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Published in final edited form as: Epidemiology. 2012 Mar;23(2):353–356. doi: 10.1097/EDE.0b013e318246073e

Maternal Urinary Phthalates and Phenols and Male Genital Anomalies

Cécile Chevrier 1, Claire Petit 2, Claire Philippat 3, Marion Mortamais 4, Rémy Slama 5, Florence Rouget 6, Antonia M Calafat 7, Xiaoyun Ye 8, Manori J Silva 9, Marie-Aline Charles 10, Sylvaine Cordier 11
PMCID: PMC4724202  NIHMSID: NIHMS742840  PMID: 22317818

To the Editor

Concerns have been raised about adverse health effects from ubiquitous exposure during pregnancy to phthalates and phenols. Toxicologic data suggest that some of these compounds can disrupt the hormonal signaling that regulates male genital organogenesis. Evidence from the epidemiologic literature assessing association between in utero exposure to these compounds and male genital anomalies is limited and inconclusive.13

We evaluated whether prenatal exposure to select phthalates and phenols was associated with occurrence of hypospadias and undescended testes in a case-control study (eTable 1, http://links.lww.com/EDE/A558) nested in the EDEN and PELAGIE mother–child cohorts (5200 pregnant women).4 Cases of hypospadias (n = 21) and undescended testis (unilateral or bilateral, not in scrotum, n = 50) were identified during the first days after birth by pediatricians or midwives. Three controls per case were selected among male singleton live births, matched with cases for residence area, gestational age at urine sample collection, and date and day of collection (Sunday–Monday vs. other). Urinary concentrations of 11 phthalate metabolites and 9 phenols (samples collected in the morning, eTable 2, http://links.lww.com/EDE/A558), determined without knowledge of case-control status, were standardized by sampling conditions that varied among participants using a 2-step standardization method based on regression residuals as described previously.4 As an alternative exposure metric, we used a specific job-exposure matrix (JEM).2,3

In all, 13 women (9%) were classified as possibly exposed to phthalates in the workplace. No correlation between occupational exposure to phthalates and the urinary concentrations of phthalate metabolites was seen (eTable3, http://links.lww.com/EDE/A558). Due to the short-lived nature of these compounds, the morning urinary biomarkers do not necessarily capture occupational exposures, such that both exposure metrics might reflect complementary exposure sources. Using conditional logistic regression, we observed slightly reduced risks of hypospadias with increasing urinary concentrations of all phthalate metabolites (Table, eTable4, http://links.lww.com/EDE/A558). Increased risk of undescended testis was observed in association with the second or third tertiles of urinary concentrations of bisphenol A (BPA), 2,4-dichlorophenol, and ethylparaben compared with the first tertile (Table); increases were more pronounced among term boys (eTable5, http://links.lww.com/EDE/A558). The odds ratio (OR) for hypospadias associated with possible maternal occupational exposure to phthalates was 4.2 (95% confidence interval [CI] 0.4–41.3; 2 exposed cases and 2 exposed matched controls), whereas the OR for undescended testes was 0.3 (0.0–3.1; 1 exposed case and 6 exposed matched controls). A possible role of co-occurring compounds in the corresponding occupations (n = 9 hairdressers in our study) cannot be discarded.

TABLE.

ORs for Undescended Testis and Hypospadias According to Tertiles of Urinary Concentrations of Phthalate Metabolites and Phenols

Undescended Testis
Hypospadias
No. Controls No. Cases OR (95% CI)a Test for Trend No. Controls No. Cases OR (95% CI)a Test for Trend
Phthalate sums (nmol/L)
 Low-MWPb
  <1426c 48 19 1.00 P = 0.43 19 12 1.00 P = 0.06
  1426–3276 44 12 0.74 (0.3–1.9) 25   3 0.15 (0.02–0.9)
  ≥3276 57 19 0.67 (0.2–1.9) 13   4 0.19 (0.02–2.3)
 ΣDEHP metabolitesd
  <433 49 20 1.00 P = 0.35 18   8 1.00 P = 0.20
  433–986 51 17 0.72 (0.3–1.8) 19   8 0.60 (0.2–2.2)
  ≥986 49 13 0.60 (0.2–1.7) 20   3 0.21 (0.04–2.1)
 High-MWPe
  <676 49 19 1.00 P = 0.98 18 10 1.00 P = 0.07
  676–1591 50 15 0.78 (0.3–2.1) 20   6 0.22 (0.02–1.4)
  ≥1591 50 16 1.01 (0.3–2.9) 19   3 0.05 (0.00–1.5)
Phenols (μg/L)
 Bisphenol A
  <2.2 42 12 1.00 P = 0.97   6   4 NA
  2.2–4.7 36 17 2.54 (0.8–7.9) 11   4
  ≥4.7 35   9 1.03 (0.3–3.2) 13   2
 Benzophenone 3
  <0.7 43 19 1.00 P = 0.24   5   4 NA
  0.7–2.7 30 12 0.87 (0.3–2.5) 17   4
  ≥2.7 40   7 0.51 (0.2–1.5)   8   2
 Triclosan
  <4 33 12 1.00 P = 0.64 15   3 NA
  4–51 39 10 0.59 (0.2–1.7)   9   3
  ≥51 41 16 0.74 (0.3–2.1)   6   4
 2,4-dichlorophenol
  <0.6 33   7 1.00 P = 0.63 14   4 NA
  0.6–1.4 39 20 2.41 (0.7–8.6) 10   3
  ≥1.4 41 11 0.93 (0.2–3.5)   6   3
 2,5-dichlorophenol
  <4.1 33 14 1.00 P = 0.54 14   6 NA
  4.1–14.2 38   9 0.44 (0.1–1.5) 11   1
  ≥14.2 42 15 0.61 (0.2–1.8)   5   3
 Methylparaben
  <66 37 14 1.00 P = 0.32 10   3 NA
  66–213 37   8 0.79 (0.3–2.4) 11   6
  ≥213 39 16 1.64 (0.6–4.5)   9   1
 Ethylparaben
  <0.6 38 12 1.00 P = 0.14   9   5 NA
  0.6–4.0 37   9 0.72 (0.2–2.7) 12   5
  ≥4.0 38 17 2.12 (0.7–6.2)   9   0
 Propylparaben
  <5 37 16 1.00 P = 0.62 10   2 NA
  5–25s 38 11 1.13 (0.4–3.4) 10   4
  ≥25 38 11 1.34 (0.4–4.2) 10   4
 Butylparaben
  <0.7 36 13 1.00 P = 0.98 11   4 NA
  0.7–7.3 35 13 1.01 (0.3–2.9) 13   3
  ≥7.3 42 12 1.01 (0.3–3.0)   6   3
 Paraben sumf (nmol/L)
  <500 37 14 1.00 P = 0.39 11   3 NA
  500–1636 38 10 0.90 (0.3–2.6) 10   6
  ≥1636 38 14 1.60 (0.6–4.6)   9   1
a

