiota composition in dams at GD18 and increased susceptibility to dysbiosis in HFD-fed offspring at 19W. Notably, the family Erysipelotrichaceae, previously linked to diet-induced obesity, , was significantly enriched in HFD-fed offspring from BPA-exposed dams. It has been reported that multiple gut taxa contribute to SCFA production, including (but not limited to) f_Prevotellaceae, f_Ruminococcaceae, and genera such as Bifidobacterium and Bacteroides, among others. In our study, SCFA-producing bacteria such as f_Prevotellaceae and g_Bacteroides were depleted in both pregnant dams and their offspring. These results indicate that BPA-induced alterations in the maternal gut microbiota during gestation may be vertically transmitted to the offspring, thereby compromising the establishment of gut microbial homeostasis and predisposing them to heightened susceptibility to microbial and metabolic disturbances in their later life. Research suggests that changes in maternal gut microbiota during critical developmental windows can have long-lasting effects on offspring metabolic health. Beyond composition, gut microbiota-derived metabolites also play a key role in metabolic disorders. ,

SCFAs act not only as metabolic substrates but also as signaling molecules, activating GPR41 and GPR43 in the fetal intestine and pancreas. In this study, maternal BPA exposure significantly reduced circulating SCFA levels in both pregnant dams and ED18.5 embryos. This reduction was accompanied by downregulation of Gpr41 and Gpr43 expression, as well as impaired expression of key pancreatic development genes (FoxO1, Pdx1, MafA, Insulin) in embryos and offspring. These molecular changes corresponded to reduced β-cell mass and disrupted islet architecture. Similarly, intestinal development was compromised, evidenced by shortened villi and reduced expression of essential differentiation genes (Cdx2, Pax4, Pax6, Tjp1). HFD feeding in adulthood further exacerbated these abnormalities, highlighting a gene-environment interaction established during early development.

Previous research demonstrated that free fatty acid receptor 2 (FFA2) deficiency impairs SCFA-induced secretion of GLP-1 and PYY both in vitro and in vivo. GLP-1 and PYY, secreted by enteroendocrine cells, play crucial roles in regulating energy balance, and PYY also influences cholesterol homeostasis in intestinal cells. Our current findings showed that maternal low-dose BPA exposure reduced the concentrations of GLP-1 and PYY in offspring at various stages, with a particularly pronounced reduction observed in HFD-fed adult offspring. Therefore, maternal BPA exposure during pregnancy likely impairs embryonic intestinal and pancreatic development, thereby affecting the function of the metabolic system in adult offspring and leading to an increased susceptibility to metabolic disorders.

SCFAs, primarily derived from microbial fermentation of dietary fiber, are known to improve insulin sensitivity and lipid and glucose homeostasis. , Clinical studies have demonstrated that specific dietary interventions such as inulin intake can improve metabolism by promoting the production of SCFAs. − A recent study has shown that SCFAs in maternal blood during pregnancy can enter the developing embryo through the placenta. Our findings revealed that maternal HFiD intake during pregnancy not only restored SCFA-producing bacteria: f_Prevotellaceae, g_Bacteroides, and systemic SCFA levels in dams but also elevated SCFA concentrations in fetuses, with protective effects persisting into adulthood. Consequently, HFiD supplementation mitigated BPA-aggravated metabolic disturbances, including dyslipidemia, insulin resistance, and glucose intolerance in HFD-fed adult offspring. Mechanistically, the rescue of Gpr41 and Gpr43 expression in fetal and postnatal tissues supports the hypothesis that SCFA-GPR signaling is a key developmental axis disrupted by BPA and responsive to dietary intervention.

Several limitations must be acknowledged. First, microbiota depletion or fecal microbiota transplantation as well as genetic or pharmacological perturbation of GPR41/43 signaling during gestation are needed to further establish causal links. Second, future work needs to integrate luminal SCFAs with targeted measurements of intestinal transport and hepatic clearance together with isotope tracing to refine source attribution and strengthen mechanistic inference. Finally, cohort studies involving pregnant women are needed to assess the association between maternal BPA exposure and metabolic abnormalities in their children during adulthood.

5. Conclusion

In summary, maternal exposure to environmentally relevant low-dose BPA during pregnancy disrupts gut microbiota homeostasis and SCFA production, accompanied by reduced embryonic GPR41/43 expression and abnormal pancreatic and intestinal development, which may contribute to increased susceptibility to glucose and lipid metabolic disorders in the adult offspring. Maternal high-fiber diet supplementation partially improved maternal gut microbiota composition and circulating SCFA levels with concurrent restoration of embryonic GPR41/43 signaling and attenuation of offspring susceptibility to adult metabolic disorders after prenatal BPA exposure. These findings offer new insights into preventing metabolic disorders linked to EDCs by targeting maternal gut microbiota modulations.

Supplementary Material

eh6c00171_si_001.pdf (761.9KB, pdf)

Acknowledgments

This work was supported by the National Natural Science Foundation of China:(No. 82073594). Promotion Plan for Research of Anhui Medical University (2021xkjT011), Foundation for Top Academic Talents in University of Anhui Province (gxbjZD2022012).

The 16S rRNA gene sequencing data from this study were deposited into the NCBI Sequence Read Archive (SRA), and an NCBI reviewer’s link (https://dataview.ncbi.nlm.nih.gov/object/PRJNA1189853?reviewer=h0v0krn0nqul8lb7lgd0h4ovgu) that reviewers can use to access the data.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/envhealth.6c00171.

  • Food composition in different dietary groups, sequences of the primers for RT-qPCR, effects of gestational exposure to various doses of BPA on birth outcomes; effects of maternal BPA exposure on offspring lipid metabolism and glucose homeostasis; impact of maternal BPA exposure on pancreatic and intestinal functions in offspring; effects of maternal BPA exposure on gut microbiota composition in dams and offspring; influences of maternal high-fiber diet supplementation on offspring metabolic disorders, gut microbial composition, and short-chain fatty acid profiles (PDF)

Yun Hong: Data curation, Investigation, Writing-original draft. Yujie Qiu and Qingqing Yang: Technical support and data interpretation. Bingbing Sun: Methodology, Validation. Yuheng Zhang, Zhiyuan Zhu and Zuo Li: Methodology, Resources. Tong Shen: Conceptualization ideas, Project administration, Writing-Review & Editing, Supervision & Funding acquisition.

The authors declare no competing financial interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

eh6c00171_si_001.pdf (761.9KB, pdf)

Data Availability Statement

The 16S rRNA gene sequencing data from this study were deposited into the NCBI Sequence Read Archive (SRA), and an NCBI reviewer’s link (https://dataview.ncbi.nlm.nih.gov/object/PRJNA1189853?reviewer=h0v0krn0nqul8lb7lgd0h4ovgu) that reviewers can use to access the data.

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