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Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15 Page 253

involvement in zinc homeostasis critical for prostatic fluid synthesis [50,51] . Remarkably, targeted depletion of
macrophages using antibody targeting colony-stimulating factor 1 receptor (CSF1R) resulted in decreased
zinc concentration specifically within the prostate gland, confirming the presumed role of MAC-MT
[47]
macrophages in zinc regulation . Furthermore, the distinct functions of dendritic cell subsets, such as
cDC1 and cDC2, in antigen presentation and T-cell activation, respectively, underscore the dual importance
of MNPs in both maintaining prostatic function and regulating immune responses [47,48] .

Contrary to conventional theory, there is growing evidence to suggest that tissue-resident macrophages are
seeded in the embryonic stage and self-maintained throughout adulthood. Transcriptomic analyses revealed
that MAC-MT, with upregulated levels of zinc transporters genes, SLC39A8 and SLC30A1, might be seeded
in the prostate from the prenatal stage, as it is transcriptionally similar to the yolk sac-derived
[47]
macrophages . The expression of the zinc transporters and metallothionein genes were also identified to be
highly expressed in embryonically seeded macrophages in the murine prostate gland, further highlighting
the developmental origin of these specialized immune cells. Conversely, MAC2 was suggested to be
monocyte-derived and specific to the prostate gland [47-49,52] . These insights underscore the intricate interplay
between immune cell populations and tissue-specific functions within the prostate, providing valuable
insights into potential therapeutic targets for prostate cancer and related disorders.

HORMONAL DYSREGULATION IN AN AGING PROSTATE
Hormonal imbalances, tissue atrophy, and chronic inflammation are characteristic features of an aging
[53]
prostate . Additionally, with aging, there is an increased likelihood of transitioning from adult
differentiated biology to repair-centric/emergent systems biology in tissues, resulting in the activation of
reactive stromal response. This reactive stroma plays a crucial role in regulating epithelial proliferation and
modulating the immune microenvironment. Notably, hormonal dysregulation is one of the primary
contributors to the transformation of the prostate stroma into a reactive phenotype .
[53]

Aging men experience an upregulation of estrogen production due to declining testosterone levels, a
process exacerbated by comorbidities like obesity and type 2 diabetes [53-56] . Testosterone deficiency is
implicated in inducing chronic inflammation within the prostate tissue, as testosterone plays a crucial role
in inhibiting the pro-inflammatory response of prostate stromal cells by activating AR and inhibiting the
secretion of inflammatory cytokines and growth factors [57,58] . Additionally, testosterone protects against
inflammation caused by uropathogenic bacteria like Escherichia coli by downregulating the Janus Kinases
(JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathway in the prostate
[59]
epithelium . Indeed, chronic inflammation of the prostate gland induced by bacteria was observed to
induce premalignant and malignant lesions in the prostate gland of Mongolian gerbils .
[60]

Obesity exacerbates hormonal imbalance by increasing aromatase activity, leading to the conversion of
testosterone to estradiol, the most potent form of estrogen in men . The increase in the
[61]
estrogen/testosterone (E/T) ratio due to aging can lead to estrogen dominance, promoting stromal cell
proliferation and fibrosis, which can accelerate clinical progression in BPH, and induce premalignant
lesions in the prostate gland [62,63] . Racial disparities in prostate cancer incidence and mortality rates,
particularly among African American men, have been linked to dysregulated estrogenic action on the
prostate gland, with higher serum levels of estradiol observed in Non-Hispanic black men compared to
Non-Hispanic white men [39,64-68] . Additionally, exposure to elevated estrogen levels during early gestation has
been suggested to be a contributing factor to racial differences in prostate cancer risk, which needs to be
substantiated through population-based studies. However, in vivo rodent studies support the induction of
abnormalities in the prostate gland by early estrogenic exposure [37,69-71] .