Environmental Obesogens: What You Need to Know

Background and Objective: Obesity has evolved into a present-day pandemic, impacting individuals of all ages globally. Various factors have been implicated in the worldwide increase of obesity and diseases related to it, examined from numerous viewpoints. Environmental obesogen is characterized as a chemical agent that promotes obesity in humans or animals. This review offers an up-to-date synopsis of findings from both animal and human research concerning the contribution of environmental obesogens to obesity, as well as a detailed perspective on the mechanisms by which they exert their effects. Methods: The review was created by searching Pubmed and Google Scholar, using many keywords, such as: “Obesity”, “Obesogens”, “obesogenic compounds”, “Endocrine-disrupting chemicals”, “mechanism of action”, “in vivo model”, “in vitro model”, “PPARγ”. Results: Several mechanisms have been proposed to explain the mechanism of action of obesogens, including activation of PPARγ, altering the gut microbiome, altering appetite, satiety and food preferences, DNA methylation, regulatory role of micro-RNAs, impaired thermogenesis. In vivo and in vitro studies have provided evidence of the effects of obesogenes and have proposed additional mechanisms to explain their mechanism of action. Conclusions: Although great progress has been made, s tudies about obesogens are still in the early stages, and more research is needed to discover the obesogens that are still unknown, and to understand the precise mechanisms of the previously discovered obesogens.


INTRODUCTION
Obesity has evolved into a present-day pandemic, impacting individuals of all ages globally 1 .It may be described as a persistent and extensive growth of adipose tissue, which is partly attributed to a prolonged disparity between caloric intake and energy output, with environmental and genetic factors playing contributory roles 2 .The World Health Organization states that worldwide obesity rates have almost tripled since 1975, and this prevalence is continuing to rise 1 .
Obesity is not merely aesthetic issues; it also correlates with concomitant conditions like increased susceptibility to cardiovascular diseases, type 2 diabetes, various metabolic disorders, and several types of cancer.These have culminated in around 4 million deaths globally from 1980 to 2015.Comprehending the multifactorial contributors to obesity is imperative to To cite this article: Jabaqji, M.; Shaimaa Nakameh, S.; Kabeer, O.; Joujeh, D. Environmental Obesogens: What You Need to Know.J. Adv.Pharm.Res.2024, 8 (3), 135-149.DOI: 10.21608/aprh.2024.284605.1266devise treatment strategies that have, up to this point, remained challenging to pinpoint and execute 3 .
Various factors have been implicated in the worldwide increase of obesity and diseases related to it, examined from numerous viewpoints.These include genetic variations, as well as the intake of too many calories paired with a lack of physical activity.This discussion was prominent.In 2002, Baillie-Hamilton presented the hypothesis that the rise in obesity over the last forty years could be connected to the increased number of new industrial chemicals.This surge in obesity rates seemed to coincide with the escalated chemical production that occurred after World War II 4 .The term "environmental obesogen" was released by Grün and Blumberg in 2006 5 , environmental obesogen is characterized as a chemical agent that promotes obesity in humans or animals 4 .It has the capability to disrupt lipid homeostasis, thereby fostering adipogenesis and the accumulation of lipids 6 .Compounds known as obesogens have been demonstrated to induce metabolic disruptions that can persist later in life and may be transmitted across generations after exposure 1 .
Three factors that can impact the action of obesogens which are the partition constant -which is an equilibrium constant that quantifies the distribution of a compound between two solvents that are not miscible-, half-life, and molecular weight.Low molecular weight lipophilic compounds can readily pass through cellular membranes.Moreover, substances with extended halflives may be stored in fatty tissue for extensive periods, ranging from months to years.A number of obesogens that have been extensively studied exhibit these particular properties 7 .
Obesogens originally comes from natural sources such as metals and viruses, from prescription medications, environmental agents including insecticides and plastics, or even from dietary elements like fructose and food additives.Individuals can encounter these substances through the air, water, ingestion, dermal contact, or inhalation of dust.Nowadays, everyone is exposed to a wide array of obesogenic compounds.Although such exposure is widespread, the impact of obesogens can differ greatly based on factors like genetic susceptibility, age, gender, geographic location, lifestyle, and diet 8 .As the synthesis, usage, and environmental release of chemical substances continue to grow, the obesogenic consequences of such activities have elicited significant concerns 5 .
This review offers an up-to-date synopsis of findings from both animal and human research concerning the contribution of environmental obesogens to obesity, as well as a detailed perspective on the mechanisms by which they exert their effects.

