SAT011 Neonatal Endotoxin Exposure Has Long-term Effects On Glucocorticoid Regulation In Blood And Lymphoid Organs Of Mice

Disclosure: A. Mazurenko: None. M. Salehzadeh: None. S.R. Lim: None. K.K. Soma: None. Glucocorticoids (GCs) are steroid hormones that play vital roles in immunity. GCs are produced by the adrenal glands and also by lymphoid organs, such as bone marrow, thymus, and spleen. There is a period of decreased adrenocortical activity in neonatal humans and mice termed the stress hyporesponsive period (SHRP), which protects developing tissues from high circulating GCs and allows for fine-tuning of GC levels in lymphoid organs. In neonatal mice, GC levels increase acutely in response to the bacterial endotoxin, lipopolysaccharide (LPS). Yet, it is not known how early-life LPS exposure affects systemic and local GC levels in adulthood. We assessed whether LPS administration during the SHRP (‘first hit’) affects GC regulation in blood and lymphoid organs in adulthood when challenged again with LPS (‘second hit’). We administered LPS (50 μg/kg i.p.) or saline (vehicle control) to male and female C57BL/6J neonatal mice (PND 4 and 6, within the SHRP). We then split the mice into two groups and administered LPS (50 μg/kg i.p.) or saline to adults (PND90) (2x2 design). We collected whole blood, bone marrow, thymus, and spleen 4 hr after LPS administration at PND90. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to measure 7 steroids, including 11-deoxycorticosterone (DOC; corticosterone precursor), corticosterone (main active GC in mice), and 11-dehydrocorticosterone (DHC; corticosterone metabolite). Preliminary results show that neonatal LPS treatment altered LPS-stimulated corticosterone levels (but not baseline corticosterone levels) in adult mice. Specifically, neonatal LPS treatment increased blood corticosterone levels in LPS-treated adult males, but not females. In contrast, neonatal LPS treatment increased thymus and spleen corticosterone levels in LPS-treated adult females. There were no effects of neonatal LPS treatment on DOC and DHC levels in adult males. In contrast, neonatal LPS treatment increased thymus DOC and spleen DHC levels in LPS-treated adult females. Altogether, our results suggest that LPS exposure during the SHRP has long-term effects on GC regulation in the blood and lymphoid organs when challenged with a ‘second hit’ in adulthood. This research offers vital insights into understanding the development and regulation of the immune and endocrine systems. Critically, this study demonstrates that lymphoid organs modulate local GC levels independently of circulating GC levels. More generally, these data elucidate the long-lasting programming effects of an immunological stressor, such as neonatal sepsis, early in life. Presentation: Saturday, June 17, 2023