Skip to main content

Effects of bisphenol A treatment during pregnancy on kidney development in mice: a stereological and histopathological study

  • P. Nuñez (a1), T. Fernandez (a2), M. García-Arévalo (a3) (a4) (a5), P. Alonso-Magdalena (a3) (a4), A. Nadal (a3) (a4), C. Perillan (a1) and J. Arguelles (a1)...

Bisphenol A (BPA) is a chemical found in plastics that resembles oestrogen in organisms. Developmental exposure to endocrine-disrupting chemicals, such as BPA, increases the susceptibility to type 2 diabetes (T2DM) and cardiovascular diseases. Animal studies have reported a nephron deficit in offspring exposed to maternal diabetes. The aim of this study was to investigate the prenatal BPA exposure effects on nephrogenesis in a mouse model that was predisposed to T2DM. This study quantitatively evaluated the renal structural changes using stereology and histomorphometry methods. The OF1 pregnant mice were treated with a vehicle or BPA (10 or 100 μg/kg/day) during days 9–16 of gestation (early nephrogenesis). The 30-day-old offspring were sacrificed, and tissue samples were collected and prepared for histopathological and stereology studies. Glomerular abnormalities and reduced glomerular formation were observed in the BPA offspring. The kidneys of the BPA10 and BPA100 female offspring had a significantly lower glomerular number and density than those of the CONTROL female offspring. The glomerular histomorphometry revealed a significant difference between the female and male CONTROL offspring for the analysed glomerular parameters that disappeared in the BPA10 and BPA100 offspring. In addition, the kidney histopathological examination showed typical male cuboidal epithelial cells of the Bowman capsule in the female BPA offspring. Exposure to environmentally relevant doses of BPA during embryonic development altered nephrogenesis. These structural changes could be associated with an increased risk of developing cardiometabolic diseases later in life.

Corresponding author
*Address for correspondence: P. Nuñez, Departamento de Biología Funcional, Área de Fisiología, Facultad de Medicina, Universidad de Oviedo, C/Julián Claveria 6, E-33006 Oviedo, Spain. (Email
Hide All
1. Barker, DJ, Osmond, C, Golding, J, Kuh, D, Wadsworth, ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Br Med J. 1989; 298, 564567.
2. Barker, DJ, Eriksson, JG, Forsén, T, Osmond, C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol. 2002; 31, 12351239.
3. Langley-Evans, SC, McMullen, S. Developmental origins of adult disease. Med Princip Pract. 2010; 19, 8798.
4. Nuñez, P, Arguelles, J, Perillan, C. Offspring’s hydromineral adaptive responses to maternal undernutrition during lactation. J Dev Orig Health Dis. 2015; 6, 520529.
5. You, L, Zhu, X, Shrubsole, MJ, et al. Renal function, bisphenol A, and alkylphenols: results from the National Health and Nutrition Examination Survey (NHANES 2003–2006). Environ Health Perspect. 2011; 119, 527533.
6. Gowder, SJ. Nephrotoxicity of bisphenol A (BPA) – an updated review. Curr Mol Pharmacol. 2013; 6, 163172.
7. Li, M, Bi, Y, Qi, L, et al. Exposure to bisphenol A is associated with low-grade albuminuria in Chinese adults. Kidney Int. 2012; 81, 11311139.
8. Trasande, L, Attina, TM, Trachtman, H. Bisphenol A exposure is associated with low-grade urinary albumin excretion in children of the United States. Kidney Int. 2013; 83, 741748.
9. Nyengaard, JR, Bendtsen, TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992; 232, 194201.
10. Beeman, SC, Zhang, M, Gubhaju, L, et al. Measuring glomerular number and size in perfused kidneys using MRI. Am J Physiol Renal Physiol. 2011; 300, 14541457.
11. Bertram, JF. Analyzing renal glomeruli with the new stereology. Int Rev Cytol. 1995; 161, 111172.
12. Hard, GC, Khan, KN. A contemporary overview of chronic progressive nephropathy in the laboratory rat, and its significance for human risk assessment. Toxicol Pathol. 2004; 32, 171180.
13. Bonventre, JV, Vaidya, VS, Schmouder, R, Feig, P, Dieterle, F. Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol. 2010; 28, 436440.
14. Hughson, MD, Douglas-Denton, R, Bertram, JF, et al. Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States. Kidney Int. 2006; 69, 671678.
