title: In utero exposure to benzophenone-2 causes hypospadias through an estrogen receptor dependent mechanism.
abstract: OBJECTIVE
  Additives such as benzophenone-2 are commonly used in cosmetic products and food container plastics to filter out ultraviolet light. In pregnant women exposure may result in transplacental transfer of benzophenone-2 to fetuses. Benzophenone-2 is estrogenic in vitro and in the rat uterotropic assay. Estradiol causes hypospadias in mice and estrogen-like compounds are also postulated to cause hypospadias. We determined whether hypospadias would develop in male mice exposed to benzophenone-2 in utero and whether this outcome depended on estrogen receptor pathways.
  
  
  METHODS
  Timed pregnant C57BL/6 mice were administered benzophenone-2 (6.25 mg) or control vehicle by oral gavage from gestational days 12 through 17 and they were sacrificed on day 18. Fetuses were weighed and sexed, anogenital distance was measured and genital tubercles were harvested for paraffin sections or quantitative reverse transcriptase-polymerase chain reaction analysis of genes purportedly involved in genital tubercle development.
  
  
  RESULTS
  Eight of 57 benzophenone-2 treated male fetuses (14%) whose genital tubercles were examined histologically had hypospadias (p = 0.0064). Co-administration of benzophenone-2 with the estrogen receptor antagonist EM-800 resulted in normal genital tubercles, ie no hypospadias, in 26 of 26 mice. Likewise no EM-800 or control treated male genital tubercles showed hypospadias. Benzophenone-2 treated male mice had no changes in body mass adjusted anogenital distance relative to controls. Reverse transcriptase-polymerase chain reaction revealed that genital tubercles of benzophenone-2 treated male mice expressed higher levels of estrogen receptor-beta relative to male controls (p = 0.04).
  
  
  CONCLUSIONS
  These findings suggest that benzophenone-2 may cause hypospadias via signaling through the estrogen receptor. Further study of human benzophenone-2 exposure and its effects is needed to support this hypothesis.
authors: Department of Urology, University of California-San Francisco, San Francisco, California, USA. mhsieh@urology.ucsf.edu
authors: Michael H
authors: MH
authors: Hsieh
authors: Erin C
authors: EC
authors: Grantham
authors: Benchun
authors: B
authors: Liu
authors: Reginald
authors: R
authors: Macapagal
authors: Emily
authors: E
authors: Willingham
authors: Laurence S
authors: LS
authors: Baskin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001577:Benzophenones / Q000633:toxicity*; D005260:Female; D005837:Genitalia, Male / Q000196:embryology* / Q000378:metabolism; D007021:Hypospadias / Q000139:chemically induced* / Q000196:embryology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011960:Receptors, Estrogen / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001577:Benzophenones; D011960:Receptors, Estrogen; C035476:2,2',4,4'-tetrahydroxybenzophenone