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Obesity

• Assessment of the impact of glyphosate and 2,4-D herbicides on the kidney injury and transcriptome changes in obese mice fed a Western diet.
  The development of chronic kidney disease has been associated with comorbidities resulting from the consumption of Westernized dietary (WD) patterns, including obesity and other metabolic dysfunctions. Kidneys also have a crucial role in the metabolism and excretion of xenobiotics, including herbicides. There is limited knowledge regarding the simultaneous exposure to WD and glyphosate (glypho) and 2,4-D, the most used herbicides globally. Thus, this study examined whether exposure to glypho and/or 2,4-D, either individually or in mixed, could impact the early effects of WD intake on kidney histology and gene expression in a rodent model. Male C57BL6J mice were fed a WD containing 20% lard, 0.2% cholesterol, 20% sucrose, and high sugar solution with 23.1 and 18.9 g/L of D-fructose and D-glucose for six months. During this period, the mice also received glypho (0.05 or 5 mg/kg/day), 2,4-D (0.02 or 2 mg/kg/day), or a mixture of both (0.05 +0.02, 5 +2 mg/kg/day) via intragastric administration five times per week. The doses were within or below the established regulatory limits. While single or mixed exposures did not alter WD-induced obesity, tubular lipid vacuolation, or increased serum creatinine levels; the exposure to higher doses of the mixture (5 +2) reduced the mesangial matrix area and tubular cell proliferation, while increasing the density of F4/80 macrophages in the renal interstitium. In terms of transcriptomic analysis, the herbicide mixture altered the expression of 415 genes in the kidney, which were found to be associated with immune response processes, particularly those related to phagocyte activity. While discrete, findings indicate that herbicide mixtures, rather than single exposures, might induce minor deleterious effects on the kidneys of obese mice under WD intake.
  [Romualdo, G.R., de Souza, J.L.H., Valente, L.C. and Barbisan, L.F., 2023. Toxicology Letters, 385, pp.1-11.]
• Effect of Pesticides on Peroxisome Proliferator-Activated Receptors (PPARs) and Their Association with Obesity and Diabetes
  Obesity and diabetes mellitus are considered the most important diseases of the XXI century. Recently, many epidemiological studies have linked exposure to pesticides to the development of obesity and type 2 diabetes mellitus. The role of pesticides and their possible influence on the development of these diseases was investigated by examining the relationship between these compounds and one of the major nuclear receptor families controlling lipid and carbohydrate metabolism: the peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ; this was possible through in silico, in vitro, and in vivo assays. The present review aims to show the effect of pesticides on PPARs and their contribution to the changes in energy metabolism that enable the development of obesity and type 2 diabetes mellitus.
  [Hernández-Valdez, J., Velázquez-Zepeda, A. and Sánchez-Meza, J.C., 2023. PPAR research, 2023.]
• Pesticides and insulin resistance-related metabolic diseases: Evidences and mechanisms.
  The use of pesticides in the past century has lot helped humankind in improving crops' field and general hygiene level. Nevertheless, there has been countless evidences on the toxic effects of pesticides on the living systems. The link of exposure to pesticides with different human chronic diseases in the context of carcinogenicity, neurotoxicity, developmental toxicity, etc., have been evaluated in various types of studies. There are also some evidences on the link of exposure to pesticides with higher incidence of metabolic diseases associated with insulin resistance like diabetes, obesity, metabolic syndrome, hypertension, polycystic ovary syndrome and chronic kidney diseases. Physiologically, weakening intracellular insulin signaling is considered as a compensatory mechanism for cells to cope with cellular stresses like xenobiotic effects, oxidative stress and inflammatory responses, but it can pathologically lead to a defective cycle with lowered sensitivity of the cells to insulin which happens in metabolic disorders. In this work, the data related to metabolic toxicity of pesticides categorized in the mentioned metabolic diseases with a focus on the effects of pesticides on insulin signaling pathway and the mechanisms of development of insulin resistance will be systematically reviewed and presented.
  [Arab, A. and Mostafalou, S., 2023. Pesticide Biochemistry and Physiology, p.105521.]
• A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on
  

  Abstract

  The WHO just released in May 2022 a report on the state of the obesity pandemic in Europe, stating that 60% of citizens in the area of Europe are either overweight or obese, and highlighting the implications of the obesity pandemic, especially as it interacts with the COVID pandemic to create a twin pandemic, to increase morbidity and mortality. Obesity is a complex disease which has reached pandemic dimensions. The worldwide prevalence of obesity has nearly tripled since 1975, mainly due to the adoption of a progressively more sedentary lifestyle and the consumption of less healthy diets. We first report herein updated prevalence rates of overweight and obesity by sex, age, and region first in Europe, per the WHO report, and then worldwide between 1980 and 2019, as we analyze and present herein the data provided by the Global Burden of Disease Study. The prevalence of obesity is higher in women than in men of any age and the prevalence of both overweight and obesity increases with age and has reached their highest point between the ages of 50 to 65 years showing a slight downward trend afterwards. The age-standardized prevalence of obesity has increased from 4.6% in 1980 to 14.0% in 2019. The American and European region have the highest obesity prevalence and the USA and Russia are the countries with the most obese residents. Given dire implications in terms of comorbidities and mortality, these updated epidemiological findings call for coordinated actions from local and regional governments, the scientific community and individual patients alike, as well as the food industry for the obesity pandemic to be controlled and alleviated. We can hopefully learn from the COVID-19 pandemic, where collaborative efforts worldwide, focused intense work at both the local and global level and well-coordinated leadership have demonstrated that humankind is capable of amazing accomplishments by leveraging science and public health, and that we can finally make strides in terms of understanding and combating the obesity pandemic and its dire comorbidities including diabetes, NAFLD, CVD and obesity associated malignancies.