Endocrine-disrupting chemicals (EDCs)
Endocrine-disrupting chemicals (EDCs) are substances that can mimic the body's natural hormones and interrupt the normal functioning of the endocrine system by meddling with the body's hormonal balance 1 .In 2003, Jerry Heindel was the first to draw a connection between EDCs and obesity.The theory that EDCs could affect obesity was credible considering the endocrine system plays a central role in regulating appetite, satiety feelings, metabolism, and the management of fat reserves 3 .
Over the course of the 20th and 21st centuries, the widespread application of pharmaceuticals and pesticides in farming practices and the escalation of industrial byproducts have increased worries regarding the spread of EDCs into our surrounding environment 9 .Directly or indirectly, these chemicals are broadly used as major elements or additives in the production of a multitude of consumer goods.Once manufactured or implemented, EDCs are effortlessly dispersed into the environment, leading to spread and exposure of both humans and wildlife, which has now escalated into a concern of global significance 10 .EDCs can be found in substances including pesticides, herbicides, fungicides, flame retardants, surfactants, plastics, sunscreens, cosmetics, and personal care products, among others 4 .Presently, it has been reported that more than a thousand chemicals have been recognized to have an impact on the endocrine system 6 .A group of EDC known as Phthalates, these compounds build the fat cells within the body.Phthalates are found in about 40% of all consumer products utilized by humans.Over time, these chemicals seep out of the materials containing them.Consequently, they invade indoor air and dust, embedding themselves in the environments humans inhabit 11 .
Nicotine functions as an endocrine disruptor.By the year 2013, there were already more than thirty distinct epidemiological studies all reporting a consistent observation; children experienced an elevation in weight gain if their mothers smoked during pregnancy.Past studies in both humans and animals have revealed that nicotine contributes to an increase in body weight and fat distribution, an enlargement of fat cell size, and an upregulation of genes associated with fat cell formation, along with a reduction in physical activity levels 12 .
Acrylamide is also regarded as a potential EDC, primarily deriving from fried, baked, and roasted foods, which are consumed extensively by children, adolescents, and adults globally 13 14 .Phytoestrogens function as endocrine disruptors through pathways mediated by estrogen receptors 15 . in both in vitro studies and obesity-related animal models, phytoestrogens have demonstrated effects similar to estrogen on the formation and metabolism of fat cells.Yet, the impact of consuming phytoestrogens on the development of obesity in humans remains somewhat uncertain.Findings from randomized controlled trials indicate that phytoestrogens' effects on body weight are specific to the compound and vary depending on the metabolic state 16 .

Obesogens: mechanisms of action
Obesogenic substances can act either directly on adipocytes or indirectly.Direct action involves increasing the number of adipocytes, stimulating fat storage in the existing adipocyte, or producing dysfunctional adipocyte.On the other hand, indirect action occurs through multiple mechanisms, such as disrupting metabolism and appetite control, altering metabolic setpoints, inducing unfavorable changes in microbiome composition, and increasing the proportion of calories that are stored as fat 17 .(Figure 1)

