High urinary phthalate concentration associated with delayed pubarche in girls

Department of Growth and Reproduction, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
International Journal of Andrology (Impact Factor: 3.7). 03/2012; 35(3):216-26. DOI: 10.1111/j.1365-2605.2012.01260.x
Source: PubMed


Phthalates are a group of chemicals present in numerous consumer products. They have anti-androgenic properties in experimental studies and are suspected to be involved in human male reproductive health problems. A few studies have shown associations between phthalate exposure and changes in pubertal timing among girls, although controversies exist. We determined the concentration of 12 phthalate metabolites in first morning urine samples from 725 healthy Danish girls (aged 5.6-19.1 years) in relation to age, pubertal development (breast and pubic hair stage) and reproductive hormone levels (luteinizing hormone, oestradiol and testosterone). Furthermore, urinary phthalates were determined in 25 girls with precocious puberty (PP). In general, the youngest girls with less advanced pubertal development had the highest first morning urinary concentration of the monobutyl phthalate isoforms (∑MBP((i+n))), monobenzyl phthalate (MBzP), metabolites of di-(2-ethylhexyl) phthalate (∑DEHPm) and of di-iso-nonyl phthalate (∑DINPm). After stratification of the urinary phthalate excretion into quartiles, we found that the age at pubarche was increasing with increasing phthalate metabolite quartiles (except for MEP). This trend was statistically significant when all phthalate metabolites (except MEP) were summarized and expressed as quartiles. No association between phthalates and breast development was observed. In addition, there were no differences in urinary phthalate metabolite levels between girls with PP and controls. We demonstrated that delayed pubarche, but not thelarche, was associated with high phthalate excretion in urine samples from 725 healthy school girls, which may suggest anti-androgenic actions of phthalates in our study group of girls.