  
  [Boutari, C. and Mantzoros, C.S. (2022) ‘A 2022 update on the epidemiology of obesity and a call to action: As its twin covid-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on’, Metabolism, 133, p. 155217. doi:10.1016/j.metabol.2022.155217. ]
• Association between pesticide exposure and obesity: A cross-sectional study of 20,295 farmers in Thailand
  Background: Obesity is a serious condition because it is associated with other chronic diseases which affect the quality of life. In addition to problems associated with diet and exercise, recent research has found that pesticide exposure might be another important risk factor. The objective of this study was to determine the association between pesticide exposure and obesity among farmers in Nakhon Sawan and Phitsanulok province, Thailand.
  Methods: This study was a population-based cross-sectional study. Data on pesticide use and obesity prevalence from 20,295 farmers aged 20 years and older were collected using an in-person interview questionnaire. The association was analysed using multivariable logistic regression, adjusted for its potential confounding factors.
  Results: Obesity was found to be associated with pesticide use in the past. The risk of obesity was significantly predicted by types of pesticides, including insecticides (OR = 2.10, 95% CI 1.00-4.38), herbicides (OR = 4.56, 95% CI 1.11-18.62), fungicides (OR = 2.12, 95% CI 1.34-3.36), rodenticides (OR = 2.55, 95% CI 1.61-4.05), and molluscicides (OR = 3.40, 95% CI 2.15-5.40). Among 35 surveyed individual pesticides, 22 were significantly associated with higher obesity prevalence (OR = 1.78, 95% CI 1.10-2.88 to OR = 8.30, 95% CI 2.54-27.19), including herbicide butachlor, 15 insecticides (two carbamate insecticides, five organochlorine insecticides, and eight organophosphate insecticides), and six fungicides.
  Conclusion: This study found obesity in farmers in Nakhon Sawan and Phitsanulok province, Thailand, to be associated with the long-term use of several types of pesticides. The issue should receive more public attention, and pesticide use should be strictly controlled.
  [Noppakun, K. and Juntarawijit, C. (2022) Association between pesticide exposure and obesity: A cross-sectional study of 20,295 farmers in Thailand, F1000Research. Available at: https://f1000research.com/articles/10-445/v3. ]
• Pesticides as endocrine disruptors: programming for obesity and diabetes
  Exposure to pesticides has been associated with obesity and diabetes in humans and experimental models mainly due to endocrine disruptor effects. First contact with environmental pesticides occurs during critical phases of life, such as gestation and lactation, which can lead to damage in central and peripheral tissues and subsequently programming disorders early and later in life. We reviewed epidemiological and experimental studies that associated pesticide exposure during gestation and lactation with programming obesity and diabetes in progeny. Maternal exposure to organochlorine, organophosphate and neonicotinoids, which represent important pesticide groups, is related to reproductive and behavioral dysfunctions in offspring; however, few studies have focused on glucose metabolism and obesity as outcomes. We provide an update regarding the use and metabolic impact of early pesticide exposure. Considering their bioaccumulation in soil, water, and food and through the food chain, pesticides should be considered a great risk factor for several diseases. Thus, it is urgent to reformulate regulatory actions to reduce the impact of pesticides on the health of future generations.
  [Miranda, R.A., Silva, B.S., de Moura, E.G. and Lisboa, P.C., 2022. Endocrine, pp.1-11.]
• The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue
  Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discover that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impairs BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This is associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.
  [Wang, B., Tsakiridis, E.E., Zhang, S., Llanos, A., Desjardins, E.M., Yabut, J.M., Green, A.E., Day, E.A., Smith, B.K., Lally, J.S. and Wu, J. Nature communications, 12(1), pp.1-12.]
• Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology
  Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.
  [Kubsad, D., Nilsson, E.E., King, S.E., Sadler-Riggleman, I., Beck, D. and Skinner, M.K., 2019. Scientific reports, 9(1), pp.1-17.]
• Chronic chlorpyrifos exposure elicits diet-specific effects on metabolism and the gut microbiome in rats.
  Chlorpyrifos is a commonly-used pesticide which was reported to interfere with hormone signaling and metabolism, however, little is known about its effect on gut microbiota. In this study, adult male rats fed a normal (NF) or high fat (HF) diet were exposed to 0.3 or 3.0 mg chlorpyrifos/kg bodyweight/day or vehicle alone for 9 weeks. Effects on bodyweight, serum levels of glucose, lipid, cytokines, and gut microbiome community structure were measured. The effects of chlorpyrifos on metabolism were dose- and diet-dependent, with NF-fed rats administered the low dose showing the largest metabolic changes. NF-fed rats exposed to chlorpyrifos exhibited a pro-obesity phenotype compared with their controls, whereas there was no difference in pro-obesity phenotype between HF-fed groups. Chlorpyrifos exposure significantly reduced serum insulin, C-peptide, and amylin concentrations in NF- and HF-fed rats, leaving serum glucose and lipid profiles unaffected. Chlorpyrifos exposure also significantly altered gut microbiota composition, including the abundance of opportunistic pathogens, short chain fatty acid-producing bacteria and other bacteria previously associated with obese and diabetic phenotypes. The abundance of bacteria associated with neurotoxicity and islet injury was also significantly increased by chlorpyrifos. Our results suggest risk assessments for chlorpyrifos exposure should consider other effects in addition to neurotoxicity.
  [Fang B, Li JW, Zhang M, Ren FZ, Pang GF. 2018. Food Chem Toxicol. 111:144-152]
• Increased levels of persistent organic pollutants in serum one year after a great weight loss in humans: Are the levels exceeding health based guideline values?
  With the growing prevalence of obesity, an increased number of bariatric surgeries are being performed. Lipophilic persistent organic pollutants (POPs) are stored in adipose tissue, and an increased release of lipophilic POPs into the blood circulation may occur following rapid weight loss such as after bariatric surgery.To evaluate and compare POP levels in serum before and after bariatric surgery, and to assess if the POP levels exceeded health based guideline values, with particular focus on women of childbearing age (WCBA). Serum samples from 63 patients before and one year after bariatric surgery were analysed for organochlorine pesticides (OCPs); polychlorinated biphenyls (PCBs); and brominated flame retardants (BFRs).
