Formation and Retention of Cotinine during Placental Transfer of Nicotine in Human Placental Cotyledon

Abstract

Maternal smoking during pregnancy causes reduction of fetal breathing movements, an effect attributed to nicotine in fetal blood. Nicotine is metabolized to cotinine which has a long plasma half-life and exhibits slow clearance across membrane barriers. It is also known to activate placental phospholipase-A₂-like enzymes, resulting in formation of prostaglandins. Therefore, we studied transport of nicotine in isolated perfused cotyledon of normal human term placenta. The placental cotyledon was perfused with aerated (21% O₂, 5% CO₂) Krebs-Ringer bicarbonate buffer (pH 7.4, 37°C) containing 2% albumin on both maternal (230 ml, 15 ml/min, 35 mm Hg) and fetal (93 ml, 1.75 ml/min, 70 mm Hg) sides in a closed recirculating system. Nicotine (2 mg) was added to the maternal perfusate; perfusate samples (1 ml) were collected from both sides at regular intervals and analyzed for nicotine and cotinine by high-pressure liquid chromatography. This study gave the following results: (1) In about 60–80 min, 18.6% of the nicotine added to the maternal perfusate was transferred to the fetal perfusate, and the maternal/fetal concentration ratio reached 1.0. These results show rapid placental transfer of nicotine, consistent with its high lipid solubility. (2) Less than 1% is metabolized to cotinine in placenta. The ratio of cotinine concentrations in maternal and fetal perfusates reached 1.0 in about 40 min. These studies were also verified using ¹⁴C-nicotine. (3) Maximal reduction in fetal breathing movements occurs at about 30 min, and recovery occurs at 90 min after tobacco smoking by the mother. These observations agree with the rate of placental transfer of nicotine. (4) When nicotine was added on the fetal side, part of it was metabolized to cotinine. However, the maximal concentration of cotinine was twice higher on fetal than on maternal side. These observations suggest that accumulation of cotinine on fetal side may activate prostaglandin formation and trigger spontaneous abortions in pregnant smokers.

Maternal Smoking, Intrauterine Growth Restriction, and Placental Apoptosis

“…The placenta retains substantial amounts of compounds from cigarette smoke, both in their native forms and in intracellular substrates [32,33]. Cotinine levels in plasma have been shown to correlate with uteroplacental vascular resistance estimated from blood flow velocity measures by Doppler [4,34].…”

Quantification of nicotine, cotinine, trans-3′-hydroxycotinine, nornicotine and norcotinine in human meconium by liquid chromatography/tandem mass spectrometry

“…[4] Nicotine readily crosses the placenta with less than 1% converted to cotinine. [5] No published reports describe the placental transfer of cotinine, OH-cotinine, nornicotine or norcotinine or the fetus' metabolic capabilities, although cotinine has been detected in the placenta, amniotic and coelomic fluids. [6,7] Several neonatal matrices are available for monitoring in utero nicotine exposure, including hair, urine, plasma and meconium.…”

Transgenerational Effects of Maternal Nicotine Exposure During Gestation and Lactation on the Respiratory System

“…Once it entered the amniotic fluid it is absorbed via the skin of the fetus [21]. Nicotine enters breast milk, and can reach concentrations that are approximately 2-3 times that in maternal plasma due to the partitioning of nicotine into the high-lipid-containing [22], more acidic milk [23,24].…”

“…This can be achieved in two ways: by having a direct effect on cells and/or by reducing the nutrient supply to the fetus during gestation and lactation. It has been shown that long-term nicotine exposure results in a predisposition for genetic instability [22,33,34]. This may result in changes in the genetic "program" that controls lung development, maintenance of lung structure and aging of lung tissue, which may render the lungs more prone to disease.…”