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Background: Phthalate esters (PAEs) are known to have hormone-like properties, and there is a growing trend of children expressing a gender identity different from assigned sex. However, there has been limited research in the potential links between PAEs exposure and gender identity. Methods: A total of 571 children (278 boys) completed the follow-up from Oct 2017 to Oct 2020 in Childhood Blood Pressure and Environmental Factors (CBPEF) cohort in Xiamen, China. Urinary PAE metabolites were measured at three time of visits using ultraperformance liquid chromatography-tandem mass spectrometry. The Children's Sex Role Inventory scale was used to assess gender identity (masculinity, femininity, androgyny and undifferentiated), and Tanner definition was used to define puberty timing. Generalized linear models and log-binomial regression were used to assess the relationships between PAEs exposure, gender trait scores and gender identity. Results: Overall, the concentration of most PAEs in more than 90% of participants was above the limit of detection values. In visit 1, there were 10.1% boys with femininity and 11.3% girls with masculinity; while these figures increased to 10.8% and 12.3% during follow-up, respectively. Early puberty onset accounted for 24.8% and 25.6% among boys and girls. Long-term exposure to mono-2-ethylhexyl phthalate (MEHP) (β = 1.20, 95%CI = 0.13, 2.28), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (β = 1.25, 95%CI = 0.22, 2.28) and mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (β = 1.40, 95%CI = 0.24, 2.56) was associated with the increased differences of femininity trait scores in boys who enter puberty earlier, prolonged exposure to di(2-ethylhexyl) phthalate (DEHP) might also have such a positive impact (β = 1.38, 95%CI = 0.36, 2.41). For gender identity, persistent exposure to low molecular weight phthalates (LMWP) was negatively associated with undifferentiated type among boys entering puberty earlier (RR = 0.18, 95%CI = 0.05, 0.75, P < 0.05), and most of the PAE metabolites exposures showed risk ratios > 1 for their femininity. Conclusion: Long-term exposure to PAEs increase the femininity trait scores in boys with early onset of puberty. Although the mechanisms remain to be determined, environmental pollution might have subtle, yet measurable effects on childhood gender identity. Reducing these chemicals exposure has important public implications on gender development. [ABSTRACT FROM AUTHOR]

The relationship between childhood phthalates (PAEs) exposure, DNA methylation, and cardiometabolic risk (CMR) factors is not well understood. Children were included from a longitudinal cohort 2018–2020 in Xiamen, China. A nest case-control study was additionally conducted, and methylation in lysyl oxidase-like 3 (LOXL3) and solute Carrier Family 6 Member 19 (SLC6A19) were measured. Generalized linear models were used to estimate the associations between PAEs exposure and CMR factors, and mediation analyses of DNA methylation were conducted. The longitudinal study included 835 children aged 7–11 years, and the nest case-control study included 120 cases and 120 controls. Exposure to higher PAEs was correlated with increased CMR scores at baseline (β = 0.299, 95 %CI = 0.114, 0.485) and the final visit (β = 0.202, 95 %CI = 0.008, 0.397). In nest case-control study, higher mono-n-butyl phthalate (MnBP) exposure was related with elevated triglycerides (TG) (β = 0.283, 95 %CI = 0.025, 0.540). A decrement of methylation of CpG 33.34 of LOXL3 was found in response to MnBP exposure (β = −0.014, 95 %CI = −0.027, −0.001). Furthermore, increased methylation of LOXL3_ CpG 33.34 and SLC6A19_ CpG 11.12 was related to reduced TG. De-methylation of LOXL3_ CpG 33.34 and SLC6A19_ CpG 11.12 could mediate MnBP-TG pathways. Childhood exposure to PAEs was associated with increased CMR scores, and mediation of PAE exposure on childhood cardiometabolic health by LOXL3 and SLC6A19 de-methylation was observed. [Display omitted] • Childhood PAEs exposure longitudinally increased cardiometabolic risk (CMR) scores. • PAEs exposure reduced DNA methylation of insulin-resistant-related LOXL3 and SLC6A19. • LOXL3 and SLC6A19 de-methylation mediate childhood PAEs-CMR, especially TG increase. • Add epidemiological and epigenetic evidence about PAEs and cardiometabolic health. [ABSTRACT FROM AUTHOR]