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Obesity linked to prostate cancer risk: Latest study uncovers inherited dangers from fathers

In a recent review published within the journal Nutrients, researchers investigated available literature on the impacts of obesity and chubby on prostate cancer. Moreover, they discuss whether a father’s offspring can inherit the condition. Their review of over 280 publications reveals that obesity does indeed contribute to carcinogenesis risk, and obesity-associated epigenetic modifications can promote cancer cell viability and proliferation. Alarmingly, obesity-related traits were found to be heritable, leading to offspring of obese fathers presenting a greater risk of obesity and, in turn, prostate cancer.



Review: Decoding the Influence of Obesity on Prostate Cancer and Its Transgenerational Impact. Image Credit: Kateryna Kon / Shutterstock

The worldwide burden of metabolic disorders

Metabolic disorders, characterised by the partially suppressed ability of the body’s processing and distribution of macronutrients, including proteins, carbohydrates, and fats, have depicted an alarming trend of worldwide surging prevalence up to now few many years. Increasing global pollution levels, urbanization, poor dietary decisions, and sedentary lifestyles have been identified because the foremost contributors to this trend, with predictions estimating metabolic disorder-associated morbidity and mortality further increasing in forthcoming many years.

Obesity and chubby are two of probably the most prevalent and debilitating metabolic disorders on this planet today. The World Health Organization (WHO) has classified these conditions as body mass indexes (BMIs) exceeding 30 and 25, respectively, with over 1.9 billion adults affected by the condition. The worldwide incidence is estimated to have increased by 50% for obesity and 80% for chubby, with prediction models forecasting even worse future outcomes.

Conditions related to abnormal weight gain are most frequently because of shifts in lifestyle and health behaviors, notably marked fluctuations in physical activity levels, Western-style diets, and sedentary lifestyles. Recent research suggests that moreover, genetics may play a big role within the manifestation of chubby and obesity, as do hormonal dynamics, pharmaceutical interactions, environmental pollutants, and endocrine disruptors.

“…monogenic obesity describes a disorder promoted by single-gene mutations, often in genes related to endocrine regulation, that ends in an obese phenotype. In parallel, epigenetic markers like DNA methylation and histone modifications exert their influence on genes intertwined with growth and metabolic processes.”

The outcomes of obesity are similarly alarmingly – the condition has been related to a number of comorbidities, including type 2 diabetes (T2D), heart problems, mental health disorders, and increased mortality risk. Recent studies have identified a link between obesity and certain cancers, with estimates of 20% of all cancer cases linked to obesity. In the USA, obesity has outcompeted smoking because the leading explanation for cancers inside the country. Identifying the role and mechanisms of obesity in cancer development will allow for novel therapeutic interventions targeting each conditions, leading to significantly improved quality of life for patients and their families.

Concerning the study

The review peruses over 280 publications investigating associations and mechanisms linking obesity and cancer. It attempts to decipher how obesity triggers cancers and allows them to persist and progress, the impacts and mechanisms of motion of obesity on male prostate cancer risk, and the inherent genetic and epigenetic contributors to the transmission of obesity from fathers to their offspring.

Obesity, inflammation, and cancer

WHO defines obesity because the abnormal and excessive buildup of fat. This fat escalation profoundly impacts normal physiological processes, especially in regards to the adipose tissue. Excessive fat accumulation within the adipose tissue causes adipocyte hypertrophy and hyperplasia, the previous of which further promotes fat deposition, and the latter promotes a surge in adipocyte count. Together, these conditions block blood flow to adipose tissue, inducing a state of hypoxia, which, in turn, stimulates necrosis and the overexpression of pro-inflammatory aspects (mainly chemokines). Over time, these aspects promote localized and systemic inflammation, adipocyte rupture, and consequent death.

Schematic representation of inflammation, hormonal dysregulation, and OS in the adipose tissue due to obesity. In individuals with obesity, a notable expansion of adipose tissue triggers an aberrant production and secretion of cytokines, accompanied by the disruption of adipokine regulation. This cascade instigates a series of interconnected events: cytokines foster heightened ROS production, inciting apoptosis, which then exacerbates cytokine release, perpetuating a self-perpetuating cycle. This cytokine orchestration not only contributes to the perpetuation of low-grade chronic inflammation but also significantly augments the landscape for tumor development. Concurrently, elevated leptin levels in obesity correlate with heightened inflammatory cytokine levels, fostering an environment conducive to both the initiation and progression of tumors. In contrast, the diminished presence of adiponectin compounds the scenario, offering a conducive milieu for tumor development. In summary, the complex interplay between obesity, cytokine dynamics, and adipokine regulation unveils a multifaceted process that intricately contributes to chronic inflammation and the initiation and advancement of tumorigenesis. (↓) downregulation; (↑) upregulation; (+) promotion.Schematic representation of inflammation, hormonal dysregulation, and OS within the adipose tissue because of obesity. In individuals with obesity, a notable expansion of adipose tissue triggers an aberrant production and secretion of cytokines, accompanied by the disruption of adipokine regulation. This cascade instigates a series of interconnected events: cytokines foster heightened ROS production, inciting apoptosis, which then exacerbates cytokine release, perpetuating a self-perpetuating cycle. This cytokine orchestration not only contributes to the perpetuation of low-grade chronic inflammation but additionally significantly augments the landscape for tumor development. Concurrently, elevated leptin levels in obesity correlate with heightened inflammatory cytokine levels, fostering an environment conducive to each the initiation and progression of tumors. In contrast, the diminished presence of adiponectin compounds the scenario, offering a conducive milieu for tumor development. In summary, the complex interplay between obesity, cytokine dynamics, and adipokine regulation unveils a multifaceted process that intricately contributes to chronic inflammation and the initiation and advancement of tumorigenesis. (↓) downregulation; (↑) upregulation; (+) promotion.

