LPS-Induced Systemic Inflammation Caused mPOA-FSH/LH Disturbance and Impaired Testicular Function

Abstract

Male reproductive function is key to the continuation of species and is under sophisticated regulation, challenged by various stressors including inflammation. In the lipopolysaccharide (LPS) intraperitoneal injection-induced acute systemic inflammation, male fecundity was compromised with decreased testosterone level, damaged spermatogenesis, and downregulations of testicular gene expression levels involved in steroidogenesis regulation and blood–testis barrier. It is also noteworthy that the testis is more sensitive to acute stress caused by LPS-induced systemic inflammation. LPS treatment resulted in lower testicular gene expression levels of steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, and cytochrome P450 family 11 subfamily B member 1 after LPS treatment, while no such decrease was found in the adrenal gland. In parallel to the significant decreases in testicular intercellular adhesion molecule 1, tight junction protein 1, and gap junction alpha-1 protein gene expression with LPS treatment, no decrease was found in the epididymis. In the brain, LPS treatment caused higher medial preoptic area (mPOA) activation in the hypothalamus, which is accompanied by elevated blood follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, suggesting a disturbed hypothalamic–pituitary–gonad axis function. Besides mPOA, brain c-fos mapping and quantitative analysis demonstrated a broad activation of brain nuclei by LPS, including the anterior cingulate cortex, lateral septum, paraventricular nucleus of the hypothalamus, basolateral amygdala, ventral tegmental area, lateral habenular nucleus, locus coeruleus, Barrington’s nucleus, and the nucleus of the solitary tract, accompanied by abnormal animal behavior. Our data showed that LPS-induced inflammation caused not only local testicular damage but also a systemic disturbance at the brain–testis axis level.

Lipopolysaccharide-induced chronic inflammation increases female serum gonadotropins and shifts the pituitary transcriptomic landscape

“…Acute LPS was demonstrated to suppress the HPG axis through impacts on the hypothalamus, and serum LH was found to decrease consistently across various animal models including rats, mice, monkeys, and ewes, despite differences in LPS serotypes and sources ( 4 , 40 – 42 ). Some recent studies show increase of serum FSH similar to our study in response to LPS in male mice ( 43 ), laying geese ( 10 ), and ewes( 44 ) with implications for activation upstream of the pituitary, though the time frames were limited to acute or less than a week.…”

Gut microbiota is involved in male reproductive function: a review

“…Furthermore, Zheng et al directly observed that macrophages and dendritic cells capture spermatozoa in the caudal cavity of the epididymis for the first time, directly proving that chronic epididymitis is a possible cause of oligospermia in patients (Zheng et al, 2021). We suggest that one of the potential reasons for the association between gut microbiota and male infertility is elevated LPS, which can result in local testicular inflammation and oxidative stress disorders, and does harm to the normal testicular structure such as the BTB (Shen et al, 2022).…”

“…The detrimental impact of the gut microbiota on BTB can be partially ascribed to inflammation and oxidation, mainly caused by LPS. A study found that LPS treatment can lead to orchitis and significantly decrease the expression of cell junctions, such as testicular intercellular adhesion molecule 1, tight junction protein 1, and gap junction α-1 protein (Shen et al, 2022). Furthermore, IL-6, induced by gut microbiota, can damage the tight junctions of Sertoli cells by disrupting the ERK-MAPK signaling pathway and changing the localization and number of BTB component proteins (Zhang et al, 2014).…”

Inhibition of inosine metabolism of the gut microbiota decreases testosterone secretion in the testis

“…Consistent with this hypothesis, our results showed that the defects in the intestinal mucus barrier can also increase serum LPS levels. It has been found that the intraperitoneal injection of LPS could induce dysfunction of the testis and epididymis and significantly reduce serum testosterone levels via induction systemic inflammation ( 48 , 49 ). Besides, LPS could directly induce pyroptosis of Leydig cells and decrease testosterone production ( 50 ).…”