Table 2.
Major animal studies showing associations between BPA and phthalates and obesity.
| Author, Year | Type of Animal Used | Main Findings | Remarks |
|---|---|---|---|
| Bisphenol A and obesity | |||
| Pu et al., 2017 [161] | Primiparous female sheep | 1. ↑ differentiation rate in adipocytes 2. ↑ mRNA expression of PPARγ in fetal adipose tissue 3. ↑ expression of FABP4, GLUT4 and SOX6 in the offspring 4. ↑ gene expression of GR, ESR1, ESR2 and ERRα |
1. Type of exposure: sc 2. Exposure duration: 147 days 3. Daily BPA dose: 0.5 mg/kg |
| Desai et al., 2018 [160] | 12-week-old female Sprague–Dawley rats | 1. ↑ body weight 2. ↑ mass of adipose tissue 3. Hypertophic adipocytes in male offspring 4. ↑ expression of PPARγ 5. ↑ TNF-α and CD68 in adipose tissue |
1. Findings occurred in the offspring 2. Type of exposure: drinking water 3. Exposure duration: 2 weeks before mating up to weaning 4. Daily BPA dose: 5 mg/L |
| Stoker et al., 2019 [173] | 90-day-old female Wistar rats | 1. ↑ food intake 2. ↑ epididymal and perirenal fat deposition 3. ↑ fasting serum glucose and leptin in male mice 4. ↑ expression of hypothalamic orexigenic neuropeptides in male mice |
1. Findings occurred in the offspring 2. Type of exposure: drinking water 3. Exposure duration: pregnancy day 9 to weaning 4. Daily BPA dose: 50 µg/kg |
| Lin et al., 2019 [174] | 3-week-old male Wistar rats | 1. ↑ fat deposition (visceral, liver) 2. ↑ TCHOL, LDL, TGs 3. ↓ HDL 4. ↑ TNF-α, IL-17 5. ↑ mRNA of SREBP1 and ACC1 6. ↑ TLR4 and NF-κB in the liver 7. ↓ HSL, ERα and ZAG in the liver |
1. Type of exposure: drinking water 2. Exposure duration: 8 weeks 3. Daily BPA dose: 1 µg/mL |
| Tian et al., 2021 [113] | 5-month-old wild-type adult male Danio rerio | 1. ↑ weight gain, length, food intake 2. ↑ lipid accumulation in liver 3. Microvesicular fatty changes, hepatocyte ballooning, infiltration with inflammatory cells 4. ↑ of CB1 5. ↑ of insulin signaling pathways 6. ↓ expression of PPARα in adipose tissue and liver 7. ↓ gpr55 |
1. Type of exposure: water in static system 2. Exposure duration: 28 days 3. Daily BPA dose: 20, 100 and 500 μg/L |
| Shih et al., 2021 [175] | 15-week-old female Sprague–Dawley rats | 1. ↑ abdominal lipid weight up to 77% in female offspring 2. ↑ TCHOL, LDL, TGs 3. ↓ HDL 4. ↑ leptin 5. ↑ of Prevotella, C. perfringens, C. ruminantius in feces |
1. Type of exposure: oral gavage 2. Exposure duration: 6th-36th day after pregnancy 3. Daily BPA dose: 50 µg/kg |
| Zhuang et al., 2023 [165] | 7-week-old male and female ICR mice | 1. ↑ weight gain in the offspring 2. ↑ size of adipocytes 3. ↓ insulin sensitivity 4. No obesogenic effects via estrogen signaling pathway 5. Obesogenic effects via TGF-β signaling pathway |
1. Type of exposure: drinking water 2. Exposure duration: 7 days treatment up to delivery 3. Daily BPA dose: 0.5 μg/kg |
| Phthalates and obesity | |||
| Hao et al., 2013 [162] | C57BL/6J mice | 1. ↑ expression of PPARγ, aP2, LPL and FAS 2. ↑ expression of C/EBP, Srebf1 3. ↑ glucose, TCHOL, TGs in serum 4. Obese phenotype only at the dose of 0.25 mg/kg in female offspring 5. ↑ weight gain in male offspring |
1. Type of phthalate: DEHP 2. Ip DEHP at the dose of 0.5 mg/kg in six-week-old male mice 3. Female mice: - Type of exposure: gavage - Exposure duration: from day 12 of gestation until day 7 of lactation - Daily DEHP dose: 0.05, 0.25 or 0.5 mg/kg |
