Skip to main content

Advertisement

SpringerLink
Log in

Assessment of Adrenotoxicity Induced on Prenatal Exposure to Bacterial Endotoxin Lipopolysaccharide: an Age-Related Study in Mice

  • Research Article
  • Published:
Proceedings of the National Academy of Sciences, India Section B: Biological Sciences Aims and scope Submit manuscript

Abstract

Preclinical and clinical studies have reported that psychiatric illness stems from exposure to infection during early life. Infection-induced increase in proinflammatory cytokines and further activation of the hypothalamic–pituitary–adrenal (HPA) axis are considered the main factors behind mental illness. The present study elucidated the impairment of HPA axis of female mice prenatally challenged with bacterial endotoxin lipopolysaccharide (LPS). The impairment was evaluated through detailed investigation of adrenal histopathology, the end target endocrine gland of HPA axis, plasma levels of pituitary adrenocorticotropic hormone (ACTH) and corticosterone (CORT). In view of the role of pituitary hormone prolactin (PRL) in modulation of HPA axis under infection, plasma level of PRL was also assessed. The evaluation was done at three different life stages of adulthood, i.e., postnatal day (PND) 85, PND 120 and PND 200. Distinct histopathological alterations in adrenal were revealed: distorted arrangement of zona fasciculata cells, localized cytoplasmic vacuolization and accumulation of lipid droplets were some of the disruptions of the adrenal cortex. Medulla showed distinct vascular congestion and disruptions of chromaffin cells with pyknotic nuclei. Plasma levels of ACTH and CORT were significantly elevated, but PRL was lowered. Bacterial endotoxin LPS might have interfered at different levels of hypothalamus, pituitary and directly on adrenal as well acting through its receptors to induce adrenotoxicity. An age-dependent HPA axis impairment was noted; the persistence of the adrenal toxicity was to a greater degree at PND 200 than PND 120 and PND 85 suggesting the reason for the susceptibility of old age to mental illness.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Meltzer-Brody S, Larsen JT, Petersen L, Guintivano J, Florio AD, Miller WC, Sullivan PF, Munk-Olsen T (2018) Adverse life events increase risk for postpartum psychiatric episodes: a population-based epidemiologic study. Depress Anxiety 35(2):160–167. https://doi.org/10.1002/da.22697

    Article  CAS  PubMed  Google Scholar 

  2. Weinstock M (2017) Prenatal stressors in rodents: effects on behavior. Neurobiol Stress 6:3–13. https://doi.org/10.1016/j.ynstr.2016.08.004

    Article  PubMed  Google Scholar 

  3. Khandaker GM, Zimbron J, Lewis G, Jones PB (2013) Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med 43(2):239–257. https://doi.org/10.1017/S0033291712000736

    Article  CAS  PubMed  Google Scholar 

  4. Boksa P (2010) Effects of prenatal infection on brain development and behavior: a review of findings from animal models. Brain Behav Immun 24(6):881–897. https://doi.org/10.1016/j.bbi.2010.03.005

    Article  PubMed  Google Scholar 

  5. Ronovsky M, Berger S, Zambon A, Reisinger SN, Horvath O, Pollak A, Lindtner C, Berger A, Pollak DD (2017) Maternal immune activation transgenerationally modulates maternal care and offspring depression-like behavior. Brain Behav Immun 63:127–136. https://doi.org/10.1016/j.bbi.2016.10.016

    Article  CAS  PubMed  Google Scholar 

  6. Kumar V (2019) Toll-like receptors in the pathogenesis of neuroinflammation. J Neuroimmunol. https://doi.org/10.1016/j.jneuroim.2019.03.012

    Article  PubMed  Google Scholar 

  7. Kanczkowski W, Chatzigeorgiou A, Samus M, Tran N, Zacharowski K, Chavakis T, Bornstein SR (2013) Characterization of the LPS-induced inflammation of the adrenal gland in mice. Mol Cell Endocrinol 371(1–2):228–235. https://doi.org/10.1016/j.mce.2012.12.020

    Article  CAS  PubMed  Google Scholar 

  8. Kentner AC, Pittman QJ (2010) Minireview: early-life programming by inflammation of the neuroendocrine system. Endocrinology 151(10):4602–4606. https://doi.org/10.1210/en.2010-0583

    Article  CAS  PubMed  Google Scholar 

  9. Haddad JJ, Saadé NE, Safieh-Garabedian B (2002) Cytokines and neuro–immune–endocrine interactions: a role for the hypothalamic–pituitary–adrenal revolving axis. J Neuroimmunol 133(1–2):1–19. https://doi.org/10.1016/S0165-5728(02)00357-0

    Article  CAS  PubMed  Google Scholar 

  10. Dahlgren J, Samuelsson AM, Jansson T, Holmäng A (2006) Interleukin-6 in the maternal circulation reaches the rat fetus in mid-gestation. Pediatr Res 60(2):147. https://doi.org/10.1203/01.pdr.0000230026.74139.18

    Article  CAS  PubMed  Google Scholar 

  11. Shanks N, Larocque S, Meaney MJ (1995) Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress. J Neurosci 15(1):376–384. https://doi.org/10.1523/JNEUROSCI.15-01-00376.1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shanks N, Windle RJ, Perks PA, Harbuz MS, Jessop DS, Ingram CD, Lightman SL (2000) Early-life exposure to endotoxin alters hypothalamic–pituitary–adrenal function and predisposition to inflammation. Proc Natl Acad Sci 97(10):5645–5650. https://doi.org/10.1073/pnas.090571897

    Article  CAS  PubMed  Google Scholar 

  13. Nilsson C, Jennische E, Ho HP, Eriksson E, Bjorntorp P, Holmang A (2002) Postnatal endotoxin exposure results in increased insulin sensitivity and altered activity of neuroendocrine axes in adult female rats. Eur J Endocrinol 146(2):251–260. https://doi.org/10.1530/eje.0.1460251

    Article  CAS  PubMed  Google Scholar 

  14. Basta-Kaim A, Budziszewska B, Leśkiewicz M, Fijał K, Regulska M, Kubera M, Wędzony K, Lasoń W (2011) Hyperactivity of the hypothalamus–pituitary–adrenal axis in lipopolysaccharide-induced neurodevelopmental model of schizophrenia in rats: effects of antipsychotic drugs. Eur J Pharmacol 650:586–595. https://doi.org/10.1016/j.ejphar.2010.09.083

    Article  CAS  PubMed  Google Scholar 

  15. Enayati M, Solati J, Hosseini MH, Shahi HR, Saki G, Salari AA (2012) Maternal infection during late pregnancy increases anxiety-and depression-like behaviors with increasing age in male offspring. Brain Res Bull 87(2–3):295–302. https://doi.org/10.1016/j.brainresbull.2011.08.015

    Article  PubMed  Google Scholar 

  16. Martinez-Arguelles DB, Guichard T, Culty M, Zirkin BR, Papadopoulos V (2011) In utero exposure to the antiandrogen di-(2-ethylhexyl) phthalate decreases adrenal aldosterone production in the adult rat. Biol Reprod 85(1):51–61. https://doi.org/10.1095/biolreprod.110.089920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Medwid S, Guan H, Yang K (2016) Prenatal exposure to bisphenol a disrupts adrenal steroidogenesis in adult mouse offspring. Environ Toxicol Pharmacol 43:203–208. https://doi.org/10.1016/j.etap.2016.03.014

    Article  CAS  PubMed  Google Scholar 

  18. Ping J, Wang JF, Liu L, Yan YE, Liu F, Lei YY, Wang H (2014) Prenatal caffeine ingestion induces aberrant DNA methylation and histone acetylation of steroidogenic factor 1 and inhibits fetal adrenal steroidogenesis. Toxicology 321:53–61. https://doi.org/10.1016/j.tox.2014.03.011

    Article  CAS  PubMed  Google Scholar 

  19. He Z, Zhu C, Huang H, Liu L, Wang L, Chen L, Magdalou J, Wang H (2016) Prenatal caffeine exposure-induced adrenal developmental abnormality in male offspring rats and its possible intrauterine programming mechanisms. Toxicol Res 5(2):388–398. https://doi.org/10.1039/c5tx00265f

    Article  CAS  Google Scholar 

  20. Yan YE, Liu L, Wang JF, Liu F, Li XH, Qin HQ, Wang H (2014) Prenatal nicotinic exposure suppresses fetal adrenal steroidogenesis via steroidogenic factor 1 (SF-1) deacetylation. Toxicol Appl Pharmacol 277(3):231–241. https://doi.org/10.1016/j.taap.2014.03.019

    Article  CAS  PubMed  Google Scholar 

  21. Huang H, He Z, Zhu C, Liu L, Kou H, Shen L, Wang H (2015) Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms. Toxicol Appl Pharmacol 288(1):84–94. https://doi.org/10.1016/j.taap.2015.07.005

    Article  CAS  PubMed  Google Scholar 

  22. Calejman CM, Astort F, Di Gruccio JM, Repetto EM, Mercau M, Giordanino E, Sanchez R, Pignataro O, Arias P, Cymeryng CB (2011) Lipopolysaccharide stimulates adrenal steroidogenesis in rodent cells by a NFκB-dependent mechanism involving COX-2 activation. Mol Cell Endocrinol 337(1–2):1–6. https://doi.org/10.1016/j.mce.2010.12.036

    Article  CAS  Google Scholar 

  23. Held Hales K, Diemer T, Ginde S, Shankar BK, Roberts M, Bosmann HB, Hales DB (2000) Diametric effects of bacterial endotoxin lipopolysaccharide on adrenal and Leydig cell steroidogenic acute regulatory protein. Endocrinology 141(11):4000–4012. https://doi.org/10.1210/endo.141.11.7780

    Article  Google Scholar 

  24. Ferreira LG, Prevatto JP, Freitas HR, Reis RA, Silva PM, Martins MA, Faria RX, Carvalho VF (2019) Capsaicin inhibits lipopolysaccharide-induced adrenal steroidogenesis by raising intracellular calcium levels. Endocrine 64(1):169–175. https://doi.org/10.1007/s12020-019-01849-5

    Article  CAS  PubMed  Google Scholar 

  25. De Laurentiis A, Pisera D, Caruso C, Candolfi M, Mohn C, Rettori V, Seilicovich A (2002) Lipopolysaccharide-and tumor necrosis factor-α-induced changes in prolactin secretion and dopaminergic activity in the hypothalamic-pituitary axis. NeuroImmunoModulation 10(1):30–39. https://doi.org/10.1159/000064412

    Article  PubMed  Google Scholar 

  26. Hollis JH, Lightman SL, Lowry CA (2005) Lipopolysaccharide has selective actions on sub-populations of catecholaminergic neurons involved in activation of the hypothalamic–pituitary–adrenal axis and inhibition of prolactin secretion. J Endocrinol 184(2):393–406. https://doi.org/10.1677/joe.1.05839

    Article  CAS  PubMed  Google Scholar 

  27. Kumar U, Mohanty B (2015) Atypical antipsychotic paliperidone prevents behavioral deficits in mice prenatally challenged with bacterial endotoxin lipopolysaccharide. Eur J Pharmacol 747:181–189. https://doi.org/10.1016/j.ejphar.2014.09.011

    Article  CAS  PubMed  Google Scholar 

  28. Kaufman MH, Kaufman MH (1992) The atlas of mouse development, vol 428. Academic press, London

    Google Scholar 

  29. Mishra AC, Mohanty B (2010) Lactational exposure to atypical antipsychotic drugs disrupts the pituitary-testicular axis in mice neonates during post-natal development. J Psychopharmacol 24(7):1097–1104. https://doi.org/10.1177/0269881109348162

    Article  CAS  PubMed  Google Scholar 

  30. Hewagalamulage SD, Clarke IJ, Rao A, Henry BA (2016) Ewes with divergent cortisol responses to ACTH exhibit functional differences in the hypothalamo-pituitary-adrenal (HPA) axis. Endocrinology. 157(9):3540–3549. https://doi.org/10.1210/en.2016-1287

    Article  CAS  PubMed  Google Scholar 

  31. Bhaskar R, Mishra AK, Mohanty B (2017) Neonatal exposure to endocrine disrupting chemicals impairs learning behaviour by disrupting hippocampal organization in male Swiss Albino mice. Basic Clin Pharmacol Toxicol 121(1):44–52. https://doi.org/10.1111/bcpt.12767

    Article  CAS  PubMed  Google Scholar 

  32. Doosti MH, Bakhtiari A, Zare P, Amani M, Majidi N, Babri S, Salari AA (2013) Impacts of early intervention with fluoxetine following early neonatal immune activation on depression-like behaviors and body weight in mice. Prog Neuropsychopharmacol Biol Psychiatry 43:55–65. https://doi.org/10.1016/j.pnpbp.2012.12.003

    Article  CAS  PubMed  Google Scholar 

  33. Walker FR, Owens J, Ali S, Hodgson DM (2006) Individual differences in glucose homeostasis: do our early life interactions with bacteria matter? Brain Behav Immun 20(4):401–409. https://doi.org/10.1016/j.bbi.2005.11.004

    Article  CAS  PubMed  Google Scholar 

  34. Tkachenko IV, Jaaskelainen T, Jaaskelainen J, Palvimo JJ, Voutilainen R (2011) Interleukins 1α and 1β as regulators of steroidogenesis in human NCI-H295R adrenocortical cells. Steroids 76(10–11):1103–1115. https://doi.org/10.1016/j.steroids.2011.04.018

    Article  CAS  PubMed  Google Scholar 

  35. Olukole SG, Lanipekun DO, Ola-Davies EO, Oke BO (2019) Melatonin attenuates bisphenol a-induced toxicity of the adrenal gland of Wistar rats. Environ Sci Pollut Res 26(6):5971–5982. https://doi.org/10.1007/s11356-018-4024-5

    Article  CAS  Google Scholar 

  36. Rosol TJ, Yarrington JT, Latendresse J, Capen CC (2001) Adrenal gland: structure, function, and mechanisms of toxicity. Toxicol Pathol 29(1):41–48. https://doi.org/10.1080/19262301301418847

    Article  CAS  PubMed  Google Scholar 

  37. Sayed MM (2016) Effect of prenatal exposure to nicotine/thiocyanate on the pituitary–adrenal axis of 1-month-old rat offspring. Egypt J Histol 39(4):307–316. https://doi.org/10.1097/01.EHX.0000512120.79296.60

    Article  Google Scholar 

  38. Douglas SA, Sreenivasan D, Carman FH, Bunn SJ (2010) Cytokine interactions with adrenal medullary chromaffin cells. Cell Mol Neurobiol 30(8):1467–1475. https://doi.org/10.1007/s10571-010-9593-x

    Article  CAS  PubMed  Google Scholar 

  39. Duijne SV (2012) Stress-related changes in adrenal glands of stranded Harbour Porpoises (Phocoena phocoena) on the Dutch coast (Master’s thesis)

Download references

Acknowledgements

The research work was supported partially by a grant from the Indian Council of Medical Research (ICMR), India, Project No. 58/10/2010-BMS to Dr. Banalata Mohanty. Fellowship of University Grant Commission to Mrs. Preeti Gupta is also acknowledged.

Author information

Authors and Affiliations

  1. Department of Zoology, University of Allahabad, Allahabad, 211002, India

    Preeti Gupta & Banalata Mohanty

Authors
  1. Preeti Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Banalata Mohanty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Banalata Mohanty.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest to publish this manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Significance Statement

This study suggests that early-life infection could have long-lasting impact to cause impairment of the hypothalamic–pituitary–adrenal axis which may lead to not only the diseases related to adrenal but also reflect in other diseases at later ages.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gupta, P., Mohanty, B. Assessment of Adrenotoxicity Induced on Prenatal Exposure to Bacterial Endotoxin Lipopolysaccharide: an Age-Related Study in Mice. Proc. Natl. Acad. Sci., India, Sect. B Biol. Sci. 90, 1035–1044 (2020). https://doi.org/10.1007/s40011-020-01167-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40011-020-01167-1

Keywords

Search

Navigation