  Mean weight loss one year after surgery was 32.1kg. The levels of all the analysed POPs in serum increased during the study period. Median levels of dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzen (HCB) and PCB-153 increased from 90.2ng/g lipid weight (lw) to 158.5ng/glw, from 21.1ng/glw to 36.4ng/glw and from 48.7ng/glw to 71.5ng/glw, respectively. The highest percentage increase was observed for PCB -138, with 83.1%. BFRs were detected in low sample numbers and at low levels. Guideline values for ΣPCB6 in serum were exceeded for 5% of the participants. Weight loss after bariatric surgery resulted in increases of POPs levels in serum between 46.7%-83.1%. Guideline values for ΣPCB6 in serum were exceeded for 5% of the participants. For WCBA, the possible transfer of comparable levels to infants warrants further attention.
  [Jansen A, Polder A, Müller MHB, et al. 2018. Sci Total Environ. 622-623:1317-1326. ]
• Association between organic food consumption and metabolic syndrome: cross-sectional results from the NutriNet-Santé study.
  Metabolic syndrome (MetS), a multicomponent condition, is a cardiovascular disease predictor. Although exposure to agricultural pesticides has been suggested as a potential contributor to the rising rates of obesity, type 2 diabetes, and other features of metabolic disorders, no studies have focused on the association between consumption of organic food (produced without synthetic pesticides) and MetS. We aimed to investigate the cross-sectional association between organic food consumption and MetS in French adults to determine whether it would be worth conducting further studies, particularly large prospective and randomised trials.A total of 8174 participants from the NutriNet-Santé study who attended a clinical visit and completed an organic food frequency questionnaire were included in this cross-sectional analysis.Higher organic food consumption was negatively associated with the prevalence of MetS: adjusted prevalence ratio was 0.69 (95% CI 0.61, 0.78) when comparing the third tertile of proportion of organic food in the diet with the first one (p value <0.0001). Higher consumption of organic plant-based foods was also related to a lower probability of having MetS. In addition, when stratifying by lifestyle factors (nutritional quality of the diet, smoking status, and physical activity), a significant negative association was detected in each subgroup (p values <0.05), except among smokers. Our results showed that a higher organic food consumption was associated with a lower probability of having MetS. Additional prospective studies and randomised trials are required to ascertain the relationship between organic food consumption and metabolic disorders.
  [Baudry J, Lelong H, Adriouch S, Julia C, et al. 2017. Eur J Nutr. doi: 10.1007/s00394-017-1520-1. ]
• Diet and contaminants: driving the rise to obesity epidemics?
  The obesity epidemic is spreading worldwide without reversal trend and despite specific policies oriented to dietary habits and lifestyle, which seem to have modest effects. Genetic factors only partly explain the rise, whereas environmental factors seem to play a key role, mainly by gene-environment interactions through epigenetic mechanisms. A number of animal and human studies point to maternal diet, intestinal microbiota and chemicals introduced as contaminants with food, all factors able to increase the risk of obesity. Widely diffused toxics (mainly BPA, phthalates, pesticides) are able to promote obesity in children and adults, mainly by acting on the differentiation pathway linking multipotent stromal stem cell to mature adipocyte, modulating epigenetic factors and influencing a series of mechanisms finally leading to altered dietary habits, increased adipocyte formation and fat storage. Furthermore, the adipose tissue is an important target for several chemicals (mainly POPs) which represent a threat to metabolic health. In conclusion, besides excessive individual energy intake and inadequate lifestyle, other broadly diffused and modifiable factors (mainly ingestion of toxic chemicals with food) seem to have a critical role in the rapid epidemiological growing of obesity, also considering trans-generational transmission of risk and later development of obesity due to exposure during early life. Further studies are needed, to better assess interactions between cumulative effects of toxic food contaminants and modification of diet and lifestyle, and to verify the efficacy of primary prevention strategies acting on all these factors and potentially able to reverse the continuous rising of the obesity epidemic.
  [Di Ciaula A, Portincasa P. 2017. Curr Med Chem. doi: 10.2174/0929867324666170518095736]
• Early-life chemical exposures and risk of metabolic syndrome.
  The global prevalence of obesity has been increasing at a staggering pace, with few indications of any decline, and is now one of the major public health challenges worldwide. While obesity and metabolic syndrome (MetS) have historically thought to be largely driven by increased caloric intake and lack of exercise, this is insufficient to account for the observed changes in disease trends. There is now increasing evidence to suggest that exposure to synthetic chemicals in our environment may also play a key role in the etiology and pathophysiology of metabolic diseases. Importantly, exposures occurring in early life (in utero and early childhood) may have a more profound effect on life-long risk of obesity and MetS. This narrative review explores the evidence linking early-life exposure to a suite of chemicals that are common contaminants associated with food production (pesticides; imidacloprid, chlorpyrifos, and glyphosate) and processing (acrylamide), in addition to chemicals ubiquitously found in our household goods (brominated flame retardants) and drinking water (heavy metals) and changes in key pathways important for the development of MetS and obesity.
  [De Long NE, Holloway AC. 2017. Diabetes Metab Syndr Obes. 10:101-109. ]
• Endocrine Disrupting Chemicals, Transgenerational Epigenetics and Metabolic Diseases
  Exposure to environmental chemicals can produce effects on the endocrine system through epigenetic mechanisms. These can considerably decrease or increase the sensitivity of multiple hormones depending on the dose, route, or time of exposure. The exposure of endocrine disrupting chemicals (EDCs) during the in utero period could be a critical window, altering the epigenome profile. Recently, several researchers suggest a role of EDCs in the obesity epidemic. In this
  brief review, we focused on how four EDCs (bisphenol A, dichlorodiphenyltrichloroethane, di-(2-ethylhexyl) phthalate and tributyltin) may underlay transgenerational epigenetic effects. We also discuss the adipogenesis signaling pathway and the impact of exposure to individual or mixtures of EDCs on the developing endocrine system. Understanding the molecular determinants
  of epigenetic memory across generations will provide essential insight into how environmental exposure can affect the health of individuals, as well as subsequent generations.
