Associations of Urinary Phthalate Metabolites with Thyroid Function and the Mediated Role of Cytokines: A Panel Study of Healthy Children

Abstract

Evidence on joint association of a phthalate mixture with thyroid function among children and its underlying mechanism is largely unknown. We aimed to explore the associations of 10 urinary phthalate metabolites (mPAEs), either as individuals or as a mixture, with thyroid function indicators [free thyroxine, free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH)] in 144 children aged 4–12 years with up to 3 repeated visits across 3 seasons. Significant and positive associations were observed for mono-(2-ethylhexyl) phthalate (MEHP), mono-iso-butyl phthalate (MiBP), and mono-n-butyl phthalate (MnBP) with TSH, as well as monobenzyl phthalate (MBzP) with FT3 in dose–response manners. The relationship between MEHP and TSH remained robust in multiple-phthalate models. Bayesian kernel machine regression (BKMR) models revealed overall linear associations of the 10 mPAE mixture with higher TSH and FT3 levels, and MEHP and MBzP were major contributors. Meanwhile, MEHP, MiBP, and MnBP were linked to the elevation of multiple cytokines including CCL 27, CCL3, CXCL1, and IL-16. Among them, IL-16 mediated the relationships of MEHP and MiBP with TSH, and the mediated proportions were 24.16% and 24.27%, respectively. Our findings suggested that mPAEs dominated by MEHP were dose-responsively associated with elevated TSH among healthy children and mediated by IL-16.

Thyroid Hormone Biomonitoring: A Review on Their Metabolism and Machine-Learning Based Analysis on Effects of Endocrine Disrupting Chemicals

“…Regarding phthalate metabolites, mono- n -butyl phthalate (MnBP) has been linked to a decline in TSH levels (Figure a), , and associated with an increase in TT4, TT3, and FT3 (Figures c, S2, and S3). Similarly, monobenzyl phthalate (MBzP) has been found to lead to an increase in FT3 levels in children (Figure c) . Phthalates, such as diethyl phthalate, can also strongly interact with blood TTR. ,, …”

“…229 Similarly, monobenzyl phthalate (MBzP) has been found to lead to an increase in FT3 levels in children (Figure 7c). 230 Phthalates, such as diethyl phthalate, can also strongly interact with blood TTR. 193,194,231 In general, chemicals tend to competitively bind with TTR and TRs, leading to an increase in FTHs levels in circulation.…”

Exposure to MEHP during Pregnancy and Lactation Impairs Offspring Growth and Development by Disrupting Thyroid Hormone Homeostasis

“…5 A study of urine samples from children showed a significant correlation between MEHP and elevated thyroidstimulating hormone (TSH). 6 Additionally, another study of urine from preschool children found a significant correlation between MEHP and free triiodothyronine (FT3). 7 Several potential mechanisms exist for the disruption of the TH homeostasis by phthalates.…”

“…Current research suggests that the MEHP level may be associated with the homeostasis of the THs . A study of urine samples from children showed a significant correlation between MEHP and elevated thyroid-stimulating hormone (TSH) . Additionally, another study of urine from preschool children found a significant correlation between MEHP and free triiodothyronine (FT3) .…”

Point-of-Use SERS Approach for Efficient Determination and Removal of Phthalic Acid Esters Based on a Metal–Organic Framework-Coated Melamine Sponge

“…Phthalic acid esters (PAEs) are extensively utilized as plasticizers and easily migrate into the natural environment, resulting in presentation everywhere. , To make matters worse, some PAEs, including dibutyl phthalate (DBP) and di­(2-ethylhexyl) phthalate (DEHP), have been identified as endocrine disruptors that threaten ecosystem function and human health. , Notably, DBP and DEHP are two frequently detected carcinogenic environmental toxins in human body fluids , and have been involved in the priority pollutant list of the United States Environmental Protection Agency (U.S. EPA) and the European Union (EU) . Till now, methods for PAEs determination mainly include gas chromatography-tandem mass spectrometry (GC-MS/MS), gas chromatography (GC), liquid chromatography-mass spectrometry (LC-MS/MS), and high-performance liquid chromatography .…”