Phthalates and Non-Phthalate Plasticizers and Thyroid Dysfunction: Current Evidence and Novel Strategies to Reduce Their Spread in Food Industry and Environment

Abstract

Thyroid hormones (THs) play a crucial role in various biological functions, including metabolism, cell growth, and nervous system development, and any alteration involving the structure of the thyroid gland and TH secretion may result in thyroid disease. Growing evidence suggests that phthalate plasticizers, which are commonly used in a wide range of products (e.g., food packaging materials, children's toys, cosmetics, medical devices), can impact thyroid function, primarily affecting serum levels of THs and TH-related gene expression. Like phthalate compounds, recently introduced alternative plasticizers can leach from their source material into the environment, particularly into foods, although so far only a very limited number of studies have investigated their thyroid toxicity. This review aimed at summarizing the current knowledge on the role of phthalate and non-phthalate plasticizers in thyroid dysfunction and disease, describing the major biological mechanisms underlying this relationship. We will also focus on the food industry as one of the main players for the massive spread of such compounds in the human body, in turn conveyed by edible compounds. Given the increasing worldwide use of plasticizers and the essential role of THs in humans, novel strategies should be envisaged to reduce this burden on the thyroid and, in general, on human health.

Keywords: alternative plasticizers; chemical leaching; chemical migration; endocrine disruption; environmental exposure; food contact materials; food packaging; phthalates; plasticizers; thyroid.

Figure 1

Schematic representation of checkpoints within the hypothalamic-pituitary-thyroid axis on which plasticizers may exert their effects (see text for details). Abbreviations: DIO: deiodinase; fT3: free triiodothyronine; fT4: free thyroxine; rT3: reverse triiodothyronine; T2: diiodothyronine; T3: triiodothyronine; T4: thyroxine; TH: thyroid hormone; TR: thyroid receptor; TRH: thyrotropin-releasing hormone; TRHR: thyrotropin-releasing hormone; TSH: thyroid stimulating hormone; TSHR: thyroid stimulating hormone; TT3: total triiodothyronine; TT4: total thyroxine.

Figure 2

Diagram illustrating the sources and routes of exposure to phthalates and their effects on health based on the developmental stage (see text for details).

Figure 3

Summary of known effects of phthalates and some of their metabolites on molecules potentially involved in thyroid dysfunction. The up, down, and horizontal arrows indicate upregulation, downregulation, and absence of significant effects, respectively (see text for details). Abbreviations: AKT: protein kinase B; AIM2: absent in melanoma 2; DBP: dibutyl phthalate; DEHP: di-(2-ethylhexyl) phthalate; DEP: diethylphthalate; DIO: deiodinase; ER: estrogen receptor; GPx: glutathione peroxidase; HO-1: heme oxygenase; MEHP: mono(2-ethylhexyl) phthalate; NF-κB: nuclear factor kappa B; NIS: sodium-iodide symporter; NLRC4: NLR family caspase activation and recruitment domain (CARD) domain-containing protein 4 NLRP1/3: NOD-like receptors (NLRs) family pyrin domain containing protein 1/3; Nrf2: nuclear factor-erythroid 2 related factor; NQO1: NAD(P)H quinone dehydrogenase 1; PAX8: paired box gene 8; PPAR: peroxisome proliferator-activated receptor; SOD: superoxide dismutase; TG: thyroglobulin; TPO: thyroid peroxidase; TR: thyroid receptor, TRH: thyrotropin-releasing hormone; TRHR: thyrotropin-releasing hormone; TSH: thyroid stimulating hormone; TSHR: thyroid stimulating hormone; TTF-1: thyroid transcription factor-1; TTR: transthyretin; UGT: uridine 5′-diphospho-glucuronosyltransferase.

Figure 4

Schematic representation of checkpoints within the hypothalamic-pituitary-thyroid axis on which plasticizers may exert their effects (see text for details). Abbreviations: FCMs: food contact materials.

Figure 5

Schematic summary of multiple interactions of phthalate with the hypothalamic-pituitary-thyroid axis and the molecules or pathways involved in these processes (see text for details). Abbreviations: AKT: protein kinase B; AIM2: absent in melanoma 2; DIO: deiodinase; E2: 17β-estradiol; GPx: glutathione peroxidase; HO-1: heme oxygenase; MDA: malondialdehyde; NF-κB: nuclear factor kappa B; NIS: sodium-iodide symporter; NLRC4: NLR family caspase activation and recruitment domain (CARD) domain-containing protein 4 NLRP1/3: NOD-like receptors (NLRs) family pyrin domain containing protein 1/3; Nrf2: nuclear factor-erythroid 2 related factor; NQO1: NAD(P)H quinone dehydrogenase 1; PAX8: paired box gene 8; PKA: protein kinase 1; PPAR: peroxisome proliferator-activated receptor; ROS: reactive oxygen species; SOD: superoxide dismutase; TG: thyroglobulin; TH: thyroid hormone; TPO: thyroid peroxidase; TR: thyroid receptor; TRH: thyrotropin-releasing hormone; TRHR: thyrotropin-releasing hormone; TSH: thyroid stimulating hormone; TSHR: thyroid stimulating hormone; TTF-1: thyroid transcription factor-1; TTR: transthyretin; UGT: uridine 5′-diphospho-glucuronosyltransferase.