  [Feroe, A. et al. (2017) Endocrine disrupting chemicals, transgenerational epigenetics and metabolic diseases, EC Endocrinol Metab Res. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563023/. ]
• Endocrine Disruptors and Obesity
  The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure. Recent findings demonstrate that such endocrine-disrupting chemicals, termed "obesogens", can promote adipogenesis and cause weight gain. This includes compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and as ingredients in personal care products. Animal models and epidemiological studies have shown that an especially sensitive time for exposure is in utero or the neonatal period. In summarising the actions of obesogens, it is noteworthy that as their structures are mainly lipophilic, their ability to increase fat deposition has the added consequence of increasing the capacity for their own retention. This has the potential for a vicious spiral not only of increasing obesity but also increasing the retention of other lipophilic pollutant chemicals with an even broader range of adverse actions. This might offer an explanation as to why obesity is an underlying risk factor for so many diseases including cancer.
  [Darbre PD. 2017. Curr Obes Rep. 6(1):18-27]
• Environmental endocrine disruptors: New diabetogens?
  The prevalence of type-2 diabetes has dramatically increased worldwide during the last few decades. While lifestyle factors (sedentariness, noxious food), together with genetic susceptibility, are well-known actors, there is accumulating evidence suggesting that endocrine disrupting chemicals (EDCs) may also play a pathophysiological role in the occurrence of metabolic diseases. Both experimental and epidemiological evidence support a role for early and chronic exposure to low doses of chemical pollutants with endocrine and metabolic disrupting effects. Most are present in the food chain and accumulate in the fat mass after absorption. In rodents, bisphenol A stimulates synthesis and secretion of pancreatic β cells and disturbs insulin signaling in liver, muscle and adipose tissue through epigenetic changes leading to insulin resistance and β cell impairment. In humans, epidemiological reports show statistical link between exposure to pesticides, polychlorinated bisphenyls, bisphenol A, phthalates, dioxins or aromatic polycyclic hydrocarbides or heavy metals and DT2 after acute accidental releases or early in life and/or chronic, low doses exposure. More prospective, longitudinal studies are needed to determine the importance of such environmental risk factors.
  [Fénichel P, Chevalier N. 2017. C R Biol. pii: S1631-0691(17)30124-5]
• Facts and Fallacies in the Debate on Glyphosate Toxicity.
  The safety profile of the herbicide glyphosate and its commercial formulations is controversial. Reviews have been published by individuals who are consultants and employees of companies commercializing glyphosate-based herbicides in support of glyphosate's reapproval by regulatory agencies. These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by academic scientists independent of industry report toxic effects below regulatory limits, as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures. Two authors in particular (Samsel and Seneff) have published a series of commentaries proposing that long-term exposure to glyphosate is responsible for many chronic diseases (including cancers, diabetes, neuropathies, obesity, asthma, infections, osteoporosis, infertility, and birth defects). The aim of this review is to examine the evidential basis for these claimed negative health effects and the mechanisms that are alleged to be at their basis. We found that these authors inappropriately employ a deductive reasoning approach based on syllogism. We found that their conclusions are not supported by the available scientific evidence. Thus, the mechanisms and vast range of conditions proposed to result from glyphosate toxicity presented by Samsel and Seneff in their commentaries are at best unsubstantiated theories, speculations, or simply incorrect. This misrepresentation of glyphosate's toxicity misleads the public, the scientific community, and regulators. Although evidence exists that glyphosate-based herbicides are toxic below regulatory set safety limits, the arguments of Samsel and Seneff largely serve to distract rather than to give a rational direction to much needed future research investigating the toxicity of these pesticides, especially at levels of ingestion that are typical for human populations.
  [Mesnage R, Antoniou MN. 2017. Front Public Health. 5:316]
• Imidacloprid Promotes High Fat Diet-Induced Adiposity in Female C57BL/6J Mice and Enhances Adipogenesis in 3T3-L1 Adipocytes via the AMPKα-Mediated Pathway.
  Imidacloprid, a neonicotinoid insecticide, was previously reported to enhance adipogenesis and resulted in insulin resistance in cell culture models. It was also reported to promote high fat diet-induced obesity and insulin resistance in male C57BL/6J mice. Thus, the goal of the present study was to determine the effects of imidacloprid and dietary fat interaction on the development of adiposity and insulin resistance in female C57BL/6J mice. Mice were fed with a low (4% w/w) or high fat (20% w/w) diet containing imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) for 12 weeks. Mice fed with imidacloprid (0.6 mg/kg bw/day) significantly enhanced high fat diet-induced weight gain and adiposity. Treatment with imidacloprid significantly increased serum insulin levels with high fat diet without effects on other markers of glucose homeostasis. AMPKα activation was significantly inhibited by 0.6 and 6 mg imidacloprid/kg bw/day in white adipose tissue. Moreover, AMPKα activation with 5-aminoimidazole-4-carboxamide ribonucleotide abolished the effects of imidacloprid (10 μM) on enhanced adipogenesis in 3T3-L1 adipocytes. N-Acetyl cysteine also partially reversed the effects of imidacloprid on reduced phosphorylation of protein kinase B (AKT) in C2C12 myotubes. These results indicate that imidacloprid may potentiate high fat diet-induced adiposity in female C57BL/6J mice and enhance adipogenesis in 3T3-L1 adipocytes via the AMPKα-mediated pathway. Imidacloprid might also influence glucose homeostasis partially by inducing cellular oxidative stress in C2C12 myotubes.
  [Sun Q, Qi W, Xiao X, Yang SH, et al. 2017. J Agric Food Chem. 65(31):6572-6581]
• Metabolic syndrome is associated with exposure to organochlorine pesticides in Anniston, AL, United States.
