Antioxidants in mitigating phthalate-induced male reproductive toxicity: A comprehensive review.

Phthalates, widely used as plasticizers, have been increasingly linked to male reproductive toxicity through mechanisms including oxidative stress, endocrine disruption, inflammation, and apoptosis. This comprehensive review evaluates the protective role of various antioxidants in mitigating the detrimental effects of phthalates such as di-(2-ethylhexyl) phthalate (DEHP), di-butyl phthalate (DBP), mono-(2-ethylhexyl) phthalate (MEHP), and monobutyl phthalate (MBP) on male reproductive health. Antioxidants such as lycopene, ellagic acid, genistein, and selenium compounds exhibit significant efficacy in counteracting phthalate-induced damage by neutralizing reactive oxygen species (ROS), enhancing endogenous antioxidant defenses, reducing inflammatory responses, and preventing apoptosis. Lycopene demonstrates broad-spectrum protective effects, particularly through its high ROS-scavenging capacity and ability to preserve mitochondrial function. Ellagic acid effectively ameliorates oxidative stress and inflammation, while genistein enhances the Nrf2 pathway and restores hormonal balance, offering robust protection against reproductive toxicity. Selenium compounds improve antioxidant enzyme activities, providing essential support against oxidative damage. These findings underscore the potential of antioxidants as therapeutic agents against phthalate-induced male reproductive dysfunction. Future research should focus on optimizing antioxidant combinations, understanding dose-response relationships, and assessing long-term efficacy and safety to develop effective interventions for safeguarding male reproductive health.

Glucose transporters (GLUTs): Underreported yet crucial molecules in unraveling testicular toxicity.

Glucose transporters (GLUTs) are crucial in maintaining glucose homeostasis and supporting energy production in various tissues, including the testes. This review article delves into the distribution and function of GLUTs in distinct testicular cell types, namely Leydig cells, Sertoli cells, germ cells, and spermatozoa, shedding light on their significance in the context of male reproductive health-an issue of mounting global concern. Furthermore, this article examines the implications of GLUT dysregulation in testicular dysfunction. Altered GLUT expression has been associated with impaired steroidogenesis, spermatogenesis, sperm count, and motility in various animal models. Lastly, the article underscores the potential therapeutic implications of targeting GLUTs concerning testicular toxicity. Insights gleaned from studies in diabetes and cancer suggest that modulating GLUT expression and translocation could present novel strategies for mitigating testicular dysfunction and safeguarding male fertility. In summary, the intricate interplay between GLUTs, glucose metabolism, and testicular health underscores the significance of sustaining testicular glucose homeostasis for male reproductive health. Manipulating GLUTs presents an innovative avenue to address testicular dysfunction, potentially revolutionizing therapeutic strategies to restore male fertility and overall reproductive well-being. Future research in this field holds great promise for advancing male fertility treatments and reproductive health interventions.

Diethyl phthalate, a plasticizer, induces adipocyte inflammation and apoptosis in mice after long-term dietary administration.

The incidence of metabolic diseases is increasing alarmingly in recent times. Parallel to nutritional excess and sedentary lifestyle, the random usage of several endocrine disrupting chemicals including plasticizers is reported to be closely associated with metabolic diseases. Diethyl phthalate (DEP) is a widely used plasticizer in a host of consumer and daily care products. Adipose tissue plays a central role in energy storage and whole-body metabolism. The impairment of adipose function is critically implicated in the pathogenesis of insulin resistance, diabetes, and related metabolic diseases. Recently, exposure to certain phthalate esters has been linked to the development of obesity and diabetes, although there are contradictions and the mechanisms are not clearly understood. In an effort to ascertain the metabolic consequences of chronic phthalate exposure and the underlying mechanism, the present study was designed to examine the effects of long-term dietary consumption of DEP in adipocytes. DEP-treated mice were hyperglycemic but nonobese; their body weight initially increased which subsequently was reduced compared to control. DEP exposure at lower levels impaired adipogenesis by downregulating the key transcription factor, peroxisome proliferator-activated receptor γ and its downstream insulin-sensitizing adipokine, adiponectin, thereby severely compromising adipocyte function. The activation of master regulator nuclear factor κB led to rise in proinflammatory cytokines. We found that DEP triggered intrinsic apoptotic pathways through activated cytochrome c-Apaf1-caspase 9-caspase 3 axis in adipocytes. Taken together, our data revealed that chronic administration of dietary DEP could unleash adverse metabolic outcomes by initiating oxidative stress, inflammation, and apoptosis in the adipocytes, thus leading to adipose tissue dysfunction.

From oxidative imbalance to compromised standard sperm parameters: Toxicological aspect of phthalate esters on spermatozoa.

The exponential rise in global male infertility and subfertility-related issues raises severe concern. One of the major contributors is phthalate esters, typical endocrine disruptors affecting millions of lives. The inevitable exposure to phthalates due to their universal application as plasticizers leaves the human population vulnerable to this silent threat. This review explicitly deals with the spermiotoxic effects of different phthalate esters on in vivo and in vitro models and on surveyed human populations to find the most plausible link between global usage of phthalates and poor sperm health. As the free radicals in spermatozoa are prerequisites for their standard structure and functioning, the precise regulation and phthalate-mediated impairment of pro-oxidant:anti-oxidant balance with subsequent loss of structural and functional integrity have also been critically discussed. Furthermore, we also provided future directives, which, if addressed, will fill the still-existing lacunae in phthalate-mediated male reproductive toxicity research.

Bisphenol A and Male Murine Reproductive System: Finding a Link between Plasticizer and Compromised Health.

The global burden of male infertility is rising at an alarming rate affecting the lives of millions in terms of physical, emotional, and societal perspectives. Among several existing endocrine-disrupting chemicals, bisphenol A (BPA) has been reported by many to inflict male reproductive toxicity in different experimental models, especially in mice. This review article critically discusses the overall reproductive toxicity of BPA with a special note to its ubiquitous existence, contamination route, effects on the reproductive system, and toxicity mechanisms in male mice. Disturbed redox status in germ cells and spermatozoa plays a pivotal role in BPA-induced male reproductive toxicity. In this context, the involvement of mitochondria and endoplasmic reticulum is also of grave importance. Induction of caspase-dependent apoptosis is the extreme consequence that leads to deterioration of cellular parameters. Besides the oxidative cellular and histoarchitectural damages, perturbed endocrine regulation, subsequent impaired hormonal and cellular genesis program, epigenetic alterations, and inflammation cumulatively reflect poor sperm quality leading to compromised reproduction. Moreover, several key issues have also been highlighted that, if addressed, will strengthen our understanding of BPA-mediated male reproductive toxicity.

Chronic dietary administration of lower levels of diethyl phthalate induces murine testicular germ cell inflammation and sperm pathologies: Involvement of oxidative stress.

The wide occurrence of male infertility is a matter of grave concern. One of the major causes being exposure to endocrine disrupting chemicals (EDCs) many of which are known reproductive toxicants but the molecular mechanisms of action remain much unexplored. Diethyl phthalate (DEP) is ubiquitous in the environment due to its extensive use as plasticizer in myriad consumer products. In the present study, we sought to find out whether chronic DEP exposure affects reproductive function in sexually mature adult male mice. For this, 8-week old Swiss albino mice were treated with DEP (1 mg and 10 mg kg-1 body weight day-1) in diet for three months, mirroring the relevant doses of human exposure, and various analyses were carried out in the testicular germ cells and epididymal spermatozoa. We found that altered testicular histoarchitecture was accompanied with disturbed prooxidant: antioxidant balance in the germ cells. Involvement of Nrf2-HO-1 pathway was crucial in this altered cellular redox state. Besides, NFκB mediated inflammatory response was triggered in the germ cells leading to enhanced levels of proinflammatory cytokines. DEP adversely affected sperm count, motility, viability and morphology. Numerous structural anomalies were found in DEP treated mice spermatozoa reflecting decline in sperm function. Our results revealed overactivation of PARP-1 and subsequent cleavage in spermatozoa with induction of apoptosis as a key mechanism in DEP mediated sperm pathology. Given the indiscriminate use of plasticizers and long term low level human exposure, the present study highlights the undesirable male reproductive outcomes following chronic DEP exposure.