INTRODUCTION

Human metabolism is geared to respond adaptively to periods of overnutrition and undernutrition. Multiple cross regulating systems govern the distribution or mobilisation of carbohydrates, fatty acids and amino acids to maintain metabolic homeostasis in response to variable energy demand.

Metabolic dysregulation can be driven by persistent over/undernutrition and by adipose tissue dysfunction, and culminates in a number of chronic health complications such as obesity, metabolic syndrome, cardiovascular disease and renal failure. Such cardiometabolic diseases are well characterized in humans at least since the development of agriculture and continue to pose a significant threat to human health.

The global incidence of obesity has reportedly tripled since 1975 [1] at a rate that appears not attributable solely to over-nutrition and lack of exercise. Indeed, a growing volume of literature suggests that lifestyle changes in the last 50 years are insufficient to explain the prominent surge in obesity over the same period. Between 1988 and 2006, average adult BMI increased by 2.3 kg/m2 despite equivalent caloric intake and physical activity [2]. A substantial volume of evidence supports the existence of a metabolic set point for body weight [3], which is established by several biological factors including heritable epigenetic modifications. This set point is metabolically defended during periods of over/undernutrition by adaptive changes in energy expenditure, and can shift upwards in an obesogenic environment [4,5]. The theory of environmental obesogens posits that exogenous chemicals derived from environmental pollutants are capable of driving obesity at a cellular level, and are partly responsible for disproportionate rates of obesity [6]. Microplastics and plastic-associated chemicals (PACs), which leach into the environment as a result of the breakdown of plastic goods, are considered obesogens due to their capacity to induce metabolic dysfunction, promoting weight gain and leading to insulin resistance and cardiometabolic disease. Additionally, a growing volume of evidence supports the existence of a cardiorenal disease axis whereby metabolic dysregulation associated with increased visceral adiposity and insulin resistance is a risk factor for both cardiovascular disease and renal failure [7].

This review will examine recent evidence that details the consequence of contamination from PACs on adipose tissue function, and discuss how an increasingly plastic contaminated environment may drive cardiometabolic disease prevalence. 

Box 1:

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OBESOGENS ARE ENDOCRINE DISRUPTING CHEMICALS THAT PROMOTE OBESITY

The term Obesogen is given to chemicals that are capable of interfering with biological pathways in a way that promotes adipogenesis. Obesogens are endocrine-disrupting chemicals (EDCs) because they mimic endogenous hormones and inappropriately activate various biological pathways [8]. Obesogens can promote obesity by influencing lipid metabolism on a cellular level or promoting persistent over-nutrition by augmenting feeding behaviour, much like phytocannabinoids and some types of steroids [9,10]. One of the first obesogens identified was the recently banned Tributyltin (TBT). TBT is an organotin compound and was used as an antifouling agent and in some plastic products. TBT is a potent obesogen [11] to which humans were exposed via the ingestion of seafood, where it bioaccumulates. TBT is an agonist of both the peroxisome-proliferator activated receptor-γ (PPARγ) and retinoic X receptor (RXR), and upregulates genes involved the commitment of mesenchymal stem cells (MSCs) to the adipocyte lineage [12]. In mice, prolonged exposure to TBT causes weight gain, insulin resistance and increased serum leptin [13].

Interestingly, a similar increase in fat mass has been reported for well controlled human Type 2 diabetic patients treated for an average of 3 months [14] or 12 months [15] with the PPARγ agonist, Rosiglitazone, with the exception that insulin resistance was diminished in these human studies.

PLASTICS AND PLASTIC-ASSOCIATED CHEMICALS ACT AS OBESOGENS

Humans are exposed to contamination by plastic particulates of different sizes, including microplastics and PACs, which leach into the environment as a result of the breakdown of plastic products over time. Although traditionally considered to be inert materials, a growing volume of evidence indicates that microplastic and PAC exposure has the capacity to disrupt physiological processes.

Plastic pollution is endemic across air, land and marine environmental compartments. PACs such as BPA have been detected in water sampled from streams, lakes and wastewater.

These are ingested by marine life, and via this vector, they enter the human food chain [16].