  The Anniston Community Health Survey, a cross-sectional study, was undertaken in 2005-2007 to study environmental exposure to polychlorinated biphenyl (PCB) and organochlorine (OC) pesticides and health outcomes among residents of Anniston, AL, United States. The examination of potential risks between these pollutants and metabolic syndrome, a cluster of cardiovascular risk factors (i.e., hypertension, central obesity, dyslipidemia and dysglycemia) was the focus of this analysis. Participants were 548 adults who completed the survey and a clinic visit, were free of diabetes, and had a serum sample for clinical laboratory parameters as well as PCB and OC pesticide concentrations. Associations between summed concentrations of 35 PCB congeners and 9 individual pesticides and metabolic syndrome were examined using generalized linear modeling and logistic regression; odds ratios (OR) and 95% confidence intervals (CI) are reported. Pollutants were evaluated as quintiles and as log transformations of continuous serum concentrations. Participants were mostly female (68%) with a mean age (SD) of 53.6 (16.2) years. The racial distribution was 56% white and 44% African American; 49% met the criteria for metabolic syndrome. In unadjusted logistic regression, statistically significant and positive associations across the majority of quintiles were noted for seven individually modeled pesticides (p,p'-DDT, p,p'-DDE, HCB, β-HCCH, oxychlor, tNONA, Mirex). Following adjustment for covariables (i.e., age, sex, race, education, marital status, current smoking, alcohol consumption, positive family history of diabetes or cardiovascular disease, liver disease, BMI), significant elevations in risk were noted for p,p'-DDT across multiple quintiles (range of ORs 1.61 to 2.36), for tNONA (range of ORs 1.62-2.80) and for p,p'-DDE [OR (95% CI)] of 2.73 (1.09-6.88) in the highest quintile relative to the first. Significant trends were observed in adjusted logistic models for log10 HCB [OR=6.15 (1.66-22.88)], log10 oxychlor [OR=2.09 (1.07-4.07)] and log10 tNONA [3.19 (1.45-7.00)]. Summed PCB concentrations were significantly and positively associated with metabolic syndrome only in unadjusted models; adjustment resulted in attenuation of the ORs in both the quintile and log-transformed models. In conclusion, several OC pesticides were found to have significant associations with metabolic syndrome in the Anniston study population while no association was observed for PCBs.
  [Rosenbaum PF, Weinstock RS, Silverstone AE, et al. 2017. Environ Int. 108:11-21]
• Persistent Environmental Toxicants in Breast Milk and Rapid Infant Growth.
  Many environmental toxicants are passed to infants in utero and through breast milk. Exposure to toxicants during the perinatal period can alter growth patterns, impairing growth or increasing obesity risk. Previous studies have focused on only a few toxicants at a time, which may confound results. We investigated levels of 26 toxicants in breast milk and their associations with rapid infant growth, a risk factor for later obesity.We used data from the Norwegian HUMIS study, a multi-center cohort of 2,606 mothers and newborns enrolled between 2002 and 2008. Milk samples collected 1 month after delivery from a subset of 789 women oversampled by overweight were analyzed for toxicants including polychlorinated biphenyls (PCBs), heavy metals, and pesticides. Growth was defined as change in weight-for-age z-score between 0 and 6 months among the HUMIS population, and rapid growth was defined as change in z-score above 0.67. We used a Bayesian variable selection method to determine the exposures that most explained variation in the outcome. Identified toxicants were included in logistic and linear regression models to estimate associations with growth, adjusting for maternal age, smoking, education, pre-pregnancy body mass index (BMI), gestational weight gain, parity, child sex, cumulative breastfeeding, birth weight, gestational age, and preterm status.Of 789 infants, 19.2% displayed rapid growth. The median maternal age was 29.6 years, and the median pre-pregnancy BMI was 24.0 kg/m2, with 45.3% of mothers overweight or obese. Rapid growers were more likely to be firstborn. Hexachlorobenzene, β-hexachlorocyclohexane (β-HCH), and PCB-74 were identified in the variable selection method. An interquartile range (IQR) increase in β-HCH exposure was associated with a lower odds of rapid growth (OR 0.63, 95% CI 0.42-0.94). Newborns exposed to high levels of β-HCH showed reduced infant growth (β = -0.03, 95% CI -0.05 to -0.01 for IQR increase in breast milk concentration). No other significant associations were found. Our results suggest that early life β-HCH exposure may be linked to slowed growth. Further research is warranted on the potential mechanism behind this association and the longer-term metabolic effects of perinatal β-HCH exposure.
  [Criswell R, Lenters V, Mandal S, Stigum H, et al. 2017. Ann Nutr Metab. 70(3):210-216. ]
• Persistent Environmental Toxicants in Breast Milk and Rapid Infant Growth.
  Many environmental toxicants are passed to infants in utero and through breast milk. Exposure to toxicants during the perinatal period can alter growth patterns, impairing growth or increasing obesity risk. Previous studies have focused on only a few toxicants at a time, which may confound results. We investigated levels of 26 toxicants in breast milk and their associations with rapid infant growth, a risk factor for later obesity.We used data from the Norwegian HUMIS study, a multi-center cohort of 2,606 mothers and newborns enrolled between 2002 and 2008. Milk samples collected 1 month after delivery from a subset of 789 women oversampled by overweight were analyzed for toxicants including polychlorinated biphenyls (PCBs), heavy metals, and pesticides. Growth was defined as change in weight-for-age z-score between 0 and 6 months among the HUMIS population, and rapid growth was defined as change in z-score above 0.67. We used a Bayesian variable selection method to determine the exposures that most explained variation in the outcome. Identified toxicants were included in logistic and linear regression models to estimate associations with growth, adjusting for maternal age, smoking, education, pre-pregnancy body mass index (BMI), gestational weight gain, parity, child sex, cumulative breastfeeding, birth weight, gestational age, and preterm status.Of 789 infants, 19.2% displayed rapid growth. The median maternal age was 29.6 years, and the median pre-pregnancy BMI was 24.0 kg/m2, with 45.3% of mothers overweight or obese. Rapid growers were more likely to be firstborn. Hexachlorobenzene, β-hexachlorocyclohexane (β-HCH), and PCB-74 were identified in the variable selection method. An interquartile range (IQR) increase in β-HCH exposure was associated with a lower odds of rapid growth (OR 0.63, 95% CI 0.42-0.94). Newborns exposed to high levels of β-HCH showed reduced infant growth (β = -0.03, 95% CI -0.05 to -0.01 for IQR increase in breast milk concentration). No other significant associations were found. Our results suggest that early life β-HCH exposure may be linked to slowed growth. Further research is warranted on the potential mechanism behind this association and the longer-term metabolic effects of perinatal β-HCH exposure.
