Effect of lead exposure during perinatal period on kidney of adult offspring in rat: A stereological study

Lead is the most common toxic metal in nature, and its adverse effects on various organs, including the kidneys. Kidney development is a complex process that is influenced by various environmental factors. Although lead toxicity can occur at any age, it is important in pregnant mothers and infants. Therefore, in this study, the effects of low dose lead administration on kidney offspring in rat model were investigated using stereology technique. The animals were randomly divided into in to five groups. Group 1 (control) animals had access to normal drinking water plus 0.5 ml/liter of glacial acetic acid (as a lead acetate solvent) through the study. Group 2 animals were administrated 0.2% of lead acetate in drinking water for 30 days before mating. Group 3 rats received drinking water with 0.2% of lead for 21 days during pregnancy. Group 4 animals received 0.2% of lead acetate in drinking water for 21 days during lactation. Group 5 animals were given 0.2 % lead acetate in drinking water during pre-pregnancy (30 days), pregnancy (21 days) and lactation (21 days) periods. The left kidney was removed from male offspring 60 days after birth. The volume of the kidney, cortex, medulla, proximal convoluted tubules (PCT) and distal convoluted tubules (DCT), as well as the length of PCT and DCT, were analyzed by means of stereology. Results showed a decrease in the volume and length of the DCT and also some pathological effects in experimental groups, in comparison with the control group. Due to the ameliorating effect of lead in perinatal period even in low doses on offspring kidneys, cautiousness is needed in this period.

Keywords:

kidney, lead, stereology, perinatal period,

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1. Elgawish RAR, Abdelrazek HM. Effects of lead acetate on testicular function and caspase-3 expression with respect to the protective effect of cinnamon in albino rats. Toxicol Rep. 2014;1:795-801. doi: 10.1016/j.toxrep.2014.10.010.
2. Abadin H, Ashizawa A, Stevens YW, Llados F, Diamond G, Sage G, et al. Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profiles. Toxicological Profile for Lead. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US); 2007. PMID: 24049859.
3. Ghane T, Zamani N, Hassanian-Moghaddam H, Beyrami A, Noroozi A. Lead poisoning outbreak among opium users in the Islamic Republic of Iran, 2016–2017. Bull World Health Organ. 2018;96(3):165. doi: 10.2471/BLT.17.196287.
4. Hou S, Yuan L, Jin P, Ding B, Qin N, Li L, Liu X, et al. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theor Biol Med Model. 2013;10(1):1-9. doi: 10.1186/1742-4682-10-13.
5. Gąssowska M, Baranowska-Bosiacka I, Moczydłowska J, Frontczak-Baniewicz M, Gewartowska M, Strużyńska L, et al. Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring. Toxicology. 2016;373:13-29. doi: 10.1016/j.tox.2016.10.014.
6. Schottlaender LV, Abeti R, Jaunmuktane Z, Macmillan C, Chelban V, O’callaghan B, et al. Bi-allelic JAM2 variants lead to early-onset recessive primary familial brain calcification. Am J Hum Genet. 2020;106(3):412-21. doi: 10.1016/j.ajhg.2020.02.007.
7. Murata K, Araki S, Aono H. Effects of lead, zinc and copper absorption on peripheral nerve conduction in metal workers. Int Arch Occup Environ Health. 1987;59(1):11-20. doi: 10.1007/BF00377674.
8. Kumar A, Pandey R, Sharma B. Modulation of superoxide dismutase activity by mercury, lead, and arsenic. Biol Trace Elem Res. 2020;196(2):654-61. doi: 10.1007/s12011-019-01957-3.
9. Machoń-Grecka A, Dobrakowski M, Kasperczyk A, Birkner E, Kasperczyk S. Angiogenesis and lead (Pb): is there a connection? Drug Chem Toxicol. 2020:1-5. doi: 10.1080/01480545.2020.1734607.
10. Wildemann TM, Mirhosseini N, Siciliano SD, Weber LP. Cardiovascular responses to lead are biphasic, while methylmercury, but not inorganic mercury, monotonically increases blood pressure in rats. Toxicology. 2015;328:1-11. doi: 10.1016/j.tox.2014.11.009.
11. Kelainy EG, Ibrahim Laila IM, Ibrahim SR. The effect of ferulic acid against lead-induced oxidative stress and DNA damage in kidney and testes of rats. Environ Sci Pollut Res Int. 2019;26(31):31675-84. doi: 10.1007/s11356-019-06099-6.