Microplastic particles are endemic in our lived environment, and are readily detected within human stool samples [17]. Therefore, the assessment of microplastic internalization in humans is complicated by the technical challenge of eliminating environmental sample contamination. Recently, direct detection of small numbers of microplastics has been reported in organs such as the human placenta [18] and cirrhotic but not healthy liver tissue [19]. However, to date, there is contentious reporting of indirect evidence of microplastic chemical signature in human blood samples [20]. Mice exposed to large doses of microplastic particles via gavage show accumulation of these particles in the liver, kidney and gut [21] and such accumulations can induce changes in lipid metabolism [22▪].

Exposure to PACs is readily measured in the serum and urine of humans and multiple studies have demonstrated universal exposure to multiple PAC species. Additionally, numerous publications demonstrate associations of exposure to PACs with obesity and obesity-related diseases such as cardiovascular disease [23], and associations have been made even at concentrations lower than those considered safe for human consumption [24]. These association studies are driving studies to understand mechanistically the involvement of PACs in the development of metabolic diseases.

The two main classes of PACs being examined are Phthalates and Bisphenols. Phthalates, or phthalate esters, are used as plasticisers in commercial plastic goods to soften hard plastic polymers, or in personal care products such as fragrances and cosmetic goods. Phthalate exposure occurs primarily through ingestion and is commonly estimated via the measurement in the urine of excreted metabolites, which can be detected within hours [24]. Concentrations of urinary metabolites of several common phthalates are frequently positively correlated with abdominal obesity and insulin resistance in humans [25]. Additionally, a number of animal studies have demonstrated an association between prolonged exposure to common phthalates and onset of obesity and insulin resistance [26–28,29▪▪]. Phthalates are known to augment adipose tissue development in vitro. For example, mono(2-ethylhexyl) phthalate (MEHP) is a known endocrine disruptor with in-utero exposure of mice to MEHP resulting in significantly increased body weight and epidydimal fat volume [30].

Bisphenols, such as BPA, are also potent endocrine disruptors and potential obesogens. BPA is an established xenoestrogen and its use is strictly regulated due to its capacity to interfere with hormonal signalling and induce developmental abnormalities in mice. Recently, the regulated well tolerated exposure limit for BPA has been lowered 20 000-fold from 4 μg/kg/day to 0.2 ng/kg/day [31], a level that is likely exceeded in many human populations [24]. Additionally, BPA has been shown to bioaccumulate, after chronic oral exposure, in the visceral adipose depot of mice at concentrations at or below those considered safe for humans [32]. Importantly, the role that the pro-inflammatory cytokine IL-17a plays in obesity, via the upregulation of PPARγ, has recently been described in mice [33]. The possible synergism of PACs in developing obesity is highlighted by the report of positive associations of higher BPA, risk of obesity and higher levels of the pro-inflammatory cytokine IL-17a, measured in a human case--control study, where the threshold for obesity was a BMI at least 27.5 kg/m2[34].

Substitutes for BPA have been introduced in response to international regulation, such as BPA analogues Bisphenol S (BPS) and F (BPF), which are now commonly used in plastic manufacturing. However, these analogues may also disturb hormonal signalling [35] and influence lipid metabolism by disrupting adipose tissue at a cellular level [36,37].

ADIPOSE TISSUE FUNCTION IS TRANSCRIPTIONALLY REGULATED

Adipose tissue in humans is a critical endocrine organ. White adipose tissue (WAT) is the main adipose tissue compartment and accumulates in subcutaneous depots under the skin, and visceral depots around the organs [38–40]. WAT is composed of adipocytes, which are derived from MSC as a result of adipogenesis[38]. During adipogenesis, the MSC is stimulated to become a committed preadipocyte, before undergoing terminal differentiation into a mature, lipid-storing adipocyte [38,41].

Adipogenesis involves the transcriptional activation of genes associated with adipocyte exocrine function including leptin and adiponectin, with the expression of these adipogenic genes largely controlled by the transcription factor, peroxisome proliferator activated receptor gamma (PPARγ), which is considered the master regulator of adipogenesis. PPARγ is required for adipocyte development and maintenance [42] and it operates in concert with other independent regulatory proteins, or co-regulators, to form distinct transcription complexes and control a diverse array of gene programs. Its ligand binding cavity is relatively spacious and can interact with a diverse repertoire of ligands [43].

