Amniotic fluid phthalate levels and male fetal gonad function.
BACKGROUND
Prenatal exposure to phthalates may pose a threat to human male reproduction. However, additional knowledge about the in vivo effect in humans is needed, and reported associations with genital abnormalities are inconclusive. We aimed to study prenatal di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) exposure in relation to cryptorchidism, hypospadias, and human fetal Leydig cell function.


METHODS
We studied 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls. Second-trimester amniotic fluid samples were available from a Danish pregnancy-screening biobank (n = 25,105) covering 1980-1996. We assayed metabolites of DEHP and DiNP (n = 645) and steroid hormones (n = 545) by mass spectrometry. We assayed insulin-like factor 3 by immunoassay (n = 475) and analyzed data using linear or logistic regression.


RESULTS
Mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP, DEHP metabolite) was not consistently associated with cryptorchidism or hypospadias. However, we observed an 18% higher (95% confidence interval [CI] = 5%-33%) testosterone level, and a 41% lower (-56% to -21%) insulin-like factor 3 level in the highest 5cx-MEPP tertile compared with the lowest. Mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP, DiNP metabolite) showed elevated odds ratio point estimates for having cryptorchidism (odds ratio = 1.28 [95% CI = 0.80 to 2.01]) and hypospadias (1.69 [0.78 to 3.67]), but was not consistently associated with the steroid hormones or insulin-like factor 3.


CONCLUSIONS
Data on the DEHP metabolite indicate possible interference with human male fetal gonadal function. Considering the DiNP metabolite, we cannot exclude (nor statistically confirm) an association with hypospadias and, less strongly, with cryptorchidism.
From the aDepartment of Pediatrics, Regional Hospital of Randers; bPerinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark; cSchool of Bioscience, University of Nottingham, United Kingdom; dDanish Center for Neonatal Screening, Department of Clinical Biochemistry and Immunology, Statens Serum Institute, Copenhagen, Denmark; eDivision of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden; fDepartment of Occupational and Environmental Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; gReproductive Endocrinology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany; and hDanish Ramazzini Center, Department of Occupational Medicine, Aarhus University Hospital, Aarhus, Denmark.
Morten Søndergaard
MS
Jensen
Ravinder
R
Anand-Ivell
Bent
B
Nørgaard-Pedersen
Bo A G
BA
Jönsson
Jens Peter
JP
Bonde
David M
DM
Hougaard
Arieh
A
Cohen
Christian H
CH
Lindh
Richard
R
Ivell
Gunnar
G
Toft
D000328:Adult; D000653:Amniotic Fluid / Q000737:chemistry*; D016022:Case-Control Studies; D003456:Cryptorchidism / Q000453:epidemiology*; D003718:Denmark / Q000453:epidemiology; D004051:Diethylhexyl Phthalate / Q000032:analysis*; D004781:Environmental Exposure / Q000706:statistics & numerical data*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000032:analysis; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis; D007021:Hypospadias / Q000453:epidemiology*; D007118:Immunoassay; D007231:Infant, Newborn; D007328:Insulin / Q000032:analysis; D007985:Leydig Cells; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D013058:Mass Spectrometry; D010795:Phthalic Acids / Q000032:analysis*; D011247:Pregnancy; D011506:Proteins / Q000032:analysis
D012739:Gonadal Steroid Hormones; D007328:Insulin; C084797:Leydig insulin-like protein; D010795:Phthalic Acids; D011506:Proteins; C012125:diisononyl phthalate; D004051:Diethylhexyl Phthalate; D006854:Hydrocortisone