Activation of PPARγ
The PPARγ (peroxisome proliferator-activated receptor gamma) is a receptor that, upon activation by certain ligands, functions as a transcription factor critical in regulating gene expression associated with multiple physiological functions.PPARγ has been initially identified as a pivotal regulator in the formation and development of adipose tissue 18 .Activation of this receptor induces the differentiation of mesenchymal stem cells (MSCs) into fat cells and triggers the commencement of fat production 19 .
Tributyltin (TBT) acts as a highly effective ligand for PPARγ, prompting the differentiation of both bone marrow and adipose-derived multipotent stromal cells (MSCs) into adipocytes.TBT functions not just as a PPARγ agonist but also as an agonist for retinoid X receptors (RXR) α and β.This dual-acting capacity of organotins suggests that RXR might play a role in the effects of TBT on MSC differentiation, separately from PPARγ 20 .
Acrylamide which can promote fat cell development through several pathways-as noted aboveis also capable of initiating the differentiation of 3T3-L1 preadipocytes into fat cells by promoting the expression of adipogenesis-related transcription factors, including PPAR-γ and CCAAT/enhancer-binding protein α 14 .A growing array of natural compounds known to activate PPARγ has been discovered.Several among these not only activate PPARγ but also stimulate adipocyte formation in cellular models like 3T3-L1 cells, including substances such as flavanone, bixin, and emodin 21 .

Altering the gut microbiome
The gut microbiome is the collection of microbes that reside in the human gut.Obesogen exposure could lead to obesity by altering the gut microbiome, a relatively novel mechanism which leads to obesity.It is evident from several experimental data that many obesogens induce the gut microbiome dysbiosis in zebrafish, mice and human.
In a study investigating the relationship between Atrazine, a widely used pesticide in the US known to be an obesogen, and microbiota, zebrafish were subjected to Atrazine concentrations of 25 ng/L and 0.50 ng/L for a duration of two weeks.After exposure, bacterial DNA was extracted using real-time PCR and analyzed.The findings revealed a rise in the levels of Bifidobacterium, it is a phylum linked to carbohydrate metabolism, in the zebrafish treated with Atrazine.This suggests that obesogens may alter the host's microbiota in a way that promotes increased fat storage 22 .It has been determined that adding diethylhexyl phthalate (DEHP) into the diet contributes to worsening microbial imbalances in zebrafish, which could partially explain its function as an obesogen 23 .
Exposure to Tributyltin (TBT) has also been observed to cause dysbiosis in the gut microbiome of mice.It reduced the diversity of gut microbial species, altered the composition of the microbiome, and led to an increase in body weight, greater accumulation of visceral fat, and dyslipidemia in male mice 24 .Another study found that exposure to Tributyltin leads to an imbalance in the gut microbiome, which is associated with increased weight gain, disrupted glucose and insulin regulation, and endocrine disruption in mice 25 .
The "Western dietary pattern" has a significant correlation with obesity, and numerous recent research found that elements of the Western diet, such as ultraprocessed foods, food additives, and artificial sweeteners, have the potential to disturb the balance of

Altering appetite, satiety and food preferences
Leptin, a 16-kDa peptide hormone that promotes the feeling of fullness, is produced by the gene associated with obesity.It helps maintain energy equilibrium by reducing the sensation of hunger 28 .The set and control of appetite regulation occurs early on in the hypothalamus during a person's life.Signaling molecules such as leptin and ghrelin are crucial in programming the appetite control centers within the hypothalamus.Environmental chemicals can have direct impacts by attaching to neurons in the developing brain and by modifying the expression of essential appetiteregulating factors 29 .A recent study supports this by demonstrating that in a 3T3-L1 adipocyte model, there was a noticeable increase in the production of leptin mRNA after three weeks of exposure to 1 nM of BPA 30 .Exposure to methylparaben after weaning has been shown to raise the levels of leptin in the serum of a mouse model 31 .

