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Gut microbiota-mediated histidine deficiency drives testicular ferroptosis induced by bisphenol F exposure

ABSTRACT:

Bisphenol F (BPF), a widespread environmental contaminant and a major substitute for the restricted bisphenol A (BPA), has raised increasing concerns regarding its potential male reproductive health risks, yet its underlying mechanisms remain poorly understood. This study investigates the mechanisms underlying BPF-induced testicular damage, focusing on the interplay among gut microbiota (GM) dysbiosis, histidine metabolism disruption, and ferroptosis. Using a mouse model exposed to BPF (50, 100, and 200 mg/kg/day) for 28 days, we observed significant testicular pathology, including seminiferous tubule atrophy, vacuolation, and blood-testis barrier (BTB) impairment. Metagenomic and metabolomic analyses revealed GM dysbiosis and suppressed intestinal histidine metabolism, accompanied by decreased abundance of beneficial taxa (e.g., Bacteroides, Ligilactobacillus) and increased potential pathobionts (e.g., Akkermansia, Mucispirillum). BPF exposure also inhibited the expression of the histidine transporter LAT1, reducing histidine uptake in testes. Crucially, BPF triggered testicular ferroptosis, characterized by mitochondrial damage, iron accumulation, lipid peroxidation, and downregulation of the ferroptosis regulatory system xCT-GSH-GPX4 axis. In vitro experiments using mouse Sertoli cells (mSCs) confirmed BPF-induced ferroptosis, which was mitigated by the exogenous histidine supplementation. Histidine administration in vivo ameliorated testicular damage, restored BTB integrity, and reversed ferroptotic markers. Our findings unveil a novel “GM-histidine-testis” axis as a key mechanistic pathway for BPF-induced reproductive toxicity, providing critical insights into the health risks of emerging environmental pollutants and suggesting potential dietary intervention strategies.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13997 | MetaboLights | 2026-05-26

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13997_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13997_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13997_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13997_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:BACKGROUND: Large-scale farms struggle to effectively address summer heat stress (HS) in dairy goats, which impairs spermatogenesis and reduces reproductive performance by compromising gut and reproductive organ health in male animals. Although Clostridium butyricum (CB) and Enterococcus faecium (EF) have been used to alleviate gut dysbiosis, their protective effects and mechanisms against HS-induced spermatogenic dysfunction in dairy goats remain unclear. This study aims to evaluate the efficacy of CB and EF in mitigating HS-induced spermatogenic disorders in male dairy goats and elucidate the underlying mechanisms.RESULTS: HS leads to a significant decline in sperm quality. CB and EF ameliorate HS-induced sperm quality deterioration by reducing pro-inflammatory factors and oxidative stress levels in blood, while modulating the disrupted reproductive hormone levels caused by heat stress. 16S rRNA-based microbiota analysis revealed that CB and EF treatment shifted the gut microbiota of HS-treated male dairy goats toward a composition resembling that of the NC. To investigate whether the protective effects of these probiotics on sperm quality are mediated through gut microbiota modulation, we transplanted fecal microbiota from HS-treated dairy goats (with or without probiotic intervention) into antibiotic-induced microbiome-depleted (AIMD) mice, followed by heat stress exposure. We observed severe testicular damage and spermatogenic impairment in mice receiving HS group microbiota, whereas these pathological manifestations were significantly alleviated in mice receiving microbiota from probiotic-treated HS goats, indicating that CB and EF mitigate HS-induced spermatogenic damage in a microbiota-dependent manner. Furthermore, non-targeted metabolomics sequencing identified significant reductions in arginine (Arg) and pantothenic acid (PaA) levels in both HS-treated goats and HS microbiota-transplanted mice, metabolites that showed correlation with sperm quality parameters. Subsequent studies demonstrated that supplementation with Arg and PaA effectively attenuated the elevation of pro-inflammatory factors and oxidative stress in mouse blood, restored intercellular junctions, and ultimately ameliorated spermatogenic disorders.CONCLUSION: This study demonstrates that CB and EF alleviate HS-induced sperm quality decline in dairy goats by modulating the gut microbiota to increase blood levels of Arg and PaA. These findings highlight novel therapeutic avenues for preventing HS-induced spermatogenic disorders in dairy goats and provide fresh insights into the application of probiotics to mitigate heat stress-associated impairments in sperm production.

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Gut microbiota-mediated histidine deficiency drives testicular ferroptosis induced by bisphenol F exposure

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