12. Yang Q, Liu X, Chen J, Wen Y, Liu H, Peng Z, et al. Lead-mediated inhibition of lysine acetylation and succinylation causes reproductive injury of the mouse testis during development. Toxicol Lett. 2020;318:30-43. doi: 10.1016/j.toxlet.2019.10.012.
13. Metryka E, Chibowska K, Gutowska I, Falkowska A, Kupnicka P, Barczak K, et al. Lead (Pb) exposure enhances expression of factors associated with inflammation. Int J Mol Sci. 2018;19(6):1813. doi: 10.3390/ijms19061813.
14. Lee J-W, Choi H, Hwang U-K, Kang J-C, Kang YJ, Kim KI, et al. Toxic effects of lead exposure on bioaccumulation, oxidative stress, neurotoxicity, and immune responses in fish: A review. Environ Toxicol Pharmacol. 2019;68:101-8. doi: 10.1016/j.etap.2019.03.010.
15. Zhou J-P, Wang F, Wang X-Y, Jiang Y-S, Yi X-Q. Effects of embryonic lead exposure on motor function and balance ability in offspring rats and possible mechanisms. Zhongguo Dang dai er ke za zhi= Chinese J Contem Pediatrics. 2017;19(3):361-7. doi: 10.7499/j.issn.1008-8830.2017.03.022.
16. Ollson CJ, Smith E, Herde P, Juhasz AL. Influence of co-contaminant exposure on the absorption of arsenic, cadmium and lead. Chemosphere. 2017;168:658-66. doi: 10.1016/j.chemosphere.2016.11.010.
17. Łuszczek-Trojnar E, Drąg-Kozak E, Szczerbik P, Socha M, Popek W. Effect of long-term dietary lead exposure on some maturation and reproductive parameters of a female Prussian carp (Carassius gibelio B.). Environ Sci Pollut Res Int. 2014;21(4):2465-78. doi: 10.1007/s11356-013-2184-x.
18. Rzymski P, Tomczyk K, Poniedzialek B, Opala T, Wilczak M. Impact of heavy metals on the female reproductive system. Ann Agric Environ Med. 2015;22(2). doi: 10.5604/12321966.1152077.
19. Xie J, Yu J, Fan Y, Zhao X, Su J, Meng Y, et al. Low dose lead exposure at the onset of puberty disrupts spermatogenesis-related gene expression and causes abnormal spermatogenesis in mouse. Toxicol Appl Pharmacol. 2020;393:114942. doi: 10.1016/j.taap.2020.114942.
20. Soleimanzadeh A, Kian M, Moradi S, Mahmoudi S. Carob (Ceratonia siliqua L.) fruit hydro-alcoholic extract alleviates reproductive toxicity of lead in male mice: Evidence on sperm parameters, sex hormones, oxidative stress biomarkers and expression of Nrf2 and iNOS. Avicenna J Phytomed. 2020;10(1):35. PMCID: PMC6941692.
21. Kalahasthi R, Barman T. Assessment of lead exposure and urinary-δ-aminolevulinic acid levels in male lead acid battery workers in Tamil Nadu, India. J Health Pollut. 2018;8(17):6-13. doi: 10.5696/2156-9614-8.17.6.
22. Wang Z, Xu X, He B, Guo J, Zhao B, Zhang Y, et al. The impact of chronic environmental metal and benzene exposure on human urinary metabolome among Chinese children and the elderly population. Ecotoxicol Environ Saf. 2019;169:232-9. doi: 10.1016/j.ecoenv.2018.11.016.
23. Farag MR, Alagawany M, Abd El-Hack ME, El-Sayed SA, Ahmed SY, Samak DH. Yucca schidigera extract modulates the lead-induced oxidative damage, nephropathy and altered inflammatory response and glucose homeostasis in Japanese quails. Ecotoxicol Environ Saf. 2018;156:311-21. doi: 10.1016/j.ecoenv.2018.03.010.
24. Riaz MA, Nisa ZU, Mehmood A, Anjum MS, Shahzad K. Metal-induced nephrotoxicity to diabetic and non-diabetic Wistar rats. Environ Sci Pollut Res Int. 2019;26(30):31111-8. doi: 10.1007/s11356-019-06022-z.
