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PLACENTAL TOXICOLOGY Edited by B.V. Rama Sastry, D.S¢., Ph.D. Professor of Pharmacology Professor of Anesthesiology School of Medicine Vanderbilt University Medical Center Nashville. Tennessee CRC Press Boca Raton Ann Arbor London Tokyo 0 O~

CONTENTS I. Techniques: In Vitro Perfusion of Human Placenta ...................................................... I Hemmt.,, St'Im¢ider .-klcohol. Placental Function. and Fetal Gro~.,.th ........................................................... George I. Henderson and Steven Schenker 3. Smoking. Placental Function. and Fetal Growth ......................................................... 45 B. V. Rama Sastry attd t 7ctoria E. Janson -1.. Opioid Addiction. Placental Function. and Feta~ Growth ...........................................83 B.V. Rama Sast~3. 5. Opioid Receptors in Placenta and Their Functional Role ......................................... 107 Mahmoud S. Ahmed and Bojana Cemerikic 6. Cocaine Addiction. Placental Function. and Fetal Growth ....................................... 133 B. ~." R,tma Sastry 7. Placental Biogenic Amines and Their Transporters .................................................. 161 Vadivel Ganapatt~y and Frederick H. Leibach 8. Renin-Angiotensin System in Placenta ...................................................................... 175 Alan M. Poisner and Gregory J. Downing 9. Placental Enzymes: Cytbchrome P450s and Their Significance ............................... 197 :14o111 R. Juchau I0. Placental Metabolism or" Xenobtottcs .......................................................................... l.~ Raymond D. Harbison. Christopher J. Borgerr. and Christopher M. Tea)" II. HIV and the Placenta: Mechanisms of Transfer. Drug Therapy. and Drug "i'ox,~:,ty .................................................................................................... ... 239 Rodney I.Y. 14o, Conrad .14. Pereira. and Jashvant D. Unadkat 12. Environmental Agents and Placental Toxicity: Anticholinesterases and Other Insecticides ................................................................................................ 257 Ramesh C. Gupta Index .............................. : .............................................................................................. ~9 ~x

Chapter 3 SMOKING. PLACE.NTAL FU.NC'I'I()N. AND FETAL (;ROWTH B. V. Rama Sastry and Victnria E..|anson [I. Ill. iV. VII. CONTENTS Ao introduction .................................................................................................... ............. Smoking. Birth Weight. and Fetal Growth .......................................................... 46 Tobacco Smoke Components ............................................................................... I. Tobacco Alkaloids ........................................................................................... at) 2. Nitro,amines .................................................................................................... . 50 3. Tcbaccb Ga.~es ........................................... .. ..................................................... 5 .t. Metals .................................................................................................... ........... 52 Metabolism of Nicotine and its Placental Transfer .................................................... 52 A. Elimination and Metabolism of Nicotine ............................................................. 52 B. Cotinine Plasma Levels: Qualitative Marker of Smoking ................................... S# C. Placental Transfer or" Nicotine and its Metabolites ............................................. 55 D. The Human Placenta as a Metabolic Organ in Smokers ..................................... 56 .Maternal Smoking. Fetal Tobacco Syndrome. and R.eproducti~e To,cicit5 of Nicotine .................................................................................................... ............... 57 Maternal Smoking and Placental Function ................................................................. A. Mammal Smoking and Blood Flow in the lntervillous Spac, ............................ 38 B. Maternal Smoking and Depression of Amino Acid Uptake by Placenta ........... 60 C. Maternal Smoking and t.he Regulatory. Mechanisms for Amino Acid Upr,.kt b.~ Plactntal Trophobl~t Cells ................................................................ 60 I. The Gammaglutamyl Cycle ............................................................................. 2. Placental Acetvlcholine and Regulation .of Amino Au . Transport ............... 6_ 3. Phospholipid N=Methylation in Placental Pl~.sma Membrane and Amino Acid Transport ..................................................................................... -; Ox~d"-tix e E;:er~': Sour~¢.~ .rod P~a~ental Amino Acid T:';:n,port .................. :.'.-~ D. NIatema! Smoking and Transfer of Amino Acids from the Trophoblast to the Umbilical Circulation " ' E. Maternal Smoking and Function of Endothelial Cells in Human Placental Vasculature ............................................................................................ (55 Maternal Tobucco Smoking and Covalent DNA Adduct~ in the Human Placenta .................................................................................................... ....... ~ .Alterations m Amino Acid and Protein .Metabolism in Growth-Retarded Babies as Indicated by Blood Analysis ...................................................................... 67 Scope of Future Investigations ................................................................................... 70 A. Placental Compensator3." and Genetic F'a.ctors ............... : ...................................... -0 B. Genetic Factors in the Placental Toxicity of Tobacco Alkaloids ........................ "71