15. Kataria, A, Trasande, L, Trachtman, H. The effects of environmental chemicals on renal function. Nat Rev Nephrol. 2015; 11, 610625.
16. vom Saal, FS, Welshons, WV. Evidence that bisphenol A (BPA) can be accurately measured without contamination in human serum and urine, and that BPA causes numerous hazards from multiple routes of exposure. Mol Cell Endocrinol. 2014; 398, 101113.
17. Schecter, A, Malik, N, Haffner, D, et al. Bisphenol A (BPA) in U.S. food. Environ Sci Technol. 2010; 44, 94259430.
18. Martínez-Castelao, A, Navarro-González, JF, Górriz, JL, de Alvaro, F. The concept and the epidemiology of diabetic nephropathy have changed in recent years. J Clin Med. 2015; 4, 12071216.
19. Alonso-Magdalena, P, Quesada, I, Nadal, A. Endocrine disruptors in the etiology of T2DM mellitus. Nat Rev Endocrinol. 2011; 7, 346353.
20. Heindel, JJ, Skalla, LA, Joubert, BR, Dilworth, CH, Gray, KA. Review of developmental origins of health and disease publications in environmental epidemiology. Reprod Toxicol. 2016; 68, 3448.
21. Gore, AC, Chappell, VA, Fenton, SE, et al. EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev. 2015; 36, 1150.
22. Firmin, S, Bahi-Jaber, N, Abdennebi-Najar, L. Food contaminants and programming of T2DM: recent findings from animal studies. J Dev Orig Health Dis. 2016; 7, 505512.
23. Hu, J, Yang, S, Wang, Y, et al. Serum bisphenol A and progression of type 2 diabetic nephropathy: a 6-year prospective study. Acta Diabetol. 2015; 52, 11351141.
24. Hu, J, Wang, Y, Xiang, X, et al. Serum bisphenol A as a predictor of chronic kidney disease progression in primary hypertension: a 6-year prospective study. J Hypertens. 2016; 34, 332337.
25. Alonso-Magdalena, P, Vieira, E, Soriano, S, et al. Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environ Health Perspect. 2010; 118, 12431250.
26. García-Arevalo, M, Alonso-Magdalena, P, Rebelo Dos Santos, J, et al. Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice. PLoS One. 2014; 9, e100214.
27. Liu, XL, Chen, XY, Wang, ZC, Shen, T, Zhao, H. Effects of exposure to bisphenol A during pregnancy and lactation on the testicular morphology and caspase-3 protein expression of ICR pups. Biomed Rep. 2013; 1, 420424.
28. Tran, S, Chen, Y-W, Chenier, I, Chan, JSD, Quaggin, S. Maternal diabetes modulates renal morphogenesis in offspring. J Am Soc Nephrol. 2008; 19, 943952.
29. Chen, YW, Chenier, I, Chang, SY, Tran, S, Ingelfinger, JR. High glucose promotes nascent nephron apoptosis via NF-κB and p53 pathways. Am J Physiol Renal Physiol. 2011; 300, 147156.
30. Kanwar, YS, Nayak, B, Lin, S, Akagi, S, Xie, P. Hyperglycemia: its imminent effects on mammalian nephrogenesis. Pediatr Nephrol. 2005; 20, 858866.
31. Amri, K, Freund, N, Vilar, J, Merlet-Benichou, C, Lelievre-Pegorier, M. (1999) Adverse effects of hyperglycemia on kidney development in rats. Diabetes. 1999; 48, 22402245.
32. Hokke, SN, Armitage, JA, Puelles, VG, et al. Altered ureteric branching morphogenesis and nephron endowment in offspring of diabetic and insulin-treated pregnancy. PLoS One. 2013; 8, e58243.
33. Hokke, S, Arias, N, Armitage, JA, et al. Maternal glucose intolerance reduces offspring nephron endowment and increases glomerular volume in adult offspring. Diabetes Metab Res Rev. 2016; 32, 816826.
34. García-Arévalo, M, Alonso-Magdalena, P, Servitja, JM, et al. Maternal exposure to bisphenol-A during pregnancy increases pancreatic β-cell growth during early life in male mice offspring. Endocrinology. 2016; 157, 41584171.
35. Fernández García, MT, Núñez Martínez, P, García de la Fuente, V, et al. Practical application of stereological methods in experimental kidney animal models. Nefrologia. 2017; 37, 2933.
36. Sugimoto, H, Shikata, K, Matsuda, M, et al. Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy. Diabetologia. 1998; 41, 14261434.