DNA Methylation
DNA methylation represents an epigenetic process that is linked to the suppression of gene activity, particularly when this methylation takes place on the CpG sites within promoter sequences 32 , DNA methylation is the most extensively investigated process hypothesized to be responsible for the heritable consequences of exposure to obesogens 33 .
Bisphenol A (BPA), is considered as xenoestrogen, it is prevalent in plastic food containers, and it is one of the components that leads to obesity 34 , Analogues of BPA, known as bisphenols (BPs), possess similar chemical compositions and exhibit similar behaviors 35 .
Research has demonstrated that exposure to a low dose of Bisphenol S (BPS) at 1.5 μg/kg body weight per day significantly affects gene expression, with 374 genes showing substantial deregulation, and alters the hepatic methylome in male mice, leading to hypomethylation in 58.5% of the differentially methylated regions (DMR) 36 .
There was a notable association identified between the concentration of phthalates in urine and metabolic abnormalities including obesity and insulin resistance.Regarding epigenetics, phthalates have been found to modify the methylation of metabolic-related genes, namely PPARG, Insulin Growth Factor 2 (IGF2), and Sterol Regulatory Element-Binding Proteins (SREBPs) 37 .
Studies have also demonstrated that when F0generation mice are exposed to the obesogenic compound tributyltin (TBT) during pregnancy, it can predispose male descendants in the F4 generation to obesity in the event of a high-fat diet.Furthermore, TBT is capable of causing widespread alterations in DNA methylation and modifying the expression of genes that are important for metabolism 38 .

The regulatory role of micro-RNAs
MicroRNAs, small RNA molecules approximately 22 nucleotides in length, function by regulating gene expression at the post-transcriptional level.Various miRNAs play a role in adipogenesis, including miR-30, miR-26b, miR-199a, and miR-148a.Higher levels of these miRNAs have been observed in both obese humans and mice that have been maintained on a high-fat diet 39 , The levels of miR-17-5p and miR-132 were found to be higher in the visceral fat tissues of obese adults, with a significant correlation to body mass index, glycosylated hemoglobin, and disrupted glucose and lipid metabolism 40 .Studies have demonstrated that Tetrabromobisphenol-A (TBBPA) stimulates the expression of miR-103 and miR-107.It has been revealed that miR-103 targets Thy1, a key regulator of adipogenesis and obesity, leading to a decrease in its expression 41  Research has indicated that Benzyl Phthalate enhances adipogenesis in 3T3-L1 cells through the signaling pathway of miRNA-34a-5p 43 .

Obesogens and Impaired Thermogenesis
Placental mammals possess three types of adipose tissue -white, beige, and brown-distributed in distinct fat stores across the body.White adipocytes primarily function in the storage and release of fats, whereas beige and brown fat cells are specialized for thermogenesis, the process of burning calories to generate heat 44 .
Recent publications suggest that certain obesogens may interfere with the creation or activity of thermogenic adipocytes, affecting some of their functions 45 .
Studies have linked heightened risk of developing insulin resistance and obesity with the exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and its derivative dichlorodiphenyldichloroethylene (DDE).These adverse effects seem to stem from a downregulation of thermogenesis in brown adipose tissue (BAT), which is under the control of the sympathetic nervous system.Early life exposure to DDT or p,p'-DDE disrupts thermogenesis by altering the sympathetic neural connectivity that governs BAT regulation 46 .
La Merrill et al. demonstrated that DDT exposure during the perinatal period hampers thermogenic processes as well as carbohydrate and lipid metabolism, potentially raising the vulnerability to metabolic syndrome in adult female progeny 47 .This particular manifestation of impaired brown adipose tissue (BAT) functionality can be attributed, in part, to a reduction in the expression of a critical regulator of BAT activity, namely the peroxisome proliferator-activated receptor γ coactivator 1α (Ppargc1α, or PGC-1α).Additionally, there is a decrease in the expression of iodothyronine deiodinase 2 (Dio2), the enzyme that is responsible for converting thyroxine (T4) into the more thermogenically active hormone, triiodothyronine (T3) 48 .
Brown adipose tissue (BAT) has also been indicated as a potential target for the toxic effects of Arsenic, mediating the metalloid's influence on body fat composition [49][50] .Prior research has shown that chlorpyrifos (CPF) not only stimulates appetite but also impedes thermogenesis in brown adipose tissue (BAT) stimulated by diet.This interference exacerbates the progression of obesity, nonalcoholic fatty liver disease (NAFLD), and insulin resistance, even in low quantities 51 .