Plttt'ent~d C. Placental .Metabolism o( Tobacco Alkztlt_+~.~ ....................................................... 7 13. Influence of Environmental l=actor,~ and Other Abused on Placental Toxicity of Tobacco Smoke Compot+ents ....................................... 7 A,:k:;,,~ led,__,mc nt.-, .................................................................................................... ............. 72 References .................................................................................................... ......................... 73 I. INTRODUCTION Scientific literature published during the past century, indicates that cigarette smoking during pregnancy has significant adverse effects on the development of the fetus and the health and development of the newborn baby. The hazardous effects of smoking during pregnancy include possible abortion, fetal death, fetal growth retardation, and ,~hort- or )ong-ten'n developmental deficits in the infants. Concern about the exposure of pregnant women to tobacco dust and smoke has been expressed since 1868.. Abortion was frequent among women workers in .tobacco factories in Europe. There was also a high. rate of mortaliw among the infants of females in tobacco- feinted occupations. In 1935. Sorting and Wallace-" obse~,ed that cigarette smoking by preg- nant women increased fetal heart rate. and they speculated that this was probably due to transl~)lacental transfer of nicotine into fetal circulation. Campbell:.-" obsetwed that a woman who smoked heavily during pregnancy ~,as likely to have more difficulty during the course of pregnancy, parturition, and lactation than a nonsmoker. In 19~,0. lEssenberg and collabora- tors'* investigated the influence of nicotine and ~obacco smoke on pregnant albino rats. They found that the young of nicotine-treated as well as tobacco-smoke-exposed rats were under- weight compared to those of control untreated rats. These studies raised important questions about the effects of tobacco smoke and nicotine on intrauterine fetal growth retardation ~ IUGR). In 1957. Simpson* reported that babies of women smokers had significantly lower birth weight than those of nonsmokers. Simpson's studies were confirmed by several others in',-oi','mg more than half a million bir',hs. These studies have been discussed in detail in reports of the U.S. Surgeon'General.''~ In general, babies of p~gnant women smokers are 200 g lighter than babies born to comparable pregnant women who are nonsmokers. The mecha- nisms of smoking-induced IUGR and the role of placental function in IUGR have yet to Le established. A. SMOKING. BIRTH WEIGHT. AND FETAL GROWTH it: '~mok:,ng ~tudies. the birth ~,eights of babies in groups of smoking and nonsmoking women are expressed as mean birth weights. In some studies, the percentages of babies (of smoking and nonsmoking mothers) who at birth weighed less than a specified weight, namely 2500 g. were compared. According to the available evidence, maternal smoking during ~regnancy exe.,'t,s a retarding influence on fe',al grn~ th wh{ch i,~ manifested by decrease~;, high ~eight of the ;,nfant. The evidence that maternal smoking causes reduced birth weight is indicated by :he following:--`) I. Results are consistent in studies from many different countries, cultures, races, and geographical settings. 2. The relationship between smoking and reduced birth weight is independent of all other factors which affect birth weight, such as race. maternal size. socioeconomic status, and sex of the infant.

Smoking and Plat'et~tal Fum.'timl 47 3. This relationship is independent of gestationa[ age."' ~ [n other words, the infants smoking mothe~ are small For date r~ther than preterm t Figure I~. 4. There is a dose-response relationship between the degree of maternal smoking and fetal growth retardation.I"- The more a woman smokes during pregnancy, the greater the reduction in birth weight. This dose-response relationship is also independent of the gestational age of the fetus,I: 5. If a woman gives up smoking during pregnancy, her chance of deti~'ering a normal- weight baby is similar to that of a nonsmoker.=: Since the low birth weight associated with maternal smoking occurs at all gestationai ages and is not due ~o a significant reduction in mean gestation, it mus~ be due to a reduction in the rate of fetal growth. The pattern of fetal growth retardation ~ssociated with maternal smoking is a decrease in all dimensions." This indicates a common cause for the development of all organs of the fetus. The disparity in growth and development between the children of smokers and those of nonsmokers disappears by the age or" l I. indicating that maternal smoking produces reversibic intrauterine fetal _m'owth retardation." One of the requirements for the growth and maturation or" all organs of th~ fetus is availability, or" essential amino acids and other nutrients. The fetus is dependent on the placental transfer of amino acids and other nutrients from maternal blood to fetal circulation. The requirement of essential amino acids for fetal growth is met only when these nutrients am available in t'eta! blood in requisite proportions and enter the fetal cells. Several factors will influence the transfer of nutrients from maternal blood into fetal circulation: (1) rate of maternal blood flow through the inter~iilous space. ~2~ pO: in 130 120 100 Non-Smokers Smokers 37 40 43 37 43 Weeks of Gestation FIGURE 1. Relationships between human infant birth weishts in ounces and gestation in weeks in nonsmokers and ~mokers. Smokers used less th~n one pack (20 cigarettes) per day. Gestat|on is expressed in completed weeks. Each vertical bar in.dicates gestation in weeks from ~7 to .t4 weeks. At each gcs~ational week. the menn birth weight of smokers" bab=es =s lower than ~nt of nonsmokers" babies. The dnt= in the figur~ :tin from a report by Butler and A.Iberman" involving 17.000 births in Great Brt~in.