Upon binding to its ligand, PPARγ dissociates from its co-repressors and forms an obligate heterodimer with RXR before binding to a conserved binding sequence referred to as the PPARγ Response Element (PRE) [44]. Genome-wide analyses have mapped PREs in upstream of most genes that are involved in adipocyte differentiation, suggesting that PPARγ is involved in regulation of the entire adipogenic gene programme [45]. PPARγ is a popular target treatment of Type II diabetes. For example, thiazolidinediones (TZDs) are full PPARγ agonists that can improve insulin sensitivity by promoting insulin-dependent glucose uptake and free fatty acid (FFA) storage by stimulating adipogenesis [46]. However, there is evidence that ablation of PPARγ offers protection to diet-induced obesity [42], and it can promote adipocyte hypertrophy through the differentiation of preadipocytes into mature adipocytes [47], whilst in humans, extended use of PPARγ agonists can results in fat gain [15].

BPA has been demonstrated to increase adipogenic transcription in the human preadipocyte line STE-L1 by inducing increased expression of PPARγ, fatty acid binding protein 4/adipocyte protein 2 (FABP4/AP2) and CCAAT/enhancer binding protein (C/EBP∝) [48]. In mice, exposure of both microplastics [22▪] and PACs, such as the metabolite of di(2-ethylhexyl) phthalate (DEHP), MEHP result in the expression of adipogenic genes in mouse WAT [30]. Additionally, in-silico modelling indicates that MEHP might bind to the PPARγ molecule in a similar manner to the PPAR agonist, rosiglitazone [49]. Furthermore, the metabolites of alternative plasticizers such as Bis(7-methyloctyl) cyclohexane-1,2-dicarboxylate (DINCH) and diisononyl phthalate (DIDP) have been shown to have similar PPAR binding activities to PPARγ, and to exert a similar adipogenic potential [50▪▪].

ADIPOSE TISSUE ACTS AS A SITE OF POLLUTANT ACCUMULATION

Lipophilic chemicals have the capacity to be sequestered into the adipose tissue compartment and interfere with lipid metabolism [51–53]. Organic pollutants such as PACs which do not readily degrade can partition into adipose tissue and perturb its function, resulting in pathological endocrine disruption which correlates with body weight [25].

Sequestration of lipophilic pollutants into adipose tissue can be thought of as a protective mechanism, because it limits their access to other organs. However, significantly higher portions of adipose tissue in obese individuals accommodate a significantly larger depot for the storage of lipophilic toxins. Additionally, during weight loss, stored toxins can be mobilized into the blood, posing a significant threat to health [53].

The capacity for a toxin to partition into fat tissue depends on a range of factors. The octanol-water partitioning coefficient (KOW, also referred to as Log P) is a measure of lipophilicity. It is often used to describe and predict the uptake of certain drugs into specific tissues [54]. In general, longer chain molecules are more lipophilic and are expected to partition into adipose tissue more readily. Lipinski's rule of five regarding absorption of drugs into cells dictates that compounds should have no more than 5 hydrogen bond donors and 10 hydrogen bond acceptors, a molecular weight not exceeding 500 g/mol and a log P not greater than 5 [55]. Thus, structurally related contaminants may have varying degrees of lipophilicity depending on their degree of halogenation or position of functional groups, and thus may partition at different rates. For example, polychlorinated biphenyls (PCBs) are highly lipophilic organic toxins and can partition into 3T3-L1 adipocytes at a much higher rate than adipocytes derived from mouse embryonic fibroblasts, likely due to the much higher triglyceride content in 3T3-L1 cells. However, individual congeners of PCB showed differences in their accumulation in adipocytes [51].

PLASTIC-ASSOCIATED COMPOUND RETENTION COULD INITIATE AN OBESOGENIC FEEDBACK LOOP

PACs can be considered persistent organic pollutants because they are carbon based and resistant to biodegradation. Many PACs are also shown to interfere with adipogenesis and even result in dysfunctional adipocytes. For example, in-vitro models demonstrate that BPA exposure at environmentally relevant doses results in enhanced preadipocyte proliferation generating adipocytes, which are hypertrophic and have impaired insulin signalling and glucose utilization and are pro-inflammatory [48].

