Association of exposure to synthetic phenols and metal(loid)s

Overview

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Key numbers

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in Spanish girls. This multicentric case-control study recruited 182 girls aged 4-8 years diagnosed with PP (n = 101) or
manifesting any sign of early puberty (premature thelarche: n = 74, other: n = 7) and 128 controls in six Spanish hospitals.
overall early puberty (OR (95% CI) = 1.44 (1.19 – 1.73) per two-fold increase in urinary concentrations), PP (1.69 (1.26
(PrP), and butyl-(BuP) paraben), and benzophenones (BP- regression models for chemicals with a DF > 85%. Further
quantified by dispersive liquid–liquid microextraction and centrations (chemicals with DF > 85%); (ii) three groups,
dem mass spectrometry (UHPLC-MS/MS), as previously of 50–85%); and (iii) two groups, detected and undetected
described (31) with minor modifications, using an Acquity (chemicals with DF < 50%). A directed acyclic graph (DAG)
(Agilent 8900 triple quadrupole ICP-MS, Agilent Technol- ratio (OR) with 95% confidence interval (CI) of manifest-
by handheld refractometer (National Instrument Company, of chemicals detected in > 85% of the girls, including three
Covariates were expressed as the OR with 95% CI of any diagnosis/
Statistical analysis (44% vs. 24%) (Table 1). Most of the cases lived in urban
areas (53%), while most controls resided in rural areas
Parametric and non-parametric tests were applied to examine (48%). Over 90% of the girls were Caucasian, were born
assessed using the Kolmogorov–Smirnov test. Urinary chemi- ence between groups. Among cases, 56% were diagnosed
cal concentrations below the limit of detection (LOD) were with PP and 41% with premature thelarche, and most were
assigned LOD/√2 (36), and concentrations were summarized classified in breast development Tanner stage II (61% and
as detection frequencies (DFs) and medians. In addition, the 95%, respectively) and pubic hair Tanner stage I (54% and
molar sum of each phenolic family and of all phenols analyzed 84%, respectively) (Tables S1–S2). All controls were in
Table 1 Sociodemographic Variables Cases (n = 182) Control (n = 128) p-value*
and menarche were uncommon (Table S1). (2.02 ng/mL in both groups), but significant differences
(median = 2.58 ng/mL in cases vs. 3.10 ng/mL in controls), Exclusion of the girls from HUVA led to significant differ-
BPA (1.78 vs. 0.60 ng/mL), and BP-3 (1.30 vs. 0.48 ng/ ences in BP-8 and Pb between cases and controls (Table S3).
mL) (Table 2). Cases and controls exhibited significant dif- In adjusted single-exposure models, BPA and ∑BPs were
∑Phenols. Non-essential metal(loid)s with the highest (all diagnoses): OR (95% CI) = 1.44 (1.19–1.73) and 1.62
Table 2 Urinary concentrations Exposure biomarkers DF (%) Median DF (%) Median p-value*
and metal(loid)s Synthetic phenols Cases (n = 181) Controls (n = 126)
Metal(loid)s Cases (n = 180) Controls (n = 127)
Mann–Whitney test for phenols, their sums, and metal(loid)s with DF > 8 5%; Chi-squared test for phe-
nols and metal(loid)s with DF < 85% and categorized into detected and non-detected. Significant p-values
respectively (Table 3). In general, results of unadjusted mod- and ∑BPs were also associated with higher risk: OR (95%
on tertiles, girls with BPA and ∑BPs in the 2nd and 3rd vs. (Table 3). Likewise, BPA and ∑BPs were associated with
respectively) (Fig. 1A). In addition, girls with ∑BzPs in (1.05–1.58) and 1.47 (1.14–1.90) (Table 3). Additionally,
increase in OR (Fig. 1A), while BP-8 detection was also risk of premature thelarche (95% CI = 1.23–7.68) (data not
contrast, BuP concentrations above the median were associ- risk of early puberty (OR (95% CI) = 1.74 (1.10–2.76))
Table 3 Association between individual chemicals detected in > 85% of urine samples and odds of early puberty
Synthetic phe- OR (95% CI)a OR (95% CI)b Metal(loid)s OR (95% CI)a OR (95% CI)b
All diagnoses, BPA 1.25 (1.13– 1.44 (1.19– n = 307 (180 As 0.99 (0.87–1.12) 1.07 (0.91–1.25)
n = 307 (181 1.40)** 1.73)** cases, 127
Premature BPA 1.14 (1.01–1.29)* 1.29 (1.05–1.58)* n = 201 (74 As 1.06 (0.91–1.24) 1.06 (0.87–1.28)
PP, n = 226 (100 BPA 1.32 (1.16–1.50)** 1.69 (1.26–2.27)** n = 226 (99 As 0.92 (0.79–1.07) 1.08 (0.87–1.34)
95% CI 95% confidence interval, OR odds ratio, As arsenic, BP-3 benzophenone-3, BPA bisphenol A, Cu copper, Hg mercury, MeP methylpara-
(Fig. 1A). In contrast, higher Cd and Cu concentrations were increased risk of early puberty and PP (Table S4), mainly

Methods (brief)

Bisphenol, paraben, benzophenone (BzP), and metal(loid) concentrations were quantified in spot urine samples. Adjusted
ICP-MS Inductively coupled plasma mass risk of precocious puberty (PP) and premature thelarche in
LOD Limit of detection thelarche (9) and puberty onset (8, 28), while others found
UHPLC-MS/MS Ultra-high performance liquid Study population
Single first morning void urine samples were collected by the association of individual chemicals (single-exposure
ultra-high performance liquid chromatography with tan- based on the LOD and median value (chemicals with DF
dem mass spectrometry (UHPLC-MS/MS), as previously of 50–85%); and (iii) two groups, detected and undetected
UPLC I-Class UHPLC system (Waters, Milford, MA) and (Fig. S1) was created to select potential confounding vari-
measured by inductively coupled plasma mass spectrometry ing (37). Regression estimates were expressed as the odds
(Agilent 8900 triple quadrupole ICP-MS, Agilent Technol- ratio (OR) with 95% confidence interval (CI) of manifest-
ogies). Detailed analytical procedures, including sample ing any sign of early puberty/premature thelarche/PP per
cal concentrations below the limit of detection (LOD) were with PP and 41% with premature thelarche, and most were
assigned LOD/√2 (36), and concentrations were summarized classified in breast development Tanner stage II (61% and
BPS 35.4 < LOD (0.1) 36.5 < LOD (0.1) 0.84
BPF 10.5 < LOD (0.1) 11.1 < LOD (0.1) 0.86
EtP 48.1 < LOD (0.1) 50.0 < LOD (0.1) 0.74
PrP 49.7 < LOD (0.1) 46.8 < LOD (0.1) 0.62
BP-6 20.4 < LOD (0.1) 23.0 < LOD (0.1) 0.59

Implications

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Update history

The five most recent substantive edits to this page, classified major (evidence or structure moved), correction (a published value or statement was wrong and has been fixed), or minor (narrative rewritten without changing the underlying evidence). Each description is derived from what the edit did to this page; the linked commit is the authoritative record, routine regeneration passes are excluded, and the full version history lives in git. When DOI minting comes online (see schema docs), each entry below will also link to a version-pinned DataCite DOI.

Commit	Date	Change	Description
b01ec52c	2026-08-04	major	2 sections added
d49e450f	2026-08-03	major	5 sections added; narrative text revised