Urinary organophosphate esters metabolites, glucose homeostasis and prediabetes in adolescents☆
Graphical abstract
Introduction
Prediabetes is a high-risk state for the development of diabetes, posing a greater risk to nephron/neuropathies (Tabák et al., 2012). Amid the pandemic of type 2 diabetes worldwide, the rapidly enlarging adolescence population with prediabetic or diabetic traits is alarming (Andes et al., 2019; Newton et al., 2016; Nsiah-Kumi et al., 2013). Recent data from the 2005–2016 National Health and Nutrition Examination Survey (NHANES) suggested that there are nearly 20% of 12–19-year old adolescents have prediabetes in the U.S (Andes et al., 2019). Although traditional factors such as obesity, lack of physical activity, sedentary lifestyle, and overconsumption of calorie and fat were thought to be responsible for the epidemic of prediabetes in adolescents, exposure to environmental chemicals, particularly the endocrine disruptors, may also play an important role (Sargis and Simmons, 2019).
Organophosphate esters (OPEs) are a class of increasingly used substitutes of brominated flame retardants (BFRs) (Blum et al., 2019; Van der Veen and De Boer, 2012). The global annual production of OPEs has been dramatically increased following the phase-out of BFRs. Although known as flame retardants, unlike most of BFRs, OPEs are not tightly bound to the base materials in products, and have been additionally used as plasticizers and gradients in various products, including personal care products (Blum et al., 2019; Van der Veen and De Boer, 2012). In contrast to the persistence of BFRs in human body, OPEs are readily metabolized in the liver and excreted into urine (Van der Veen and De Boer, 2012). The estimated biological half-lives in humans are almost on the orders hours to days (Van den Eede et al., 2016; Wang et al., 2020). Human exposure to OPEs occurs via a variety of routes, such as the inhalation of indoor dusts, diet-related intake, hand-to-mouth and dermal contact with OPEs containing products (e.g., hand wipes and nail polishing materials) (Blum et al., 2019; Doherty et al., 2019; Van der Veen and De Boer, 2012).
The omnipresence of OPEs in the residential environments and consumer products has resulted in the near-ubiquitous exposure in humans. Monitoring data revealed that more than 80% percent of the general U.S. population have detectable levels of several major OPEs metabolites (Ospina et al., 2018), such as bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), dibutyl phosphate (DPHP), and bis(2-chloroethyl) phosphate (BCEP), whose concentrations have been steadily climbing since 2000s (Hoffman et al., 2017). Moreover, children and adolescents are found to be exposed at a higher level of OPEs exposure. For instance, the levels of BDCIPP and DPHP were significantly higher than those in adults (Doherty et al., 2019; Van den Eede et al., 2015), suggesting that children and adolescents may be at a greater risk.
Evidence from experimental studies indicated that OPEs may be a class of endocrine disrupting chemicals (EDCs) as they are able to disrupt the carbohydrate metabolism (Du et al., 2016; Wang et al., 2018) and glucose homeostasis (Wade et al., 2019), induce insulin resistance (Green et al., 2017; Wang et al., 2019), and promote adipogenesis (Wang et al., 2019). Increasing evidence also shows that OPEs exposure was associated with multiple adverse effects such as thyroid dysfunction (Kim et al., 2015; Liu et al., 2019; Preston et al., 2017) and altered production or action of sex hormones (Liu et al., 2012, 2013; Luo et al., 2020a). Such metabolic disruptions were chiefly mediated by altered activities of multiple nuclear receptors [e.g., peroxisome proliferator activated receptors (PPARs) (Fang et al., 2015; Pillai et al., 2014), thyroid receptors (Liu et al., 2019; Wang et al., 2013), estrogen receptors (ERs), androgen receptors (ARs) (Krumm et al., 2018), and mineralocorticoid and glucocorticoid receptors (Zhang et al., 2017)], genes expressions in arcuate nucleus (ARC) region (the key regulator of energy homeostasis) (Krumm et al., 2018), and mitochondrial dysfunction (Li et al., 2017).
However, whether the exposure to OPEs was associated with metabolic dysfunction, especially prediabetes, and alterations of glucose metabolism in adolescents is largely unknown. Thus, we utilized the data from NHANES, a publicly accessible data platform that provides unique and detailed information on OPEs exposure and cardiometabolic profiles in the U.S. general population, to investigate the associations of urinary OPEs metabolites with prediabetes and glucose homeostasis in adolescents. The findings may provide valuable hints on the contribution of increasing used environmental stressors, like OPEs, to the epidemic of prediabetes in adolescents.
Section snippets
Data source and population
NAHENS is an ongoing national survey with a multi-stage complex sampling design conducted by the Center of Disease Control and Prevention (Johnson et al., 2014). The survey aims to investigate the health and nutritional status of noninstitutionalized adults and children in the U.S. Participants in NHANES all completed a set of comprehensive questionnaires, and received physical examinations in a mobile examination center where blood and urine samples were collected. All procedures and contents
Descriptive statistics
Fig. 1 presents the participants selection process. Overall, 349 nondiabetic and non-pregnant adolescents who had indices of prediabetes and glucose homeostasis measured in at least 8 h fasting blood samples and provided complete data on urinary OPEs metabolites were initially selected. Of these, 49 adolescents with missing values on at least one of the demographic characteristics were further excluded, resulting in a total of 300 adolescents available for a complete case analysis for
Discussion
Our study provides the first epidemiological evidence on the associations of urinary OPEs metabolites with prediabetes and indices of glucose homeostasis in adolescents. The associations varied by OPEs metabolites and sex. Specifically, elevated odds of being prediabetes and increased 2 h-OGTT level were associated with BDCIPP in female adolescents, while DNBP presented consistent inverse associations with prediabetes and indices of glucose homeostasis in males. Meanwhile, an inverse
CRediT authorship contribution statement
Kai Luo: Conceptualization, Methodology, Writing - original draft. Ruxianguli Aimuzi: Software, Validation, Data curation. Yuqing Wang: Resources, Investigation, Visualization. Min Nian: Resources, Investigation. Jun Zhang: Conceptualization, Methodology, Supervision, Writing - review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
This study was partly funded by the National Natural Science Foundation of China (41991314 and 81530086) and Shanghai Municipal Health and Family Planning Commission (2020CXJQ01). The authors greatly appreciate all the participants in NHANES for making the current study possible.