Conditional logistic model adjusted for maternal age (categories), parity (categories), educational level, gestational duration (continuous), creatinine (continous).

b

Comprises MEP, MBP, MiBP.

c

Reference category.

d

Comprises the 4 metabolites of DEHP measured (ie, MEHP, MEOHP, MEHHP, MECPP).

e

Comprises MCNP, MCOP, MECPP, MEHHP, MEOHP, MEHP, MBzP, MCPP.

f

Comprises methylparaben, ethylparaben, propylparaben, butylparaben.

MWP indicates molecular weight phthalates; Σ, sum; NA, not available because of limited sample size.

The main limitation of our study was the modest sample size, especially for results concerning phenols (available only in the EDEN cohort). Despite consistency with their estrogenic molecular activity, findings reported for phenols are subject to special caution because they are not supported by animal data. The use of a single spot urine sample may not efficiently reflect the average level of weekly or monthly exposure for compounds such as di(2-ethylhexyl) phthalate (DEHP) and BPA with an important dietary pathway,57 but it provides reliable exposure measures for low-molecular-weight phthalates and parabens, likely due to regular use of personal-care products.5,7

Our prospective study did not show evidence of increased risks of male genital anomalies with prenatal exposure to phthalates. We did not confirm the inverse relation between prenatal DEHP exposure and testicular descent (assessed at approximately 1 year old) previously suggested by a study relying on 12 cases1; both the earlier study and our study found no increased risk for other phthalates.1 In contrast, we observed an unexpected decrease in the risk of hypospadias with increased concentrations of maternal urinary phthalate metabolites, for which we have no clear explanation. We speculate on a possible role of PPAR (peroxisome proliferator-activated receptors) ligands (known for some phthalates) and its critical role in placenta development, as previously proposed.8

Supplementary Material

e Table

Acknowledgments

We are indebted to the cohort members and to the medical staff that participated in these projects. We acknowledge the CDC staff for technical assistance in measuring the urinary concentrations of phthalate metabolites, phenols, and creatinine. We thank Bernard Jégou and Jacques Auger for their helpful comments and Jo Ann Cahn for editing the manuscript.

This work was supported by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES). The EDEN cohort is funded by the FRM, Inserm, IReSP, Nestlé, the French Ministry of Health, ANR, Univ. Paris-Sud, InVS, ANSES, and MGEN. The PELAGIE cohort is funded by Inserm, French Ministry of Health, French Ministry of Labor, ANSES, ANR, and InVS. The funding sources had no role in the study design, collection, data interpretation, report writing, nor in the decision to submit the paper for publication. The authors reported no other financial interests related to this research.

Footnotes

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author.

Contributor Information

Cécile Chevrier, Email: cecile.chevrier@rennes.inserm.fr, IRSET, Inserm, University Rennes I, Rennes, France.

Claire Petit, IRSET, Inserm, University Rennes I, Rennes, France.

Claire Philippat, Inserm U823, Team of Environmental Epidemiology applied to Reproduction and Respiratory, Health Institut Albert Bonniot, University Joseph Fourier Grenoble, Grenoble, France.

Marion Mortamais, Inserm U823, Team of Environmental Epidemiology applied to Reproduction and Respiratory, Health Institut Albert Bonniot, University Joseph Fourier Grenoble, Grenoble, France.

Rémy Slama, Inserm U823, Team of Environmental Epidemiology applied to Reproduction and Respiratory, Health Institut Albert Bonniot, University Joseph Fourier Grenoble, Grenoble, France.

Florence Rouget, IRSET, Inserm, “Bien naître en Ille-et-Vilaine” Perinatal Network, Rennes, France.

Antonia M. Calafat, Centers for Disease Control and Prevention, Atlanta, GA

Xiaoyun Ye, Centers for Disease Control and Prevention, Atlanta, GA.

Manori J. Silva, Centers for Disease Control and Prevention, Atlanta, GA

Marie-Aline Charles, Inserm U1018, CESP, Team Epidemiology of diabetes, obesity and renal disease: lifelong approach Villejuif, France.

Sylvaine Cordier, IRSET, Inserm, University Rennes I, Rennes, France.

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