2024: Mechanism of fluoride-induced cauda epididymal injury

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NOTE: The damage observed is due to interference with events regulated by T3 (thyroid hormone).

Yu Y, Zhu R, Qi M, Liu J, Cao K, Zhang D, Yang B, Niu R, Wang J, Zhao Y, Sun Z - "MiRNA-seq and mRNA-seq revealed the mechanism of fluoride-induced cauda epididymal injury" Sci Total Environ 930:172895 (2024) . doi: 10.1016/j.scitotenv.2024.172895
https://www.sciencedirect.com/science/a ... 9724030420

Highlights

• Fluoride, an environmental pollutant, seriously threatens male reproductive health.

• Fluoride destroyed morphology and ultrastructure and reduced sperm quality in the cauda epididymis.

• The regulatory network of miRNA-mRNA in the process was mapped by miRNA-seq and mRNA-seq.

• Fluoride disrupted tight junction and enhanced inflammatory response in the cauda epididymis.

• Fluoride raised lipid synthesis and reduced lipolysis and transport in the cauda epididymis.

Abstract

The widespread presence of fluoride in water, food, and the environment continues to exacerbate the impact of fluoride on the male reproductive health. However, as a critical component of the male reproductive system, the intrinsic mechanism of fluoride-induced cauda epididymis damage and the role of miRNAs in this process are still unclear. This study established a mouse fluorosis model and employed miRNA and mRNA sequencing; Evans blue staining, Oil Red O staining, TEM, immunofluorescence, western blotting, and other technologies to investigate the mechanism of miRNA in fluoride-induced cauda epididymal damage. The results showed that fluoride exposure increased the fluoride concentration in the hard tissue and cauda epididymis, altered the morphology and ultrastructure of the cauda epididymis, and reduced the motility rate, normal morphology rate, and hypo-osmotic swelling index of the sperm in the cauda epididymis. Furthermore, sequencing results revealed that fluoride exposure resulted in differential expression of 17 miRNAs and 4725 mRNAs, which were primarily enriched in the biological processes of tight junctions, inflammatory response, and lipid metabolism, with miR-742-3p, miR-141-5p, miR-878-3p, and miR-143-5p serving as key regulators. Further verification found that fluoride damaged tight junctions, raised oxidative stress, induced an inflammatory response, increased lipid synthesis, and reduced lipid decomposition and transport in the cauda epididymis. This study provided a theoretical basis for developing miRNA as potential diagnostic markers and therapeutic target drugs for this injury.

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Kala N, Ravisankar B, Govindarajulu P, Aruldhas MM - "Impact of foetal-onset hypothyroidism on the epididymis of mature rats" Int J Androl 25(3):139-48 (2002). doi: 10.1046/j.1365-2605.2002.00338.x.
"From the present data it is evident that persistent hypothyroidism diminishes the bioavailability of androgens and oestrogens, while transient hypothyroidism enhances the same, indicating the importance of euthyroidism during foetal and neonatal period towards the maintenance of optimal hormonal status in the epididymis required for its maturation."

Korejo NA, Wei QW, Shah AH, Shi FX - "Effects of concomitant diabetes mellitus and hyperthyroidism on testicular and epididymal histoarchitecture and steroidogenesis in male animals" J Zhejiang Univ Sci B 17(11):850-863 (2016). doi: 10.1631/jzus.B1600136
https://pubmed.ncbi.nlm.nih.gov/27819132/
"Hyperthyroidism elevated the serum testosterone levels in H and DH mice and produced critical damages to the histoarchitecture of the epididymis."

Kumar PN, Aruldhas MM, Juneja SC - "Influence of hyperthyroidism induced at prepuberty on the epididymal lipids, number and motility of spermatozoa in rats" Reprod Fertil Dev 8(3):373-8 (1996). doi: 10.1071/rd9960373
https://www.publish.csiro.au/rd/RD9960373
The study showed that chronic hyperthyroidism, induced at the prepubertal age, causes various changes in epididymal lipid composition and sperm parameters.

Maran RR, Priyadarsini D, Udhayakumar RC, Arunakaran J, Aruldhas MM - "Differential effect of hyperthyroidism on rat epididymal glycosidases" Int J Androl 24(4):206-15 (2001) doi: 10.1046/j.1365-2605.2001.00281.x.
https://onlinelibrary.wiley.com/doi/ful ... 01.00281.x
Note biphasic activity:
"While a similar decrease occurred in the corpus and cauda epididymis in the 30 day hyperthyroid group, an opposite trend was observed in 60 day hyperthyroid rats. ...These data suggest that thyroid hormones have a specific and direct influence on glycosidases in specific regions of the epididymis."

Sarkar D, Jaiswal A, Singh SK - "Ontogeny of TRα1 expression in the mouse testis and epididymis during postnatal development" Andrologia 54(9):e14507 (2022 doi: 10).1111/and.14507
https://onlinelibrary.wiley.com/doi/10.1111/and.14507

St-Pierre N, Dufresne J, Rooney AA, Cyr DG - "Neonatal hypothyroidism alters the localization of gap junctional protein connexin 43 in the testis and messenger RNA levels in the epididymis of the rat" Biol Reprod ;68(4):1232-40 (2003). doi: 10.1095/biolreprod.102.010504
https://academic.oup.com/biolreprod/art ... 32/2683588