Two key chemokines involved on this cycle are interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which have been implicated in carcinogenesis. These chemokines coax damaged adipocytes to enter a state of oxidative stress (OS) and release reactive oxygen and nitrogen species, thereby peroxidizing the encompassing lipids and triggering cell apoptosis. Apoptosis initiates a positive feedback loop wherein additional pro-inflammatory chemokines are produced, perpetuating the method.

“Concurrently, the oxidation of DNA bases promotes the occurrence of mutations and altered DNA methylation patterns, which might promote the abnormal expression of oncogenes. This underscores inflammation as a critical hallmark of cancer, which is further potentiated by obesity. Consequently, it becomes a strategic point of interest for combatting the disease.”

Prostate cancer

The prostate is a composite organ consisting of glandular and muscular tissue and serves as an adjunct gland within the male reproductive system. Histologically, the prostate is split into three foremost zones – the peripheral, central, and transition zones. Of those, the peripheral serves because the origin point for greater than 70% of currently described prostate cancers and is, hence, the goal for many research in the sphere.

The androgen receptor (AR) is the prime controller of normal prostate functioning. Notably, research has identified AR as crucial in the event and proliferation of prostate cancer (PCa). Conventional knowledge suggested that elevated levels of the male sex hormone testosterone disrupted the androgen receptor, leading to PCa initiation. Consequently, most therapeutic interventions aimed to scale back androgen and testosterone levels and involved methods resembling castration and Androgen-Deprivation Therapy (ADT). Nonetheless, recent research indicates that the role of androgen hormones in PCa is more nuanced than previously thought – low testosterone levels have been implicated within the initial development of PCas, while supraphysiological levels hinder their progression.

“The therapeutic efficacy of supraphysiological testosterone levels in treating PCa could be attributed to the elevated AR expression observed in PCa cases. This upregulation of AR expression in PCa is usually recommended to be a compensatory mechanism aimed toward counterbalancing the reduced levels of testosterone needed for initiating tumor growth”

Obesity plays a vital role in AR functioning and PCa development since it significantly reduces serum testosterone levels. Just like its effects in adipose tissue, obesity promotes inflammatory responses within the prostate, thereby creating an environment conducive to the production of reactive species, which increase cellular mutation rates, thereby triggering cancers.

“…a meta-analysis study has associated obesity with the next risk of developing aggressive phenotypes of PCa, that are immune to traditional treatment therapies [107]. Nevertheless, extra weight doesn’t appear to be a key risk factor for PCa, unless it’s related to altered testosterone or other androgen levels”

The role of genetics

Conventional wisdom assumed that epigenetic markings were solely inherited from the feminine parent because of the belief that the protamination process protected spermatozoa from the consequences of paternal epigenetic modifications. Recent research has disproved this theory and has found that between 5 and 15% of the male genome is exposed to epigenetic changes despite protamination. Moreover, obesity- and other metabolic-focused research has found that the exposed regions are hotspots of each epigenetic modifications and contain information related to metabolic disorders, including abnormal weight gain.

Studies in male mice have found that obesity is indeed heritable. Obese male mice were bred with healthy females, and their offspring were evaluated for physiological and genetic markers of abnormal metabolism. Female descendant were found to have increased adiposity and impaired glucose tolerance, and each female and male offspring carried a genetic predisposition to obesity despite its manifestation in just the feminine mice. Alarmingly, even when phenotypically healthy offspring were bred together, the F2 generation retained the epigenetic markings from the initial male obese ancestor, and within the F2 generation, each females and males expressed phenotypic obesity.

Research has previously identified the heritability of cancers. As a growing body of literature recognizes the epigenetic heritability of obesity, the prevalent fear is that these aspects could summate, leading to offspring which might be chubby or obese despite observing healthy lifestyles.

Journal reference:

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