Consequently, increased fat mass can contribute to the development of leptin insensitivity where increased leptin secretion is decoupled from an inappropriate negative feedback response, with effects on dietary responses due to a reduced sense of satiety [56]. Additionally, systemic adiponectin levels are reduced in obese subjects and as such, the ratio of adiponectin/leptin is considered a reliable parameter for measure metabolic health. A low adiponectin/leptin ratio is associated with several markers of poor cardiometabolic health [57].

The capacity of PACs such BPA and phthalates to perturb adipose tissue function is of particular concern because of the risk of establishing an obesogenic feedback loop (Fig. 1). Importantly, BPA fulfils all of Lipinski's rules for drug permeability, suggesting that it has the potential to bioaccumulate in adipose tissue. This suggests that BPA can be stored in adipocytes at concentrations proportional to body weight, and diffuse into the blood, resulting in prolonged exposure [58]. In animals such as chickens fed phthalate supplemented diets, there is evidence of a preferential storage of phthalate esters in their adipose tissue [59]. The formal testing of the degree of bioaccumulation of PACs in human adipose tissues will help clarify if this an important aspect of human plastic contamination.

FIGURE 1:

Putative role of plastic-associated chemicals driving obesogenic change leading to a positive feedback loop. Systemic exposure to PACs results in the activation of PPAR family of transcription factors, the differentiation of preadipocytes driving adipose hypertrophy. Consequent increases in leptin output triggers both leptin insensitivity resulting increased feeding behaviour and a dysregulation of fat metabolism due a counter balancing of adiponectin activity on insulin sensitivity. Created in part with BioRender.com.

CONCLUSION

It is plausible that exposure to microplastics and plastic associated chemicals has the potential to drive obesity through their interference of multiple metabolic regulatory mechanisms. The obesogenic potential of such plastic contaminants is largely overlooked by plastic manufacturing bodies and chemical safety authorities. We propose that further research is needed to fully understand the degree to which plastic pollutants drive obesity and contribute to cardiometabolic disease burden, and to mitigate this by reducing exposure.

Acknowledgements

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Financial support and sponsorship