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    • "Phthalates have been shown to affect later life events such as reproduction in mammalian species (Frederiksen et al., 2012; Giribabu et al., 2014; Higuchi et al., 2003; Noriega et al., 2009; Tyl et al., 2004; Yamasaki et al., 2009). However, there is a critical lack of data on the chronic effects of phthalates in amphibians. "
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    ABSTRACT: Polymer flexibility and elasticity is enhanced by plasticizers. However, plasticizers are often not covalently bound to plastics, and thus can leach from products into the environment. Much research effort has focused on their effects in mammalian species, but data on aquatic species are scarce. In this study, Western clawed frog (Silurana tropicalis) embryos were exposed to 1.3, 12.3, and 128.7mg/L monomethyl phthalate (MMP) until the juvenile stage (11weeks) and to 1.3mg/L MMP until the adult stage (51weeks). MMP decreased survival, hastened metamorphosis, and biased the sex ratio toward males (2M:1F) at the juvenile stage without altering the expression of a subset of thyroid hormone-, sex steroid-, cellular stress- or transcription regulation-related genes in the juvenile frog livers. At the adult stage, exposure to MMP did not have significant adverse health effects, except that females had larger interocular distance and the expression of the heat shock protein 70 was decreased by 60% in the adult liver. In conclusion, this study shows that MMP is unlikely to threaten amphibian populations as only concentrations four orders of magnitude higher than the reported environmental concentrations altered the animal physiology. This is the first complete investigation of the effects of phthalates in a frog species, encompassing the entire life cycle of the organisms. Copyright © 2015. Published by Elsevier Inc.
    General and Comparative Endocrinology 02/2015; 219. DOI:10.1016/j.ygcen.2015.01.019 · 2.47 Impact Factor
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    • "female adolescents in Puerto Rico reported that higher levels of DEP, DBP, DEHP, and MEHP were related to premature thelarche, suggesting estrogenic and antiandrogenic activity of plasticizers (Colon et al., 2000). However, other studies in Denmark assessing exposures of first morning urinary phthalate concentration (Frederiksen et al., 2012), Western Australia about prenatal exposure of phthalate metabolites (Hart et al., 2014), and US for high-molecular weight phthalate metabolites in urine samples at baseline (Wolff et al., 2014) reported delayed pubarche (Frederiksen et al., 2012), polycystic ovarian morphology (Hart et al., 2014), and delayed puberty hair development of stage 2 (Wolff et al., 2014). "
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    ABSTRACT: Phthalate esters are widely used plasticizers that are present in many daily used products. Although some of their reproductive effects have been reported, pubertal development effects from prenatal exposure to phthalates awaits further investigations. A population based birth cohort was established (N=437 at baseline) with maternal exposure to phthalates assessed in urine collected at the third trimester of pregnancy in 2001 and 2002. Their 133 children with prenatal phthalates exposure were followed up for the outcomes of pubertal development by sequential physical examinations at eight and 11 years old in 2009 and 2012. Urinary concentrations of major phthalate metabolites (i.e., mono-2-ethylhexyl phthalate [MEHP], mono-(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP], mono-(2-ethyl-5-oxohexyl) phthalate [MEOHP], mono-butyl phthalate [MBP], mono-benzyl phthalate [MBzP], monomethyl phthalate [MMP], and mono-ethyl phthalate [MEP]) were determined using liquid chromatography linked to tandem mass spectrometry. The reproductive development measurements included bone age (for both genders), testicle size (for boys), uterus size, and ovarian volume (for girls). We reported results of 133 children with complete data by applying generalized estimating equations for the repeated continuous outcomes. After controlling for Tanner stage, we detected a significant association between reduced uterus size and increasing phthalate exposure in the 2(nd) tertile relative to the 1st tertile of creatinine-corrected MEHP (B=-0.40; 95% C.I.: -0.73, -0.07, relative to the 1st tertile) and total DEHP (B=-0.39, 95% C.I.:-0.66, -0.01 for the 2nd tertile and B=0.34, 95% C.I.: -0.67, -0.01 for the 3rd tertile, relative to the 1st tertile) with a linear trend among girls. MBzP was also found negatively associated with bone age/chronological age ratio (B=-0.07, 95% CI: -0.13, -0.01 for the 3rd tertile, relative to the 1st tertile) with a linear trend for girls. We found no evidence of an association between phthalate exposure and ovarian volume or testicle size. This analysis suggests phthalate exposure may affect specific pubertal development characteristics in human beings. Further studies with larger sample sizes and longer follow-up period are warranted. Copyright © 2014. Published by Elsevier Inc.
    Environmental Research 11/2014; 136C:324-330. DOI:10.1016/j.envres.2014.10.026 · 4.37 Impact Factor
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    • "The widespread human exposure to phthalates has raised concerns for the general population and potentially susceptible subpopulations such as pregnant women and children . Recently, internal exposure to certain phthalates has been associated with various adverse health effects including obesity, neurodevelopmental and reproductive disorders (Swan et al., 2005; Sathyanarayana, 2008; Swan, 2008; Bornehag and Nanberg, 2010; Engel et al., 2010; Swan et al., 2010; Frederiksen et al., 2012; Teitelbaum et al., 2012; Braun et al., 2013; Miodovnik et al., 2014). "
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    ABSTRACT: Abstract Some phthalates and also bisphenol A (BPA) interfere with the human endocrine system and are labelled as reproductive toxicants. Children's exposure to these contaminants is suspected to be associated with developmental disorders and other health impairments. We provide biomonitoring data on 21 urinary phthalate metabolite and BPA levels in first morning urine of 8–10 year old children. Participants were children born between 1999 and 2002 of the Duisburg birth cohort (8–9 years, N = 113) and of the Bochum cohort study (8–10 years, N = 352). Additionally, for the Duisburg birth cohort we compare current data of children from Duisburg (8–9 years) with data from 2 years earlier when the children were 6–7 years old. We analyzed influences of important covariates on exposure levels by multiple regression analysis and those from two sampling time points by generalized equation estimation models adjusted for important covariates. Compared to recently published studies the phthalate metabolite and BPA concentrations were within the range of background levels. There were no significant differences between children from Bochum and Duisburg. Comparison between the two Duisburg birth cohort data sets (2007–2008 and 2009–2010) showed significant correlations for most of the phthalate metabolites (rSpearman between 0.25 and 0.51; p ≤ 0.05) but not for BPA (r = 0.162; p = 0.143). Most of the phthalate metabolites in the groups of the 6–7 and 8–9 years old Duisburg children were negatively associated with higher age, except for BPA concentrations with nearly constant levels. Exposure levels may be influenced by changes in child specific exposure patterns with age but also by the rapidly changing phthalate market.
    International Journal of Hygiene and Environmental Health 11/2014; 217(8):830-838. DOI:10.1016/j.ijheh.2014.06.001 · 3.83 Impact Factor
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