| Klöting et al., 2015 [163] | Obesity-resistant 129S6 mice | In female (but not in male) mice: 1. ↑ weight gain 2. ↑ fat mass 3. ↓ insulin tolerance 4. ↓ Pparg and adiponectin in scAT 5. ↑↑ Esr1 protein levels in SC and visceral adipose tissue 6. (-) TCHOL, TGs in serum 7. ↑ in phospholipid and carnitine |
1. Type of phthalate: DEHP 2. Type of exposure: oral 3. Exposure duration: 10 weeks 4. Daily DEHP dose: 0.05 mg/kg |
| Lv et al., 2016 [135] | Male C3H/He mice | 1. ↑ food intake, adipogenesis and weight gain in all exposure groups except for 0.05 mg/kg 2. Interruption in hypothalamic appetite-related neuropeptides: - ↑ expression of AgRP in all groups - ↑ expression of NPY at 50 and 200 mg/kg - ↓ expression of POMC at 200 mg/kg 3. Hypothalamic leptin resistance resulting in hypothyroidism 4. ↓ WAT lipid metabolism at 0.5 mg/kg 5. ↑ WAT lipid metabolism at 50 and 200 mg/kg |
1. Type of phthalate: DEHP 2. Type of exposure: gavage 3. Exposure duration: 5 weeks 4. Daily DEHP dose: 0.05, 0.5, 5, 50 and 200 mg/kg |
| Zhang et al., 2020 [176] | C57BL/6 J male and female mice | 1. Weight gain in male mice on HFD at 3 mg/kg/d 2. At the dose of 3 mg/kg/d: - ↑ activation of SREBP1 - (-) of SREBP2, PPARγ - ↑ expression of downstream regulatory genes of SREBP1 (FAS, ACC, HMGCR) 3. ↓ insulin tolerance in male mice between HFD + BBP3 and HFD groups |
1. Type of phthalate: BBP 2. Type of exposure: oral 3. Exposure duration: 16 weeks 4. Daily BBP dose: 4 μg/kg, 169 μg/kg, 3 mg/kg, 50 mg/kg |
| Guo et al., 2020 [172] | Zebrafish embryos 0.75 hpf | - ↑ expression of PPARγ due to the following: 1. Significant regional DNA demethylation 2. Upregulation of tet1 and tet2 gene transcription) - As a result, ↓ TCHOL and TGs due to ↑ expression of downstream genes involved in lipid metabolism |
1. Type of phthalate: TBPH and TBMEHP 2. Type of exposure: glass Petri dish containing 100 mL of TBPH or TBMEHP 3. Exposure duration: until 72 hpf 4. Daily TBPH and TBMEHP dose: 0.2–2000 nM |
| Buerger et al., 2020 [177] | Zebrafish (Danio rerio) | GI dysbiosis in the OF + DEHP group as a result of the following: - ↑ of Bacteroidetes - ↑ of UFAs - ↑ lipid metabolism - ↓ carbohydrate metabolism - ↓ glycerolipid metabolism - ↓ glycerophospholipid metabolism - ↓ carbohydrate, galactose, inositol phosphate, taurine and hypotaurine metabolism |
1. Type of phthalate: DEHP 2. Type of exposure: oral 3. Exposure duration: 60 days 4. Daily DEHP dose: 3 mg/kg |
Abbreviations: ACC1: acetyl-CoA carboxylase 1; AgRP: Agouti-related protein; AP2: adipocyte protein 2; BPA: bisphenol A; CB1: endocannabinoid receptor type 1; CD68: cluster of differentiation 68; C/EBP: CCAAT/enhancer-binding protein; ESR1: estrogen receptor 1; ESR2: estrogen receptor 1; ERRα: estrogen-related receptor α; FABP4: fatty-acid-binding protein 4; FAS: fatty acid synthase; GLUT4: glucose transporter type 4; GR: glucocorticoid receptor; HDL: high-density lipoprotein cholesterol; HSL: hormone-sensitive lipase; IL-17: interleukin-17; LDL: low-density lipoprotein cholesterol; LPL: lipoprotein lipase; NPY: neuropeptide Y; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PPARγ: peroxisome-proliferator-activated receptor γ; POMC: proopiomelanocortin; SC: subcutaneous; SOX6: SRY-box transcription factor 6; SREBP1: sterol regulatory element-binding transcription factor 1; TNF-α: tumor necrosis factor-α; TCHOL: total cholesterol; TGF-β: transforming growth factor-β; TGs: triglycerides; TLR4: toll-like receptor 4; WAT: white adipose tissue; ZAG: ZAG adiponectin. ↑ increase, ↓ decrease.