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.

Keywords: ABC transporters; breast cancer-related protein; decidua; fetal membranes; multidrug resistance-associated proteins; myometrium; ovary; p-glycoprotein; placenta; testes.

Figure 1

Selected ABC transporters are important mediators of key reproductive processes. ABC transporters actively efflux numerous clinically relevant compounds from cells, playing critical physiological and protective roles in regulating drug disposition, immunological responses and lipid trafficking, as well as preventing accumulation of environmental toxins. As such, ABC transporters are important factors in the regulation of gametogenesis, embryogenesis, embryo/fetal development and parturition.

Figure 2

ABC transporters in the maternal–fetal interface. The best-described placental ABC transporters are the multidrug transporters P-gp, BCRP, the multidrug resistance protein 3 (MDR3), the MRPs 1,2,3 and 5 and the cholesterol transporters ABCA1 and ABCG1. ABC transporters localized to the syncytiotrophoblast can efflux substrates toward the fetal or maternal sides. Those on the basolateral membrane will assist in the transfer of factors from the mother to the fetus, while those on the apical surface prevent transfer of factors across the placenta toward the fetus. A number of transporters have been localized to the endothelial cells of the fetal capillaries, however, little is known as to their specific cellular localization, as well as the direction of efflux.