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Conflicts of interest

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

REFERENCES 1. Organisation WH. World health statistics 2023: monitoring health for the SDGs, sustainable development goals. Geneva, Switzerland: World Health Organisation; 2023. 2. Brown RE, Sharma AM, Ardern CI, et al. Secular differences in the association between caloric intake, macronutrient intake, and physical activity with obesity. Obes Res Clin Pract 2016; 10:243–255. 3. Yu YH, Vasselli JR, Zhang Y, et al. Metabolic vs. hedonic obesity: a conceptual distinction and its clinical implications. Obes Rev 2015; 16:234–247. 4. Bennettt W, Gurin J. The Dieter's dilemma. New York: Basic Books; 1982. 5. Ganipisetti VM, Bollimunta P. Obesity and set-point theory. StatPearls. Treasure Island (FL); 2023. 6. Vermeulen R, Schymanski EL, Barabasi AL, Miller GW. The exposome and health: where chemistry meets biology. Science 2020; 367:392–396. 7. Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation 2023; 148:1606–1635. 8. Heindel JJ, Blumberg B. Environmental obesogens: mechanisms and controversies. Annu Rev Pharmacol Toxicol 2019; 59:89–106. 9. Heindel JJ, Blumberg B, Cave M, et al. Metabolism disrupting chemicals and metabolic disorders. Reprod Toxicol 2017; 68:3–33. 10. Jager G, Witkamp RF. The endocannabinoid system and appetite: relevance for food reward. Nutr Res Rev 2014; 27:172–185. 11. Antizar-Ladislao B. Environmental levels, toxicity and human exposure to tributyltin (TBT)-contaminated marine environment. a review. [email protected]. Environ Int 2008; 34:292--308. 12. Shoucri BM, Martinez ES, Abreo TJ, et al. Retinoid X receptor activation alters the chromatin landscape to commit mesenchymal stem cells to the adipose lineage. Endocrinology 2017; 158:3109–3125. 13. Zuo Z, Chen S, Wu T, et al. Tributyltin causes obesity and hepatic steatosis in male mice. Environ Toxicol 2011; 26:79–85. 14. Kim HJ, Kim SK, Shim WS, et al. Rosiglitazone improves insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2008; 81:42–49. 15. Bastien M, Poirier P, Brassard P, et al. Effect of PPARgamma agonist on aerobic exercise capacity in relation to body fat distribution in men with type 2 diabetes mellitus and coronary artery disease: a 1-yr randomized study. Am J Physiol Endocrinol Metab 2019; 317:E65–E73. 16. Seewoo BJ, Goodes LM, Mofflin L, et al. The plastic health map: a systematic evidence map of human health studies on plastic-associated chemicals. Environ Int 2023; 181:108225. 17. Schwabl P, Koppel S, Konigshofer P, et al. Detection of various microplastics in human stool: a prospective case series. Ann Intern Med 2019; 171:453–457. 18. Ragusa A, Svelato A, Santacroce C, et al. Plasticenta: first evidence of microplastics in human placenta. Environ Int 2021; 146:106274. 19. Horvatits T, Tamminga M, Liu B, et al. Microplastics detected in cirrhotic liver tissue. EBioMedicine 2022; 82:104147. 20. Leslie HA, van Velzen MJM, Brandsma SH, et al. Discovery and quantification of plastic particle pollution in human blood. Environ Int 2022; 163:107199. 21. Deng Y, Zhang Y, Lemos B, Ren H. Tissue accumulation of microplastics in mice and biomarker responses suggest widespread health risks of exposure. Sci Rep 2017; 7:46687. 22▪. Zhao J, Gomes D, Jin L, et al. Polystyrene bead ingestion promotes adiposity and cardiometabolic disease in mice. Ecotoxicol Environ Saf 2022; 232:113239. 23. James-Todd TM, Huang T, Seely EW, Saxena AR. The association between phthalates and metabolic syndrome: the National Health and Nutrition Examination Survey 2001–2010. Environ Health 2016; 15:52. 24. Frederiksen H, Nielsen O, Koch HM, et al. Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009–2017. Int J Hyg Environ Health 2020; 223:93–105. 25. Stahlhut RW, van Wijngaarden E, Dye TD, et al. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect 2007; 115:876–882. 26. Schmidt JS, Schaedlich K, Fiandanese N, et al. Effects of di(2-ethylhexyl) phthalate (DEHP) on female fertility and adipogenesis in C3H/N mice. Environ Health Perspect 2012; 120:1123–1129. 27. Kloting N, Hesselbarth N, Gericke M, et al. Di-(2-Ethylhexyl)-phthalate (DEHP) causes impaired adipocyte function and alters serum metabolites. PLoS One 2015; 10:e0143190. 28. Schaedlich K, Gebauer S, Hunger L, et al. DEHP deregulates adipokine levels and impairs fatty acid storage in human SGBS-adipocytes. Sci Rep 2018; 8:3447. 29▪▪. Hsu JW, Nien CY, Chen HW, et al. Di(2-ethylhexyl)phthalate exposure exacerbates metabolic disorders in diet-induced obese mice. Food Chem Toxicol 2021; 156:112439. 