ATP-binding cassette transporters in reproduction: a new frontier

Bloise, Enrrico; Ortiga-Carvalho, Tânia M.; Reis, Fernando M.; Lye, Stephen J.; Gibb, William; Matthews, Stephen G.

doi:10.1093/humupd/dmv049

Cited by 84 publications

(174 citation statements)

References 196 publications

(245 reference statements)

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“…Impaired P-gp activity in tissue barriers profoundly impacts fetal phenotype [9]. Exposure of pregnant Abcb1a knock-out mice to the teratogen L-652,280, an ivermectin derivative and a P-gp substrate, resulted in 100% of fetuses bearing cleft palate on GD18.5, compared to no cleft palate in controls [23].…”

Section: Discussionmentioning

confidence: 99%

“…In this context, the efflux transporter P-glycoprotein (P-gp; encoded by the ABCB1 gene) plays a key role in fetal protection against xenobiotics and environmental toxins [9]. P-gp is localized in blood-barrier sites and actively effluxes numerous xenobiotics, steroids, toxins and cytokines out of cells.…”

Section: Introductionmentioning

confidence: 99%

“…P-gp is localized in blood-barrier sites and actively effluxes numerous xenobiotics, steroids, toxins and cytokines out of cells. In pregnancy, it functions as a “gatekeeper” preventing fetal accumulation of detrimental substances circulating in the maternal blood stream [9]. …”

Section: Introductionmentioning

confidence: 99%

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Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Bloise

Petropoulos

Iqbal

et al. 2017

Cell Physiol Biochem

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Background/Aims: Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp) efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB). As such, inhibition of P-gp at these blood-barrier sites may result in increased exposure of the developing fetus to environmental toxins and xenobiotics present in the maternal circulation. We hypothesized that viral exposure during pregnancy would impair P-gp function in the placenta and in the developing BBB. Here we investigated whether the TLR-3 ligand, polyinosinic:polycytidylic acid (PolyI:C), increased accumulation of one P-gp substrate in the fetus and in the developing fetal brain. Methods: Pregnant C57BL/6 mice (GD15.5) were injected (i.p.) with PolyI:C (5 mg/kg or 10 mg/kg) or vehicle (saline). [³H]digoxin (P-gp substrate) was injected (i.v.) 3 or 23h post-treatment and animals were euthanized 1h later. Maternal plasma, ‘fetal-units’ (fetal membranes, amniotic fluid and whole fetus), and fetal brains were collected. Results: PolyI:C exposure (4h) significantly elevated maternal plasma IL-6 (P<0.001) and increased [³H]digoxin accumulation in the fetal brain (P<0.05). In contrast, 24h after PolyI:C exposure, no effect on IL-6 or fetal brain accumulation of P-gp substrate was observed. Conclusion: Viral infection modeled by PolyI:C causes acute increases in fetal brain accumulation of P-gp substrates and by doing so, may increase fetal brain exposure to xenobiotics and environmental toxins present in the maternal circulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Bloise

Petropoulos

Iqbal

et al. 2017

Cell Physiol Biochem

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“…Intrauterine infection or chorionamnionitis are responsible for up to 40% of all PTD cases worldwide [3-7]. Important components of the pathophysiology of PTD, such as infection and/or inflammation, have been shown to influence the expression of selected ATP-binding cassette (ABC) transporters [8]. The ABC transporters comprise 50 proteins, subdivided into seven sub-families (ABCA through ABCG), that actively transport a wide array of substrates.…”

Section: Introductionmentioning

confidence: 99%

“…Placental ABC transporters exert a critical role regulating steroid transport, immunological responses and drug biodisposition. Importantly, the ABC transporters namely P-glycoprotein (P-gp; encoded by ABCB1 ); breast cancer resistance protein (BCRP; ABCG2 ) and specific multidrug resistance-associated proteins (MRPs; encoded by the ABCC subset) are important components of the placental syncytiotrophoblast barrier [8, 9]. They act as “gatekeepers” protecting the fetus against accumulation of potential harmful factors that may be present in the maternal circulation [8].…”

Section: Introductionmentioning

confidence: 99%

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

Império

Bloise

Javam³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression. Methods: Gene expression of 50 ABC transporters was assessed using TaqMan® Human ABC Transporter Array, in preterm human placentas without (PTD; n=6) or with histological chorioamnionitis (PTDC; n=6). Validation was performed using qPCR, immunohistochemistry and Western blot. MicroRNAs known to regulate P-glycoprotein (P-gp) were examined by qPCR. Results: Up-regulation of ABCB9, ABCC2 and ABCF2 mRNA was detected in chorioamnionitis (p<0.05), whereas placental ABCB1 (P-gp; p=0.051) and ABCG2 (breast cancer resistance protein-BCRP) mRNA levels (p=0.055) approached near significant up-regulation. In most cases, the magnitude of the effect significantly correlated to the severity of inflammation. Upon validation, increased placental ABCB1 and ABCG2 mRNA levels (p<0.05) were observed. At the level of immunohistochemistry, while BCRP was increased (p<0.05), P-gp staining intensity was significantly decreased (p<0.05) in PTDC. miR-331-5p, involved in P-gp suppression, was upregulated in PTDC (p<0.01) and correlated to the grade of chorioamnionitis (p<0.01). Conclusions: Alterations in the expression of ABC transporters will likely lead to modified transport of clinically relevant compounds at the inflamed placenta. A better understanding of the potential role of these transporters in the events surrounding PTD may also enable new strategies to be developed for prevention and treatment of PTD.

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Disruption of small molecule transporter systems by Transporter‐Interfering Chemicals (TICs)

Nicklisch

Hamdoun

2020

FEBS Letters

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Small molecule transporters (SMTs) in the ABC and SLC families are important players in disposition of diverse endo-and xenobiotics. Interactions of environmental chemicals with these transporters were first postulated in the 1990s, and since validated in numerous in vitro and in vivo scenarios. Recent results on the co-crystal structure of ABCB1 with the flame-retardant BDE-100 demonstrate that a diverse range of man-made and natural toxic molecules, hereafter termed transporter-interfering chemicals (TICs), can directly bind to SMTs and interfere with their function. TIC-binding modes mimic those of substrates, inhibitors, modulators, inducers, and possibly stimulants through direct and allosteric mechanisms. Similarly, the effects could directly or indirectly agonize, antagonize or perhaps even prime the SMT system to alter transport function. Importantly, TICs are distinguished from drugs and pharmaceuticals that interact with transporters in that exposure is unintended and inherently variant. Here, we review the molecular mechanisms of environmental chemical interaction with SMTs, the methodological considerations for their evaluation, and the future directions for TIC discovery.

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ATP-binding cassette transporters in reproduction: a new frontier

Cited by 84 publications

References 196 publications

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

Disruption of small molecule transporter systems by Transporter‐Interfering Chemicals (TICs)

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