  [Criswell R, Lenters V, Mandal S, Stigum H, et al. 2017. Ann Nutr Metab. 70(3):210-216. ]
• Potential contribution of insecticide exposure and development of obesity and type 2 diabetes.
  The introduction of insecticides has greatly improved agricultural productivity and human nutrition; however, the wide use of insecticides has also sparked growing concern over their health impacts. Increased rate of cancers, neurodegenerative disorders, reproductive dysfunction, birth defects, respiratory diseases, cardiovascular diseases and aging have been linked with insecticide exposure. Meanwhile, a growing body of evidence is suggesting that exposure to insecticides can also potentiate the risk of obesity and type 2 diabetes. This review summarizes the relationship between insecticide exposure and development of obesity and type 2 diabetes using epidemiological and rodent animal studies, including potential mechanisms. The evidence as a whole suggests that exposure to insecticides is linked to increased risk of obesity and type 2 diabetes.
  [Xiao X, Clark JM2, Park Y. 2017. Food Chem Toxicol. 105:456-474]
• Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: from Mechanisms to Novel Test Methods.
  Endocrine disrupting chemicals (EDCs) are man-made chemicals that interfere with hormonal signalling pathways. They are used in, e.g., production of common household materials, in resin-based medical supplies, pesticides. Thus, they are environmentally ubiquitous and humans and wildlife are exposed to them on a daily basis. Early life exposure to EDCs has been associated with later life adversities such as obesity, diabetes and cancer. Mechanisms underlying such associations are unknown but are likely to be mediated by epigenetic changes induced by EDCs. Epigenetics is the study of changes in gene function that are heritable but do not entail a change in DNA sequence. EDCs have been shown to affect epigenetic marks such as DNA methylation and histone modifications. The scope of this article is to review today's knowledge about mechanisms involved in EDC-induced epigenetic changes and to discuss how this knowledge could be used for designing novel methods addressing epigenetic effects of EDCs.
  [Alavian-Ghavanini A, Rüegg J. 2017. Basic Clin Pharmacol Toxicol. doi: 10.1111/bcpt.12878.]
• Glyphosate pathways to modern diseases V: Amino acid analogue of glycine in diverse proteins
  Glyphosate, a synthetic amino acid and analogue of glycine, is the most widely used biocide on the planet. Its presence in food for human consumption and animal feed is ubiquitous. Epidemiological studies have revealed a strong correlation between the increasing incidence in the United States of a large number of chronic diseases and the increased use of glyphosate herbicide on corn, soy and wheat crops. Glyphosate, acting as a glycine analogue, may be mistakenly incorporated into peptides during protein synthesis. A deep search of the research literature has revealed a number of protein classes that depend on conserved glycine residues for proper function. Glycine, the smallest amino acid, has unique properties that support flexibility and the ability to anchor to the plasma membrane or the cytoskeleton. Glyphosate substitution for conserved glycines can easily explain a link with diabetes, obesity, asthma, chronic obstructive pulmonary disease (COPD), pulmonary edema, adrenal insufficiency, hypothyroidism, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, prion diseases, lupus, mitochondrial disease, nonHodgkin’s lymphoma, neural tube defects, infertility, hypertension, glaucoma, osteoporosis, fatty liver disease and kidney failure. The correlation data together with the direct biological evidence make a compelling case for glyphosate action as a glycine analogue to account for much of glyphosate’s toxicity. Glufosinate, an analogue of glutamate, likely exhibits an analogous toxicity mechanism. There is an urgent need to find an effective and economical way to grow crops without the use of glyphosate and glufosinate as herbicides.
  [Samsel, A. and Seneff, S., 2016. J Biol Phys Chem, 16(6), pp.9-46.]
• Adulthood dietary exposure to a common pesticide leads to an obese-like phenotype and a diabetic profile in apoE3 mice.
  Increasing evidence links the widespread exposure to organophosphate (OP) pesticides to the global epidemics of type 2 diabetes and obesity. Recent data highlighted gene×environment interactions: mice expressing the human apolipoprotein E3 (apoE3) isoform were more prone to develop obesity than those expressing apoE2 or apoE4 upon dietary challenge with chlorpyrifos (CPF), the most used OP worldwide. Study aimed to further explore the contribution of the APOE3 genotype on the emergence of obesity and related metabolic dysfunctions upon subchronic exposure to CPF. Seven-month-old targeted replacement apoE3 and C57BL/6N male mice were orally exposed to CPF at 0 or 2mg/kg body weight/day for 8 consecutive weeks. CPF exposure generally increased food ingestion, glucose and total cholesterol concentrations, and tended to elevate acyl ghrelin levels. Nonetheless, excess weight gain and increased leptin levels were inherent to apoE3 mice. Moreover, the propensity towards a diabetic profile was markedly higher in these animals than in C57BL/6N, as they showed a higher homeostatic model assessment for insulin resistance index and higher insulin levels. Although both genotypes were metabolically affected by CPF, the results of the present investigation revealed that apoE3 mice were the most vulnerable to developing obesity and related disturbances following CPF administration through the diet. Since the APOE3 genotype is the most prevalent worldwide, current findings have particular implications for human health.
  [Peris-Sampedro F, Cabré M, Basaure P, Reverte I, et al. 2015. Environ Res. 142:169-76]
• EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals.
  The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
  [Gore AC, Chappell VA, Fenton SE, Flaws JA, et al. 2015. Endocr Rev. 36(6):E1-E150.]
• Inflammatory and cardiometabolic risk on obesity: role of environmental xenoestrogens.