Model systems
Obesogens act through various complex mechanisms and follow multiple pathways to impact the living body.Currently, model systems are used to test mechanisms of obesogenic action including in vitro and in vivo systems.

In Vitro Assays for Obesogens
Research conducted in laboratories lends credence to the theory that exposure to chemicals plays a role in causing endocrine disorders in both humans and animals in the wild 52 .Models used in a lab setting are crucial for pinpointing environmental obesogens, and comprehending the mechanisms that lead to obesity 53 .In vitro models offer multiple advantages compared to different model systems.They can employ human cells, enhancing physiological relevance.Additionally, they tend to be more straightforward, quicker, suitable for parallel processing (enabling medium to high throughput analyses), and are more cost-effective 1 .
Furthermore, in vitro models offer a swift method for exploring the risks associated with exposure to EDCs and their toxic effects, thereby diminishing or completely obviating the necessity for animal experimentation 53 .Numerous in vitro research efforts have demonstrated that certain xenobiotic substances, including tributyltin chloride and bisphenol A, have the capability to encourage the differentiation of adipocytes 54 .
A widely used method for detecting chemicals that induce adipogenesis involves conducting tests using the 3T3-L1 preadipocyte model 55 .The 3T3-L1 cells are characterized as a complete, stable, and reproducible cell system 56 .However, since they are fully committed to the adipocyte lineage, the suitability of the 3T3-L1 cell line for assessing adipogenic responses remains uncertain.Furthermore, the species-specific nature of this murinederived cell line could limit the extrapolation of findings to human health risk evaluations 7 .A list of in vitro model systems and obesogens identified using these models is presented in Table 1.

In Vivo Assays for Obesogens
Various in vivo models have demonstrated that specific environmental contaminants induce adipogenesis.Although animal models are not always suitable to evaluate the obesogenic effect of certain chemicals, as they do not mimic the human physiological systems, in vivo models do provide certain benefits.They permit the study of whole-body dynamics and systematic impacts which are not possible with in vitro systems 75 .
Research using lab animals suggests that exposure to (EDCs) can produce effects associated with numerous diseases 52  specific chemicals and a rise in fat accumulation, which subsequently leads to an increase in body weight 54 .Zebrafish have become an important model organism for studies on metabolic health due to their rapid development and adipose tissue that is morphologically similar to that of humans.Like mammals, zebrafish accumulate neutral triglycerides in lipid droplets within their white adipocytes, and demonstrate similar gene expression patterns that are involved in adipocyte differentiation, lipolysis, and hormonal actions 76 .The genomes of both mammals and zebrafish exhibit a considerable degree of homology, with more than 70% overall conservation, and it is estimated that zebrafish express about 80% of genes that found in humans.Moreover, the transparent nature of zebrafish embryos, coupled with the progression of sophisticated imaging technologies, enables the noninvasive observation of internal structures and in vivo biological processes, encompassing the development of the nervous system and the distribution and fate of suspected EDCs 77 .In table 2, several in vivo models for studying obesogens have been reviewed.

CONCLUSION
Evidence is mounting about the role of environmental obesogens in the global obesity epidemic.Despite increasing knowledge about the number, nature, and properties of these substances, how they spread in the environment, and the many mechanisms that have been proposed so far to explain their mechanism of action, much is still unknown about these chemicals.Therefore, further studies are required to to understand the precise mechanisms of action, and discover the obesogens that are still unknown.We aim for this review to serve as a valuable resource for researchers, healthcare professionals and policy makers striving to address the complex challenges posed by the obesity epidemic, and help reduce the exposure of future generations to these harmful substances, and take preventative measures by advocating for stricter regulations and safer alternatives for chemicals of concern, promoting consumer awareness, and adopting healthier lifestyle practices to reduce overall chemical exposures.