25. Vyskocil A, Pancl J, Tusl M, Ettlerova E, Semecky V, Kašparová L, et al. Dose‐related proximal tubular dysfunction in male rats chronically exposed to lead. J Appl Toxicol. 1989;9(6):395-9. doi: 10.1002/jat.2550090605.
26. Karimfar MH, Bargahi A, Moshtaghi D, Farzadinia P. Long-term exposure of lead acetate on rabbit renal tissue. Iran Red Crescent Med J. 2016;18(2). doi: 10.5812/ircmj.22157.
27. Orr SE, Bridges CC. Chronic kidney disease and exposure to nephrotoxic metals. Int J Mol Sci. 2017;18(5):1039. doi: 10.3390/ijms18051039.
28. Sanders AP, Svensson K, Gennings C, Burris HH, Oken E, Amarasiriwardena C, et al. Prenatal lead exposure modifies the effect of shorter gestation on increased blood pressure in children. Environ Int. 2018;120:464-71. doi: 10.1016/j.envint.2018.08.038.
29. Qin J, Ning H, Zhou Y, Hu Y, Huang B, Wu Y, et al. LncRNA Uc. 173 is a key molecule for the regulation of lead-induced renal tubular epithelial cell apoptosis. Biomed Pharmacother. 2018;100:101-7. doi: 10.1016/j.biopha.2018.01.112.
30. McGeady TA, Quinn PJ, Fitzpatrick ES, Ryan MT, Kilroy D, Lonergan P. Veterinary embryology: John Wiley & Sons; 2017.
31. Gavaghan H. Lead, unsafe at any level. Bull World Health Organ. 2002;80:82-. PMCID: PMC2567638.
32. Al-Shimali H, Al-Musaileem A, Rao M, Khan K. Low-dose exposure to lead during pregnancy affects spatial learning, memory and neurogenesis in hippocampus of young rats. J Neurol Neurosci. 2016;7(3).
33. Nyengaard JR. Stereologic methods and their application in kidney research. J Am Soc Nephrol. 1999;10(5):1100-23. doi: 10.1681/ASN.V1051100.
34. Keller C, Katz R, Cushman M, Fried LF, Shlipak M. Association of kidney function with inflammatory and procoagulant markers in a diverse cohort: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA). BMC nephrol. 2008;9(1):1-8. doi: 10.1186/1471-2369-9-9.
35. Heidmets L-T, Zharkovsky T, Jurgenson M, Jaako-Movits K, Zharkovsky A. Early post-natal, low-level lead exposure increases the number of PSA-NCAM expressing cells in the dentate gyrus of adult rat hippocampus. Neurotoxicology. 2006;27(1):39-43. doi: 10.1016/j.neuro.2005.05.015.
36. Jaako-Movits K, Zharkovsky T, Romantchik O, Jurgenson M, Merisalu E, Heidmets L-T, et al. Developmental lead exposure impairs contextual fear conditioning and reduces adult hippocampal neurogenesis in the rat brain. Int J Dev Neurosci. 2005;23(7):627-35. doi: 10.1016/j.ijdevneu.2005.07.005.
37. Gundersen HJ, Jensen E. The efficiency of systematic sampling in stereology and its prediction. J Microsc. 1987;147(3):229-63. doi: 10.1111/j.1365-2818.1987.tb02837.x.
38. Heidari Z, Mahmoudzadeh SH, Rafighdoust H, Moien A. Analysis of Gross Anatomical Parameters of Kidney in Male Rats Following Lead Poisoning by Using a Stereological Method. Zahedan Journal Of Research In Medical Sciences (Tabib-E-Shargh). 2003; 5(2)
39. Khalil-Manesh F, Gonick HC, Cohen AH, Alinovi R, Bergamaschi E, Mutti A, et al. Experimental model of lead nephropathy. I. Continuous high-dose lead administration. Kidney Int. 1992;41(5):1192-203. doi: 10.1038/ki.1992.181.
40. Skröder H, Hawkesworth S, Moore SE, Wagatsuma Y, Kippler M, Vahter M. Prenatal lead exposure and childhood blood pressure and kidney function. Environ Res. 2016;151:628-34. doi: 10.1016/j.envres.2016.08.028.
41. Cibulskyte D, Pedersen M, Hjelm-Poulsen J, Hansen HE, Madsen M, Mortensen J. The pharmacokinetics and acute renal effects of oral microemulsion ciclosporin A in normal pigs. Int Immunopharmacol. 2006;6(4):627-34. doi: 10.1016/j.intimp.2005.09.013.