  The objective of the study was to investigate the levels of xenoestrogens (XEs) in plasma and adipose tissue (AT) depots in a sample of pre- and postmenopausal obese women undergoing bariatric surgery and their cardiometabolic impact in an obese state. Authors evaluated XE levels in plasma and visceral and subcutaneous AT samples of Portuguese obese (body mass index ≥ 35 kg/m(2)) women undergoing bariatric surgery. Association with metabolic parameters and 10-year cardiovascular disease risk was assessed. Data show that XEs are pervasive in this obese population. Distribution of individual and concentration of total XEs differed between plasma, visceral AT, and subcutaneous AT, and the pattern of accumulation was different between pre- and postmenopausal women. Significant associations between XE levels and metabolic and inflammatory parameters were found. In premenopausal women, XEs in plasma seem to be a predictor of 10-year cardiovascular disease risk.
  [Teixeira D, Pestana D, Santos C, Correia-Sá L, et al. 2015. J Clin Endocrinol Metab. 100(5):1792-801]
• Obesity, diabetes, and associated costs of exposure to endocrine-disrupting chemicals in the European Union.
  Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity.The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU.An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change.The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 in 2010 with associated costs of €24.6 million. A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200-56 400) with associated costs of €835 million (sensitivity analysis: €835 million-16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and €15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with €607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of €1.54 billion.
  [Legler J, Fletcher T, Govarts E, Porta M, et al. 2015. J Clin Endocrinol Metab. 100(4):1278-88.]
• Association of urinary phenols with increased body weight measures and obesity in children and adolescents.
  To examine the association of urinary levels of the environmental phenol pesticides 2,5-dichlorophenol, 2,4-dichlorophenol, and triclosan with body weight outcomes in children and adolescent participants in the National Health and Nutrition Examination Survey 2007-2010. Study found a statistically significant positive association between both 2,5-dichlorophenol and 2,4-dichlorophenol with BMI z-score, WC, and obesity in children and adolescents. After stratification by age, the significant associations remained only in adolescents (ages 12-19). No associations were found between triclosan and any of the body weight outcomes.
  [Buser MC, Murray HE, Scinicariello F. 2014. J Pediatr. 165(4):744-9.]
• Health Status of Children of Migrant Farm Workers: Farm Worker Family Health Program, Moultrie, Georgia
  Objectives. We evaluated the health status of migrant farmworkers’ children served by the Farm Worker Family Health Program (FWFHP) in Moultrie, Georgia.

  Methods. We analyzed data from children aged 0 to 16 years examined through the FWFHP from 2003 to 2011 (n across years = 179–415). We compared their prevalence of overweight, obesity, elevated blood pressure, anemia, and stunting with that of children in the United States and Mexico.

  Results. Across study years, prevalence of overweight, obesity, elevated blood pressure, anemia, and stunting ranged from 13.5% to 21.8%, 24.0% to 37.4%, 4.1% to 20.2%, 10.1% to 23.9%, and 1% to 6.4%, respectively. Children in the FWFHP had a higher prevalence of obesity than children in all comparison groups, and FWFHP children aged 6 to 12 years had a higher prevalence of elevated blood pressure than all comparison groups. Older FWFHP children had a higher prevalence of anemia than US children and Mexican children. Children in FWFHP had a higher prevalence of stunting than US and Mexican American children.

  Conclusions. We observed an elevated prevalence of obesity, anemia among older age groups, and stunting in this sample of children of migrant workers.
  [Nichols, M., Stein, A.D. and Wold, J.L. (2014) ‘Health status of children of migrant farm workers: Farm Worker Family Health Program, Moultrie, Georgia’, American Journal of Public Health, 104(2), pp. 365–370. Available at: https://ajph.aphapublications.org/doi/full/10.2105/AJPH.2013.301511. ]

• Prenatal exposure to dichlorodiphenyltrichloroethane and obesity at 9 years of age in the CHAMACOS study cohort.
  In-utero exposure to endocrine-disrupting compounds, including dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenylethylene (DDE), has been hypothesized to increase the risk of obesity later in life. Authors examined the associations of maternal serum concentrations of DDT and DDE during pregnancy with body mass index, obesity, waist circumference, and percentage of body fat in 9-year-old children (n = 261) in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) Study, a longitudinal birth cohort study in the Salinas Valley, California (2000-2010).Study found associations between prenatal exposure to DDT and DDE and several measures of obesity at 9 years of age in boys but not in girls. For example, among boys, 10-fold increases in prenatal DDT and DDE concentrations were associated with increased odds of becoming overweight or obese (for o,p'-DDT, adjusted odds ratio (OR) = 2.5, for p,p'-DDT, adjusted OR = 2.1, and for p,p'-DDE, adjusted OR = 1.97). The difference by sex persisted after considering pubertal status. These results provide support for the chemical obesogen hypothesis.
  [Warner M, Wesselink A, Harley KG, Bradman A, et al. 2014. Am J Epidemiol. 179(11):1312-22.]
• Infant antibiotic exposures and early-life body mass.
  Exposure to antibiotics during the first 6 months of life is associated with consistent increases in body mass from 10 to 38 months. Exposures later in infancy (6–14 months, 15–23 months) are not consistently associated with increased body mass. Although effects of early exposures are modest at the individual level, they could have substantial consequences for population health. Given the prevalence of antibiotic exposures in infants, and in light of the growing concerns about childhood obesity, further studies are needed to isolate effects and define life-course implications for body mass and cardiovascular risks.
  [Trasande, L., Blustein, J., Liu, M., Corwin, E., Cox, L.M. and Blaser, M.J., 2013. International journal of obesity, 37(1), p.16.]
