title: The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.
abstract: More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders.
  
  
  
  The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism.
  
  
  
  A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data.
  
  
  
  The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder.
  
  
  
  The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field.
authors.affiliation: Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark jens.peter.ellekilde.bonde@regionh.dk.|Institute of Public Health, University of Copenhagen, DK-1016 Copenhagen K, Denmark.
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: Bonde
authors.affiliation: Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark.
authors.forename: Esben Meulengracht
authors.initials: EM
authors.lastname: Flachs
authors.affiliation: The Royal Library/ University of Copenhagen Library, DK-2200 Copenhagen N, Denmark.
authors.forename: Susie
authors.initials: S
authors.lastname: Rimborg
authors.affiliation: Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark.
authors.forename: Clara Helene
authors.initials: CH
authors.lastname: Glazer
authors.affiliation: Molecular Reproductive Medicine, Department of Translational Medicine, Lund University, Lund, Sweden.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Giwercman
authors.affiliation: Institute of Public Health, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Cecilia Høst
authors.initials: CH
authors.lastname: Ramlau-Hansen
authors.affiliation: National Research Centre for the Working Environment, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Karin Sørig
authors.initials: KS
authors.lastname: Hougaard
authors.affiliation: Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark.|Department of Clinical Epidemiology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark.
authors.forename: Birgit Bjerre
authors.initials: BB
authors.lastname: Høyer
authors.affiliation: Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark.
authors.forename: Katia Keglberg
authors.initials: KK
authors.lastname: Hærvig
authors.affiliation: Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark.
authors.forename: Sesilje Bondo
authors.initials: SB
authors.lastname: Petersen
authors.affiliation: Department of Occupational and Environmental Medicine, University of Lund, SE-221 85 Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rylander
authors.affiliation: Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark.
authors.forename: Ina Olmer
authors.initials: IO
authors.lastname: Specht
authors.affiliation: Department of Clinical Epidemiology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Toft
authors.affiliation: Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark.|Research Center for Prevention and Health (RCPH), University of Copenhagen, DK-2600 Glostrup, Denmark.
authors.forename: Elvira Vaclavik
authors.initials: EV
authors.lastname: Bräuner
mesh_terms: D003456:Cryptorchidism / Q000139:chemically induced; D052244:Endocrine Disruptors / Q000633:toxicity*; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007021:Hypospadias / Q000139:chemically induced; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000139:chemically induced; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000453:epidemiology*; D012307:Risk Factors; D055101:Semen Analysis; D013736:Testicular Neoplasms / Q000139:chemically induced; D015262:Xenobiotics / Q000633:toxicity
chemical_list: D052244:Endocrine Disruptors; D015262:Xenobiotics
keywords: cryptorchidism; endocrine disruption; hypospadias; infertility; prenatal exposure; sperm count; testicular cancer; xenobiotics