42. Padigala KK, Hartle JE, Kirchner HL, Schultz MF. Renal cortical thickness as a predictor of renal function and blood pressure status post renal artery stenting. Angiology. 2009;60(6):719-24. doi: 10.1177/0003319709339587.
43. Coleman WB, Tsongalis GJ. Essential concepts in molecular pathology: Academic Press; 2010.
44. Jarrar BM. Histological and histochemical alterations in the kidney induced by lead. Ann Saudi Med. 2003;23(1-2):10-5. doi: 10.5144/0256-4947.2003.10.
45. Goyer RA. Results of lead research: prenatal exposure and neurological consequences. Environ Health Perspect. 1996;104(10):1050-4. doi: 10.1289/ehp.961041050.
46. Mitra P, Sharma S, Purohit P, Sharma P. Clinical and molecular aspects of lead toxicity: An update. Crit Rev Clin Lab Sci. 2017;54(7-8):506-28. doi: 10.1080/10408363.2017.1408562.
47. Korach KS. Reproductive and developmental toxicology: CRC Press; 1998.
48. Shahsavari A, Yazdi FT, Moosavi Z, Heidari A, Sardari P. A study on the concentration of heavy metals and histopathological changes in Persian jirds (Mammals; Rodentia), affected by mining activities in an iron ore mine in Iran. Environ Sci Pollut Res Int. 2019;26(12):12590-604. doi: 10.1007/s11356-019-04646-9.
49. Daehn IS, Duffield JS. The glomerular filtration barrier: a structural target for novel kidney therapies. Nat Rev Drug Discov. 2021;20(10):770-88. doi: 10.1038/s41573-021-00242-0.
50. Vyskocil A, Cizkova M, Tejnorova I. Effect of prenatal and postnatal exposure to lead on kidney function in male and female rats. J Appl Toxicol. 1995;15(4):327-8. doi: 10.1002/jat.2550150416.
51. Afshari AT, Shirpoor A, Farshid A, Saadatian R, Rasmi Y, Saboory E, et al. The effect of ginger on diabetic nephropathy, plasma antioxidant capacity and lipid peroxidation in rats. Food chem. 2007;101(1):148-53. doi.org/10.1016/j.foodchem.2006.01.013
52. Antonio-García MT, Massó-Gonzalez EL. Toxic effects of perinatal lead exposure on the brain of rats: involvement of oxidative stress and the beneficial role of antioxidants. Food Chem Toxicol. 2008;46(6):2089-95. doi: 10.1016/j.fct.2008.01.053.
53. Patriarca M, Menditto A, Rossi B, Lyon T, Fell G. Environmental exposure to metals of newborns, infants and young children. Microchemical J. 2000;67(1-3):351-61. doi.org/10.1016/S0026-265X(00)00088-6
54. Kaji M, Nishi Y. Lead and growth. Clin Pediatr Endocrinol. 2006;15(4):123-8. doi: 10.1297/cpe.15.123.
55. Azarnia M, Mirabolghasemi G, Hamauatkhah V, editors. The effect of lead acetate on histological structure of the kidney of 1-day-old rats. Toxicology; 2001: Elsevier Sci Ireland Ltd Customer Relations Manager, Bay 15, Shannon Industrial Estate Co, Clare, Ireland: Elsevier Sci Ireland Ltd.
56. Mohammadi S, Khakbaz M, Marzieh S. Effects of different doses of manganese on lead poisoning in the kidney of adult male mice. koomesh. 2016;18.
57. Flora G, Gupta D, Tiwari A. Toxicity of lead: a review with recent updates. Interdiscip Toxicol. 2012;5(2):47. doi: 10.2478/v10102-012-0009-2.
58. Gundacker C, Pietschnig B, Wittmann KJ, Lischka A, Salzer H, Hohenauer L, et al. Lead and mercury in breast milk. Pediatrics. 2002;110(5):873-8. doi: 10.1542/peds.110.5.873.
59. Hanif MO, Bali A, Ramphul K. Acute renal tubular necrosis. StatPearls [Internet]. 2021. PMID: 29939592.
60. Breshears MA, Confer AW. The urinary system. Pathologic basis of veterinary disease. 2017:617. 10.1016/B978-0-323-35775-3.00011-4