title: ATP-binding cassette transporters in reproduction: a new frontier.
abstract: BACKGROUND
  The transmembrane ATP-binding cassette (ABC) transporters actively efflux an array of clinically relevant compounds across biological barriers, and modulate biodistribution of many physiological and pharmacological factors. To date, over 48 ABC transporters have been identified and shown to be directly and indirectly involved in peri-implantation events and fetal/placental development. They efflux cholesterol, steroid hormones, vitamins, cytokines, chemokines, prostaglandins, diverse xenobiotics and environmental toxins, playing a critical role in regulating drug disposition, immunological responses and lipid trafficking, as well as preventing fetal accumulation of drugs and environmental toxins.
  
  
  METHODS
  This review examines ABC transporters as important mediators of placental barrier functions and key reproductive processes. Expression, localization and function of all identified ABC transporters were systematically reviewed using PubMed and Google Scholar websites to identify relevant studies examining ABC transporters in reproductive tissues in physiological and pathophysiological states. Only reports written in English were incorporated with no restriction on year of publication. While a major focus has been placed on the human, extensive evidence from animal studies is utilized to describe current understanding of the regulation and function of ABC transporters relevant to human reproduction.
  
  
  RESULTS
  ABC transporters are modulators of steroidogenesis, fertilization, implantation, nutrient transport and immunological responses, and function as 'gatekeepers' at various barrier sites (i.e. blood-testes barrier and placenta) against potentially harmful xenobiotic factors, including drugs and environmental toxins. These roles appear to be species dependent and change as a function of gestation and development. The best-described ABC transporters in reproductive tissues (primarily in the placenta) are the multidrug transporters p-glycoprotein and breast cancer-related protein, the multidrug resistance proteins 1 through 5 and the cholesterol transporters ABCA1 and ABCG1.
  
  
  CONCLUSIONS
  The ABC transporters have various roles across multiple reproductive tissues. Knowledge of efflux direction, tissue distribution, substrate specificity and regulation of the ABC transporters in the placenta and other reproductive tissues is rapidly expanding. This will allow better understanding of the disposition of specific substrates within reproductive tissues, and facilitate development of novel treatments for reproductive disorders as well as improved approaches to protecting the developing fetus.
authors.affiliation: Laboratory of Translational Endocrinology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: E
authors.initials: E
authors.lastname: Bloise
authors.affiliation: Laboratory of Translational Endocrinology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: T M
authors.initials: TM
authors.lastname: Ortiga-Carvalho
authors.affiliation: Division of Human Reproduction, Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: F M
authors.initials: FM
authors.lastname: Reis
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8 Department Obstetrics & Gynecology, University of Toronto, Toronto, ON, Canada Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: S J
authors.initials: SJ
authors.lastname: Lye
authors.affiliation: Department of Obstetrics & Gynecology, University of Ottawa, Ottawa, ON, Canada Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Gibb
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8 Department Obstetrics & Gynecology, University of Toronto, Toronto, ON, Canada Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada stephen.matthews@utoronto.ca.
authors.forename: S G
authors.initials: SG
authors.lastname: Matthews
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D006801:Humans; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D012098:Reproduction / Q000235:genetics / Q000502:physiology*; D014018:Tissue Distribution
chemical_list: D018528:ATP-Binding Cassette Transporters
keywords: ABC transporters; breast cancer-related protein; decidua; fetal membranes; multidrug resistance-associated proteins; myometrium; ovary; p-glycoprotein; placenta; testes