30. Hao C, Cheng X, Xia H, Ma X. The endocrine disruptor mono-(2-ethylhexyl) phthalate promotes adipocyte differentiation and induces obesity in mice. Biosci Rep 2012; 32:619–629. 31. Lambre C, Barat Baviera JM, Bolognesi C, et al. Efsa Panel on Food Contact Materials E, Processing A. Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs. EFSA J 2023; 21:e06857. 32. Wada K, Sakamoto H, Nishikawa K, et al. Life style-related diseases of the digestive system: endocrine disruptors stimulate lipid accumulation in target cells related to metabolic syndrome. J Pharmacol Sci 2007; 105:133–137. 33. Teijeiro A, Garrido A, Ferre A, et al. Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice. Nat Metab 2021; 3:496–512. 34. Hong X, Zhou Y, Zhu Z, et al. Environmental endocrine disruptor Bisphenol A induces metabolic derailment and obesity via upregulating IL-17A in adipocytes. Environ Int 2023; 172:107759. 35. Zhang YF, Ren XM, Li YY, et al. Bisphenol A alternatives bisphenol S and bisphenol F interfere with thyroid hormone signaling pathway in vitro and in vivo. Environ Pollut 2018; 237:1072–1079. 36. Ahn YA, Baek H, Choi M, et al. Adipogenic effects of prenatal exposure to bisphenol S (BPS) in adult F1 male mice. Sci Total Environ 2020; 728:138759. 37. Oliviero F, Marmugi A, Viguie C, et al. Are BPA substitutes as obesogenic as BPA? Int J Mol Sci 2022; 23:4238. 38. Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol 2011; 12:722–734. 39. Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 2019; 20:242–258. 40. Gonzalez-Muniesa P, Martinez-Gonzalez MA, Hu FB, et al. Obesity. Nat Rev Dis Primers 2017; 3:17034. 41. Lee JE, Schmidt H, Lai B, Ge K. Transcriptional and epigenomic regulation of adipogenesis. Mol Cell Biol 2019; 39:1. 42. Jones JR, Barrick C, Kim KA, et al. Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A 2005; 102:6207–6212. 43. Nolte RT, Wisely GB, Westin S, et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998; 395:137–143. 44. Haakonsson AK, Stahl Madsen M, Nielsen R, et al. Acute genome-wide effects of rosiglitazone on PPARγ transcriptional networks in adipocytes. Mol Endocrinol 2013; 27:1536–1549. 45. Nielsen R, Pedersen TA, Hagenbeek D, et al. Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev 2008; 22:2953–2967. 46. Vieira R, Souto SB, Sanchez-Lopez E, et al. Sugar-lowering drugs for Type 2 diabetes mellitus and metabolic syndrome-review of Classical and new compounds: Part-I. Pharmaceuticals (Basel) 2019; 12:8–9. 47. Kubota N, Terauchi Y, Miki H, et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999; 4:597–609. 48. Ariemma F, D’Esposito V, Liguoro D, et al. Low-dose bisphenol-A impairs adipogenesis and generates dysfunctional 3T3-L1 adipocytes. PLoS One 2016; 11:e0150762. 49. Feige JN, Gelman L, Rossi D, et al. The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis. J Biol Chem 2007; 282:19152–19166. 50▪▪. Schaffert A, Karkossa I, Ueberham E, et al. Di-(2-ethylhexyl) phthalate substitutes accelerate human adipogenesis through PPARgamma activation and cause oxidative stress and impaired metabolic homeostasis in mature adipocytes. Environ Int 2022; 164:107279. 51. Bourez S, Van den Daelen C, Le Lay S, et al. The dynamics of accumulation of PCBs in cultured adipocytes vary with the cell lipid content and the lipophilicity of the congener. Toxicol Lett 2013; 216:40–46. 52. Jackson E, Shoemaker R, Larian N, Cassis L. Adipose tissue as a site of toxin accumulation. Compr Physiol 2017; 7:1085–1135. 53. Louis C, Covaci A, Crocker DE, Debier C. Lipophilicity of PCBs and fatty acids determines their mobilisation from blubber of weaned northern elephant seal pups. Sci Total Environ 2016; 541:599–602. 54. Gobas FAPC, Kelly BC, Arnot JA. Quantitative structure activity relationships for predicting the bioaccumulation of POPs in terrestrial food-webs. Mol Infom 2003; 22:329–336. 55. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46:3–26. 56. Zhao S, Kusminski CM, Elmquist JK, Scherer PE. Leptin: less is more. Diabetes 2020; 69:823–829. 57. Fruhbeck G, Catalan V, Rodriguez A, et al. Adiponectin-leptin ratio is a functional biomarker of adipose tissue inflammation. Nutrients 2019; 11:4–5. 58. Darbre PD. Endocrine disruptors and obesity. Curr Obes Rep 2017; 6:18–27. 59. Jarasova A, Harazim J, Suchy P, et al. The distribution and accumulation of phthalates in the organs and tissues of chicks after the administration of feedstuffs with different phthalate concentrations. Veterin Med 2009; 54:427–434.