Secondary oxidized di-2-ethylhexyl phthalate metabolites may be associated with progression from isolated premature thelarche to central precocious or early puberty.

Phthalate esters (PAEs) may act as estrogen receptor agonists, and their relationship with precocious puberty is a global health concern. However, their role in isolated premature thelarche (IPT) progression remains unclear. We conducted a cohort study investigating the relationship between IPT progression and urinary PAE metabolites. Girls with IPT aged 6-8 years were regularly followed up every three months for one year. Clinical data and urine PAE metabolite levels were collected. Participants who progressed to central precocious puberty (CPP) or early puberty (EP) had significantly higher ovarian volume, breast Tanner stage, and levels of the creatinine-adjusted urinary secondary oxidized di-2-ethylhexyl phthalate (DEHP) metabolites (Σ4DEHP). Breast Tanner stage (odds ratio [OR] = 7.041, p = 0.010), ovarian volume (OR = 3.603, p = 0.019), and Σ4DEHP (OR = 1.020, p = 0.005) were independent risk factors for IPT progression. For each 10 µg/g/Cr increase in the urine level of Σ4DEHP, the risk of progression from IPT to CPP/EP within one year increased by 20%. This study demonstrated that the breast Tanner stage, ovarian volume, and Σ4DEHP in urine were independent risk factors for IPT progression, and Σ4DEHP may be associated with the progression of IPT to CPP or EP.

Association between phthalate exposure and accelerated bone maturation in Chinese girls with early puberty onset: a propensity score-matched case-control analysis.

Estrogen can promote the acceleration of bone maturation and phthalate esters (PAEs) have estrogen-mimicking effects. We investigated whether PAEs are associated with the acceleration of bone age (BA) in girls with early onset of puberty (EOP). This case-control study enrolled 254 girls with EOP from the Endocrinology Department at Shenzhen Children's Hospital between December 2018 and August 2019. Ultra-performance liquid chromatography and tandem mass spectrometry were used to analyze the 10 metabolites of PAEs (mPAEs) in urine samples. BA was measured using an artificial intelligence system. BA exceeding the chronological age (CA) by > 2 years (BA-CA ≥ 2 years) was referred to as significant BA advancement. Participants were divided into groups A (BA-CA ≥ 2 years; case group) and B (BA-CA < 2 years; control group). Propensity score matching (PSM) was performed for both groups in a 1:2 ratio with a caliper of 0.25. To identify potential dose-response relationships between PAEs exposure and BA advancement, we grouped the participants after PSM according to the tertiles of the mPAE concentrations. After PSM, 31 and 62 girls in groups A and B were selected. The concentration of Mono-ethyl phthalate (MEP) in group A was significantly higher than in group B (11.83 µg/g vs. 7.11 µg/g, P < 0.05); there was no significant difference in the levels of other mPAEs between the groups. The degree of BA advancement and proportion of significantly advanced BA in the lowest, middle, and highest tertiles of the MEP sequentially increased, as well as in the lowest, middle, and highest tertiles of Mono-(2-ethyl-5-carboxypentyl) phthalate; however, these were only statistically different between the highest and lowest MEP tertiles (both P < 0.05). For the remaining mPAEs, differences in the degree of BA advancement among the lowest, middle, and highest tertiles, as well as differences in the proportion of significantly advanced BA among the lowest, middle, and highest tertiles, were not significant (all P > 0.05). Our findings suggested that MEP was positively associated with BA advancement in girls with EOP. Exposure to PAEs may promote accelerated bone maturation.