References (64)
- et al.
Multiple exposures to organophosphate flame retardants alter urinary oxidative stress biomarkers among children: the Hokkaido Study
Environ. Int.
(2019) - et al.
Associations between urinary organophosphate ester metabolites and measures of adiposity among U.S. children and adults: NHANES 2013–2014
Environ. Int.
(2019) - et al.
TPP and TCEP induce oxidative stress and alter steroidogenesis in TM3 Leydig cells
Reprod. Toxicol.
(2015) - et al.
Is the PentaBDE replacement, tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells
Toxicol. Appl. Pharmacol.
(2011) - et al.
Perinatal triphenyl phosphate exposure accelerates type 2 diabetes onset and increases adipose accumulation in UCD-type 2 diabetes mellitus rats
Reprod. Toxicol.
(2017) - et al.
Urinary metabolites of organophosphate flame retardants and their variability in pregnant women
Environ. Int.
(2014) - et al.
Global microRNA and isomiR expression associated with liver metabolism is induced by organophosphorus flame retardant exposure in male Chinese rare minnow (Gobiocypris rarus)
Sci. Total Environ.
(2019) - et al.
An exploratory analysis of urinary organophosphate ester metabolites and oxidative stress among pregnant women in Puerto Rico
Sci. Total Environ.
(2020) - et al.
Quantification of 16 urinary biomarkers of exposure to flame retardants, plasticizers, and organophosphate insecticides for biomonitoring studies
Chemosphere
(2019) - et al.
Thyroid disruption by triphenyl phosphate, an organophosphate flame retardant, in zebrafish (Danio rerio) embryos/larvae, and in GH3 and FRTL-5 cell lines
Aquat. Toxicol.
(2015)
A novel regulator of type II diabetes: MicroRNA-143
Trends Endocrinol. Metabol.
Tris (1,3-dichloro-2-propyl) phosphate-induced apoptotic signaling pathways in SH-SY5Y neuroblastoma cells
Neurotoxicology
Effects of tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phosphate (TPP) on sex-dependent alterations of thyroid hormones in adult zebrafish
Ecotoxicol. Environ. Saf.
Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish
Aquat. Toxicol.
Effects of TDCPP or TPP on gene transcriptions and hormones of HPG axis, and their consequences on reproduction in adult zebrafish (Danio rerio)
Aquat. Toxicol.
Associations between organophosphate esters and sex hormones among 6-19-year old children and adolescents in NHANES 2013-2014
Environ. Int.
Exposure to Organophosphate esters and metabolic syndrome in adults
Environ. Int.
Exposure to organophosphate flame retardant chemicals in the U.S. General population: data from the 2013-2014 national health and nutrition examination survey
Environ. Int.
ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function
Toxicol. Appl. Pharmacol.
Associations between urinary diphenyl phosphate and thyroid function
Environ. Int.
Prediabetes: a high-risk state for diabetes development
Lancet
Age as a determinant of phosphate flame retardant exposure of the Australian population and identification of novel urinary PFR metabolites
Environ. Int.
Kinetics of tris (1-chloro-2-propyl) phosphate (TCIPP) metabolism in human liver microsomes and serum
Chemosphere
Phosphorus flame retardants: properties, production, environmental occurrence, toxicity and analysis
Chemosphere
Effects of triphenyl phosphate exposure during fetal development on obesity and metabolic dysfunctions in adult mice: impaired lipid metabolism and intestinal dysbiosis
Environ. Pollut.
Exposure of zebrafish embryos/larvae to TDCPP alters concentrations of thyroid hormones and transcriptions of genes involved in the hypothalamic-pituitary-thyroid axis
Aquat. Toxicol.
Estimating renal and hepatic clearance rates of organophosphate esters in humans: impacts of intrinsic metabolism and binding affinity with plasma proteins
Environ. Int.
Perinatal exposure to 2-Ethylhexyl Diphenyl Phosphate (EHDPHP) affected the metabolic homeostasis of male mouse offspring: unexpected findings help to explain dose- and diet- specific phenomena
J. Hazard Mater.
Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes
N. Engl. J. Med.
Prevalence of Prediabetes Among Adolescents and Young Adults in the United States, 2005-2016
Lipid peroxidation and oxidative stress responses in juvenile salmon exposed to waterborne levels of the organophosphate compounds tris(2-butoxyethyl)- and tris(2-chloroethyl) phosphates
J. Toxicol. Environ. Health
Association of exposure to di-2-ethylhexylphthalate replacements with increased insulin resistance in adolescents from NHANES 2009-2012
J. Clin. Endocrinol. Metab.
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This paper has been recommended for acceptance by Wen Chen.