4~ Placental T~.rtcnh~:4y 155 150 ~ 145 140 125 A B Non-Smokers Light-Smokers 120 37 40 43 37 ~0 43 C Heavy Smokers 37 40 43 Weeks of Gestation li~t smokm (~0 ci~y). ~d iC~ ~d ~v~ smoke~ (>~0 ci~uesldayL A¢ ~¢h smo~ng in¢~d PR ~d hmvy smo~ng i~m~d PR ~m ~ li~t smoking PR wh~ ~mp~ no~mo~'s P~ ~¢ ~ m ~e fi~ ~ from = s~y by Wing~ ¢~ ~.~= involving 7~ maternal blood. (3) uptake of amino acids and other nutrients by the p[acental trophobiast, (4) transfer of amino acids f~'om lxophoblast to umbilical circulation, and (5) rate of blood flow through the umbilical a~erial-venous system. Once amino acids and other basic nutrients enter the fetal circulation, their utilization by fetal tissues is dependent on (I) pO,. in the fetal blood and (2) uptake of amino acids by the fetal cells. Components of tobacco smoke may interfere with one or more steps in these processes and. therefore, utilization of essential amino acids and nutrients by the fetus. Placental weights ate either increased or less affected than birth weights by maternal smoking. As previously discussed, birth weights of infants axe affected by maternal smoking, and the deg~'~ of reduction in birth weight is related to the number of cigarettes smoked. Therefore. the ratio of placental weight to birth weight, or the placental ratio, tends to be larger for smokers than for nonsmokers fFigure 2).:'.~-~ The placenta] ratio increases with an increase in the degree of smoking, and this increase has been obce,,'ved at all ,.ze~ta;ional pe~ods." These observations indicate that a large or normal-size placenta tends to support the nutritional" transport requirements of a small fetus. Even then the effects of smoking on the growth of the fetus ate not overcome, and fetal gTowth is retarded in smokers. These observations suggest that smoking and tobacco components affect the functional efficiency of the placenta more than its size. B. TOBACCO SMOKE COMPONENTS The raw materials in a cigarette provide only a prelude to what happens when it is smoked. A lit cigarette generates more than 2000 known compounds by a number of processes responsive to temperature profiles. The lit cigarette has a steep temperature gradient. 880°C to 40°C, which can be demarcated into three reaction zones:=as (I) high temperature zone (900 to 600°C). which has 8% (v/v) hydrogen, 15% (v/v) carbon monoxide, and insignificant o 03 o~ o