37. Yamashita, T, Kawashima, S, Miwa, Y, et al. A 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor reduces hypertensive nephrosclerosis in stroke-prone spontaneously hypertensive rats. J Hypertens. 2002; 20, 24652473.
38. Hard, GC, Alden, CL, Bruner, RHG, et al. Non-proliferative lesion of the kidney and lower urinary tract in the rat. Guides for Toxicologic Pathology. 1999. STP/ARP/AFIP: Washington, DC.
39. Frazier, KS, Seely, JC, Hard, GC, et al. Proliferative and non-prolferative lesions of the rat and mouse urinary system. Toxicologic Pathol. 2012; 40, 1486.
40. Thornburg, KL. The programming of cardiovascular disease. J Dev Orig Health Dis. 2015; 6, 366376.
41. Kanzaki, G, Tsuboi, N, Haruhara, K, et al. Factors associated with a vicious cycle involving a low nephron number, hypertension and chronic kidney disease. Hypertens Res. 2015; 38, 633641.
42. Moritz, KM, Dodic, M, Wintour, EM. Kidney development and the fetal programming of adult disease. Bioessays. 2003; 25, 212220.
43. Chen, YW, Chenier, I, Tran, S, et al. Maternal diabetes programs hypertension and kidney injury in offspring. Pediatr Nephrol. 2010; 25, 13191329.
44. Hoy, WE, Ingelfinger, JR, Hallan, S. The early development of the kidney and implications for future health. J Dev Orig Health Dis. 2010; 1, 216233.
45. Zandi-Nejad, K, Luyckx, VA, Brenner, BM. Adult hypertension and kidney disease: the role of fetal programming. Hypertension. 2006; 47, 502508.
46. Fong, D, Denton, KM, Moritz, KM, Evans, R, Singh, RR. Compensatory responses to nephron deficiency: adaptive or maladaptive? Nephrology (Carlton). 2014; 19, 119128.
47. McMullen, S, Langley-Evans, SC. Essential hypertension: defending the contribution of a congenital nephron deficit. Hypertension. 2005; 46, e4.
48. Cagampang, FR, Torrens, C, Anthony, FW, Hanson, MA. Developmental exposure to bisphenol A leads to cardiometabolic dysfunction in adult mouse offspring. J Dev Orig Health Dis. 2012; 3, 287292.
49. Johnson, SA, Painter, MS, Javurek, AB, et al. Sex-dependent effects of developmental exposure to bisphenol A and ethinyl estradiol on metabolic parameters and voluntary physical activity. J Dev Orig Health Dis. 2015; 6, 539552.
50. Lemley, KV. A basis for accelerated progression of diabetic nephropathy in Pima Indians. Kidney Int Suppl. 2003; 83, S38S42.
51. Chen, HM, Li, SJ, Chen, HP, et al. Obesity-related glomerulopathy in China: a case series of 90 patients. Am J Kidney Dis. 2008; 52, 5865.
52. Schmitz, A, Nyengaard, JR, Bendtsen, TF. Glomerular volume in type 2 (noninsulin-dependent) diabetes estimated by a direct and unbiased stereologic method. Lab Invest.. 1990; 62, 108113.
53. Keller, G, Zimmer, G, Mall, G, et al. Nephron number in patients with primary hypertension. N Engl J Med. 2003; 348, 101108.
54. Rochester, JR, Bisphenol, A. and human health: a review of the literature. J Steroid Biochem Mol Biol. 2011; 127, 204215.
55. Frazier, KS, Seely, JC. Urinary system. In Monographs on Pathology of Laboratory Animals, 2nd edn, (eds. Jones TC, Hard GC, Mohr U), 1998; pp. 37–57. Springer: Berlin, Germany.
56. Hard, GC, Alden, CL, Stula, EF, Trump, BF. Proliferative lesions of the kidney in rats. In Guides for Toxicologic Pathology, 1995; pp. 1–19.
57. Sahota, PS, Popp, JA, Hardisty, JF, Gopinath, C, (eds.). Toxicologic Pathology: Nonclinical Safety Assessment. 2013. CRC Press: Boca Raton, USA.
58. Kilkenny, C, Browne, WJ, Cuthill, IC, et al. Improving biscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2002; 8, e1000412.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of Developmental Origins of Health and Disease
  • ISSN: 2040-1744
  • EISSN: 2040-1752
  • URL: /core/journals/journal-of-developmental-origins-of-health-and-disease
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed