Long-Term Effects of Neonatal LPS and Caspase -1 İnhibitor Administration on Gonadotropin Levels and Testicular Histology in Rats

Abstract

Aim: Endotoxins (lipopolysaccharides, LPS) negatively affect reproduction by decreasing gonadotropin levels in the acute period. The aim of this study is to investigate the long-term effects of re-injection of endotoxin in adulthood on gonadotropin release and testicular tissue in male rats injected with endotoxin with IL-1 beta inhibitor (Q-Vd-OPh; caspase-1 inhibitor, Cİ) in the neonatal period.
Material and Methods: On postnatal day 7, male rat pups were injected once with either Salin, LPS (50µg/kg), LPS (50µg/kg)+CI (1mg/kg). On postnatal 10 months, these rats were either injected with saline or LPS (50 µg/kg). 10 days after these injections, serum samples and testicular tissues were taken and the experiment was terminated.
Results: Respectively, control, Salin+LPS, LPS+Salin; LPS+LPS; LPS(CI)+Salin and LPS(CI)+LPS groups were 18.8±1.6; 11.3±1.2; 23.4±2.0; 22.2±1.2 ve 23.6±1.4 ng/ml for serum LH concentrations (p<0,05); while 33.4±2.5; 29.6±1.4; 32.1,6±2.0 28.7 0.8 and 35.5±3.3 ng/ml for FSH concentrations (p>0,05). Seminiferous tubule damage was observed in LPS groups (p<0,05).
Conclusion: This research demonstrates (1) neonatal LPS injections do not negatively affect gonadotropin release in the long term, (2) IL-1 β plays a critical role in the programming of reproduction, especially in terms of testicular histology.

Keywords

• neonatal LPS
• LH
• FSH
• seminiferous tubules
• caspase-1 inhibitor

Kaynakça

1. 1. Breen KM, Billings HJ, Debus N, Karsch FJ. Endotoxin inhibits the surge secretion of gonadotropin-releasing hormone via a prostaglandin-independent pathway. Endocrinology. 2004;145(1):221-7.
2. 2. Walker FR, Hodyl NA, Krivanek KM, Hodgson DM. Early life host-bacteria relations and development: long-term individual differences in neuroimmune function following neonatal endotoxin challenge. Physiol Behav. 2006;87(1):126-34.
3. 3. Sergeyev V, Broberger C, Hokfelt T. Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus. Brain Res Mol Brain Res. 2001;90(2):93-100.
4. 4. Shanks N, Larocque S, Meaney MJ. Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress. J Neurosci. 1995;15(1 Pt 1):376-84.
5. 5. Shanks N, Windle RJ, Perks PA, Harbuz MS, Jessop DS, Ingram CD, et al. Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation. Proc Natl Acad Sci U S A. 2000;97(10):5645-50.
6. 6. Kohman RA, Tarr AJ, Sparkman NL, Bogale TM, Boehm GW. Neonatal endotoxin exposure impairs avoidance learning and attenuates endotoxin-induced sickness behavior and central IL-1beta gene transcription in adulthood. Behav Brain Res. 2008;194(1):25-31.
7. 7. Walker AK, Nakamura T, Hodgson DM. Neonatal lipopolysaccharide exposure alters central cytokine responses to stress in adulthood in Wistar rats. Stress. 2010;13(6):506-15.
8. 8. Walker FR, March J, Hodgson DM. Endotoxin exposure in early life alters the development of anxiety-like behaviour in the Fischer 344 rat. Behav Brain Res. 2004;154(1):63-9.

9. 9. Iwasa T, Matsuzaki T, Murakami M, Kinouchi R, Shimizu F, Kuwahara A, et al. Neonatal immune challenge affects the regulation of estrus cyclicity and feeding behavior in female rats. Int J Dev Neurosci. 2009;27(1):111-4.
10. 10. Watanobe H, Hayakawa Y. Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats. Endocrinology. 2003;144(11):4868-75.
11. 11. Knox AM, Li XF, Kinsey-Jones JS, Wilkinson ES, Wu XQ, Cheng YS, et al. Neonatal lipopolysaccharide exposure delays puberty and alters hypothalamic Kiss1 and Kiss1r mRNA expression in the female rat. J Neuroendocrinol. 2009;21(8):683-9.
12. 12. Walker AK, Hiles SA, Sominsky L, McLaughlin EA, Hodgson DM. Neonatal lipopolysaccharide exposure impairs sexual development and reproductive success in the Wistar rat. Brain Behav Immun. 2011;25(4):674-84.
13. 13. Wu XQ, Li XF, Ye B, Popat N, Milligan SR, Lightman SL, et al. Neonatal programming by immunological challenge: effects on ovarian function in the adult rat. Reproduction. 2011;141(2):241-8.
14. 14. Bilbo SD, Levkoff LH, Mahoney JH, Watkins LR, Rudy JW, Maier SF. Neonatal infection induces memory impairments following an immune challenge in adulthood. Behav Neurosci. 2005;119(1):293-301.
15. 15. Watanobe H, Yoneda M. A mechanism underlying the sexually dimorphic ACTH response to lipopolysaccharide in rats: sex steroid modulation of cytokine binding sites in the hypothalamus. J Physiol. 2003;547(Pt 1):221-32.
16. 16. Lee DW, Faubel S, Edelstein CL. A pan caspase inhibitor decreases caspase-1, IL-1alpha and IL-1beta, and protects against necrosis of cisplatin-treated freshly isolated proximal tubules. Ren Fail. 2015;37(1):144-50.
17. 17. Renolleau S, Fau S, Goyenvalle C, Joly LM, Chauvier D, Jacotot E, et al. Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender. J Neurochem. 2007;100(4):1062-71. 18. Sayim F. Histopathological effects of dimethoate on testes of rats. Bull Environ Contam Toxicol. 2007;78(6):479-84.
18. 19. Pappa A, Seferiadis K, Marselos M, Tsolas O, Messinis IE. Development and application of competitive ELISA assays for rat LH and FSH. Theriogenology. 1999;51(5):911-26.
19. 20. Iwasa T, Matsuzaki T, Tungalagsuvd A, Munkhzaya M, Yiliyasi M, Kato T, et al. Prenatal undernutrition results in greater lipopolysaccharide-induced changes in hypothalamic TNF-alpha expression, but does not affect the equivalent changes in the serum levels of luteinizing hormone and testosterone, in adult male rats. Int J Dev Neurosci. 2016;48:80-3.
20. 21. Mayila Y, Matsuzaki T, Iwasa T, Tungalagsuvd A, Munkhzaya M, Yano K, et al. The reduction in sexual behavior induced by neonatal immune stress is not related to androgen levels in male rats. Int J Dev Neurosci. 2018;71:163-71.
21. 22. Munkhzaya M, Matsuzaki T, Iwasa T, Tungalagsuvd A, Kawami T, Kato T, et al. The suppressive effect of immune stress on LH secretion is absent in the early neonatal period in rats. Int J Dev Neurosci. 2015;46:38-43.
22. 23. Jafari O, Babaei H, Kheirandish R, Samimi AS, Zahmatkesh A. Histomorphometric evaluation of mice testicular tissue following short- and long-term effects of lipopolysaccharide-induced endotoxemia. Iran J Basic Med Sci. 2018;21(1):47-52.
23. 24. Zhang M, Nii T, Isobe N, Yoshimura Y. Expression of Toll-like receptors and effects of lipopolysaccharide on the expression of proinflammatory cytokines and chemokine in the testis and epididymis of roosters. Poult Sci. 2012;91(8):1997-2003.
24. 25. Palladino MA, Fasano GA, Patel D, Dugan C, London M. Effects of lipopolysaccharide-induced inflammation on hypoxia and inflammatory gene expression pathways of the rat testis. Basic Clin Androl. 2018;28:14.