The trophoblast clock controls transport across placenta in mice

Abstract

In mammals, 24-h rhythms of physiology and behavior are organized by a body-wide network of clock genes and proteins. Despite the well-known function of the adult circadian system, the roles of maternal, fetal and placental clocks during pregnancy are poorly defined. In the mature mouse placenta, the labyrinth zone (LZ) is of fetal origin and key for selective nutrient and waste exchange. Recently, clock gene expression has been detected in LZ and other fetal tissues; however, there is no evidence of a placental function controlled by the LZ clock. Here, we demonstrate that specifically the trophoblast layer of the LZ harbors an already functional clock by late gestation, able to regulate in a circadian manner the expression and activity of the xenobiotic efflux pump, ATP-binding cassette sub-family B member 1 (ABCB1), likely gating the fetal exposure to drugs from the maternal circulation to certain times of the day. As more than 300 endogenous and exogenous compounds are substrates of ABCB1, our results might have implications in choosing the maternal treatment time when aiming either maximal/minimal drug availability to the fetus/mother.

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

“…placental trophoblast cell line (BeWo) cell line, ABCB1 mRNA expression and ABCB1 protein levels were found to have rhythms peaking at 30 and 36 hours after circadian clock synchronization. 81 Overall, the removal of xenobiotics through P-gp is a phenomenon that occurs in various organs, and the confluence of data generally shows higher efflux activity during the active phase consistent with what has been observed in the brain. The precise peaks and troughs vary among organs and animal species; however, the underlying timekeeping mechanism is likely the same.…”

“…In addition, in the human placental trophoblast cell line (BeWo) cell line, ABCB1 mRNA expression and ABCB1 protein levels were found to have rhythms peaking at 30 and 36 hours after circadian clock synchronization. 81 Overall, the removal of xenobiotics through P-gp is a phenomenon that occurs in various organs, and the…”

From gestational chronodisruption to noncommunicable diseases: Pathophysiological mechanisms of programming of adult diseases, and the potential therapeutic role of melatonin

“…Key mediators in this transfer of information to the fetus include maternal melatonin and maternal glucocorticoids. Nevertheless, further research is crucial to fully understand the intricate circadian relationship between the mother, placenta, and fetus 73–75 …”

Dietary Habit-Induced Gynecologic Disorders in Young Female Students – Lessons from Rodent Experiments

“…For the fetus that cannot receive light stimulation in the uterus, transplacental glucose transport from maternal blood after food intake can be a direct signal to detect the maternal circadian rhythm during pregnancy [29]. A recent study reported that the trophoblast controls transport across the placenta in mice during pregnancy by regulating the circadian expression and activity of the xenobiotic efflux pump, ATP-binding cassette sub-family B member 1 (ABCB1) [30]. Accordingly, we speculate that the uterus is prepared to synchronize its function with food intake to provide an adequate environment for the fetus.…”