• Chronic consumption of farmed salmon containing persistent organic pollutants causes insulin resistance and obesity in mice
  Dietary interventions are critical in the prevention of metabolic diseases. Yet, the effects of fatty fish consumption on type 2 diabetes remain unclear. The aim of this study was to investigate whether a diet containing farmed salmon prevents or contributes to insulin resistance in mice. Adult male C57BL/6J mice were fed control diet (C), a very high-fat diet without or with farmed Atlantic salmon fillet (VHF and VHF/S, respectively), and Western diet without or with farmed Atlantic salmon fillet (WD and WD/S, respectively). Other mice were fed VHF containing farmed salmon fillet with reduced concentrations of persistent organic pollutants (VHF/S-POPs). We assessed body weight gain, fat mass, insulin sensitivity, glucose tolerance, ex vivo muscle glucose uptake, performed histology and immunohistochemistry analysis, and investigated gene and protein expression. In comparison with animals fed VHF and WD, consumption of both VHF/S and WD/S exaggerated insulin resistance, visceral obesity, and glucose intolerance. In addition, the ability of insulin to stimulate Akt phosphorylation and muscle glucose uptake was impaired in mice fed farmed salmon. Relative to VHF/S-fed mice, animals fed VHF/S-POPs had less body burdens of POPs, accumulated less visceral fat, and had reduced mRNA levels of TNFα as well as macrophage infiltration in adipose tissue. VHF/S-POPs-fed mice further exhibited better insulin sensitivity and glucose tolerance than mice fed VHF/S. Our data indicate that intake of farmed salmon fillet contributes to several metabolic disorders linked to type 2 diabetes and obesity, and suggest a role of POPs in these deleterious effects. Overall, these findings may participate to improve nutritional strategies for the prevention and therapy of insulin resistance.
  [Ibrahim, M.M., Fjære, E., Lock, E.J., Naville, D., Amlund, H., Meugnier, E., Le Magueresse Battistoni, B., Frøyland, L., Madsen, L., Jessen, N. and Lund, S. PloS one, 6(9), p.e25170.]
• Does early-life exposure to organophosphate insecticides lead to prediabetes and obesity
  Researchers gave neonatal rats chlorpyrifos, diazinon or parathion in doses devoid of any acute signs of toxicity, straddling the threshold for barely-detectable cholinesterase inhibition. Organophosphate exposure during a critical developmental window altered the trajectory of hepatic adenylyl cyclase/cyclic AMP signaling, culminating in hyperresponsiveness to gluconeogenic stimuli. Consequently, the animals developed metabolic dysfunction resembling prediabetes. When the organophosphate-exposed animals consumed a high fat diet in adulthood, metabolic defects were exacerbated and animals gained excess weight compared to unexposed rats on the same diet. At the same time, the high fat diet ameliorated many of the central synaptic defects caused by organophosphate exposure, pointing to nonpharmacologic therapeutic interventions to offset neurodevelopmental abnormalities, as well as toward fostering dietary choices favoring high fat intake. These studies show how common insecticides may contribute to the increased worldwide incidence of obesity and diabetes.
  [Slotkin, T.A. 2011. Reproductive Toxicology. 31: 297–301.]
• Low dose organochlorine pesticides and polychlorinated biphenyls predict obesity, dyslipidemia, and insulin resistance among people free of diabetes
  The current study examined if low dose POPs predicted future adiposity, dyslipidemia, and insulin resistance among controls without diabetes in that study. 90 controls were diabetes-free during 20 years follow-up. They were a stratified random sample, enriched with overweight and obese persons. POPs measured in 1987-88 (year 2) sera included 8 organochlorine (OC) pesticides, 22 polychlorinated biphenyls (PCBs), and 1 polybrominated biphenyl (PBB). Body mass index (BMI), triglycerides, HDL-cholesterol, LDL-cholesterol, and homeostasis model assessment value for insulin resistance (HOMA-IR) were study outcomes at 2005-06 (year 20). Parallel to prediction of type 2 diabetes, many statistically significant associations of POPs with dysmetabolic conditions appeared at low dose, forming inverted U-shaped dose-response relations. Among OC pesticides, p,p'-DDE most consistently predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 after adjusting for baseline values. Simultaneous exposure to various POPs in the general population may contribute to development of obesity, dyslipidemia, and insulin resistance, common precursors of type 2 diabetes and cardiovascular diseases. Although obesity is a primary cause of these metabolic abnormalities, POPs exposure may contribute to excess adiposity and other features of dysmetabolism.
  [Lee, D.H., Steffes, M., Sjödin, A., et al. 2011. PLoS ONE. 6: e15977.]
• The association between urinary concentrations of dichlorophenol pesticides and obesity in children
  This study was conducted to assess the association of exposure to environmental pesticides with childhood obesity.A total of 6770 subjects aged 6-19 years were selected from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey (NHANES). Exposure to environmental pesticides was determined based on the concentrations of pesticide residues in urine. A dose-dependent increase in prevalence of obesity was observed in the groups with inter-quartile urinary concentrations of 2,5-dichlorophenol (2,5-DCP). There was a significant association between urinary 2,5-DCP levels and childhood obesity. However, urinary concentrations of 2,4-dichlorophenol were not shown to be significantly associated with childhood obesity. This study suggests a possible relationship between exposure to 2,5-DCP and obesity in children.
  [Twum, C. and Wei. Y. 2011. Reviews on Environ Health.26(3): 215–219.]
• Obesity and Persistent Organic Pollutants: Possible Obesogenic Effect of Organochlorine Pesticides and Polychlorinated Biphenyls
  This study aims to assess the associations between serum levels of persistent organic pollutants (POPs) and the prevalence of obesity in a cohort of obese and lean adult men and women. POP serum samples were investigated cross-sectionally in 98 obese and 47 lean participants, aged ≥18 years. Serum samples were analyzed for the presence of polychlorinated biphenyl (PCB) congeners and for the organochlorine pesticides, dichloro-diphenyl-dichloroethylene (pp-DDE), and β-hexachlorocyclohexane (βHCH). Authors established a significant negative correlation between BMI, waist, fat mass percentage, total and subcutaneous abdominal adipose tissue, and serum levels of PCB and the sumPCBs. For βHCH, authors demonstrated a positive correlation with BMI, waist, fat mass percentage, and total and subcutaneous abdominal adipose tissue. A strong correlation was established between all POP serum levels and age. Combined, these results suggest that the diabetogenic effect of low-dose exposure to POPs might be more complicated than a simple obesogenic effect.
  [Dirinck, E., Jorens,P., Covaci, A., Geens, T., et al. 2010. Obesity. 19: 709–714.]