49 TABLE i Ma.j.r Components in Tobucco Smoke Alkaloids .%;icotm= n. 1-2..~ mLz Tobacco g~es CO 16.2 mg 17.18 CO: H~dm~=n c~nid= Pul~nuc~¢ar aromatic h~dn~a~)n Mc~ Cu i qO n~ :1 Cd Hg 4 ng 21 Ni ~0 • ,Mainstream ~mok¢ or panicula¢e..,dcig:m=tt¢. amounts of oxygen: (2) the oxygen-depleter pyrolysis-distillation zone (600 to 100°C): and ~3) the low temperature zone (<100°C3. which contains about 12% oxygen. Mainstream smoke is formed within these zones by hydrogenation, pyrolysis, oxidation, decarboxylation, dehy- dration, chemical condensation, distillation, and sublimation. The exit temperature of the mainstream smoke is about 25 to 50°C depending on butt length. Sidesu'eam smoke is produced during smoldering of the cigarette at the peak temperatures inside the glowing cone (about 800=C/. The composition of mainstream and sidestream smoke varies depending on the type of tobacco, filler mamrials, packing density, additives, moisture, and the filters. Of all the tobacco smoke constituent.s, only a limited number of compounds have been investigated for human o~ad animal toxiciw,. The placental transt'cr and toxiciw, of any of these have been completely studied. For the purposes of this chapter, tobacco smoke components are divided into five groups: (1) tobacco alkaloids and their metaboiitcs. [2) nitrosamincs. [3~ tobacco gases. I J,) metals, and ~5~ ~oxic hydrocarbons (Tables [ and 2). I. Tobacco Alkaloids The smoking of a cigarette satisfies a .~moker's ph.~ siolo,='ical and p,,ycholo,='ical needs, and nicotine is generally regarded as the principal alkaloid responsible for the pharmacodynamic effects. There arc several other alkaloids in tobacco and tobacco smoke. Nicotine in tobacco smoke particulates is about 100 to 2~00 .Lt~cigarette. while all other minor alkaloids amount to 61 ¢o 199 g~cigarette (Table I. Figure 3). All of the other alkaloids have been compared to L-nicotine in several pharmacological systems.:-" All of them were less active than nicotine. the closest being anabasine, which is 18 to 7.5% as active as nicotine in different pharmaco- logical models.:* However. in these studies, optically pure nicotine was compared with racemic forms of other alkaloids for their pharmacological activities. Racemic anabasine is about 75% as active as L-nicotine in releasing catecholamines from rat adrenal glands.:= Optically pure anabasine may be as active as L-nicotine in releasing adrenal catechotamines. Them is no intbrmation on the chronic effects of other tobacco alkaloids in man or animals. More experimental work on other tobacco alkaloids is necessary, to determine their contribu- tion to the effects and toxicity or" tobacco smoke.

5O TABLE 2 Nitros-~mines in Tobacco and Tobacco Smoke" rig/cigarette" ~;itrns-~mine Tf~ha¢¢o sme~ke smoke 680 9.4 30O • Summanzad from data r~poncd by Brunnemann and Hoffmann.= Amounts vary type of cigm'elte and length of cigareRe (70--g5 gm long). Higher limit is estimated and not determined. Average values from Hecht et al."J bIicodne Dehydronicotine Nicotyrine Cot/nine Nor-cot/n/he Myosamin¢ Bipyridyl Ambasine Anatabine FIGURE 3. Common tobacco alkaloids in tobacco smoke. 2. Nitrosamines The nitrosamines in tobacco smoke can be divided into two ,m'oups: (l) volatile nitro- samines, including N-nitrosodimethylamine (NDMA), N-nitroethylmethylamine (N]~MA). N- nitrosodiethylarnine (NDF_A), and N-nia'osopyrrolidine (NPYR): and (2) tobacco-specific nitrosamines, including N-nitrosonomicotin¢ (NNN), 4-(N-methyl-N-nitrosamino)-4-(3- pyridyl)- 1-butanal (NNA), and 4-(N-methyl-N-nitrosamino)- l-(3-pyridyl)- l-butanone (NNK). Both volatile and tobacco-specific nitrosamines (Figure ,t) have been identified in mainstream smoke (Table 2). Volatile nitrosamines have also been identified in sidestream smoke of cigarctms and cigars, and their levels in sidest~am smoke am at least t0 times higher than in mainstream smoke. During I h in a smoke-filled indoor environment, one may inhale volatile nitrosamines in quantities equal to those in the mainstream smoke of 0.5 to 30 cigarettes. If the mother smokes, volatile nitrosarnines of sidestmara smoke may b~ harrnfi~l to the fetus and the nursing baby. However. i~ has yet to be determined whether volatile nitrosamines play a role in cancer induction in the lung. oral cavity., placenta, or other tobacco-related cancer sites.

/%., Several tobacco-re!areal nitrosamines have also been identified in :obacco smok.~ (Figure ¢. Table Z~. Of all .:.~e :obacco-s.~ific ,~itros-,.'n. ines. ~ NNN;. '-t-(N-me~yI-N-nitrosamino~- ~.- • 3-py.,mdy~)- i -:.'-ut:av:n¢ : ?iNK . .':-..'-.::r.~;:~pig~=.q.:_- . NP*.P). and N-~fitrosoanab~me :NAB) ~ ccnddered m _be tumomgenic or .':a~ireg~.~ic in exaedmenml animals.'--" NNK and NPIP "-= stronger :arc!nogens :hun NNN ann .";AS. 3. Tobacco Gases In addition to mcodne '--".d "'~,-. tobacco or a!_,g.a~=¢ smoke contains a dozen gases ~,Tabie of which carbon mono'dde, hydrege.-, cTanide, and nitrogen ex,de.~ ,a mixture of NO.. and NO., genervAly mea~ur.*d as NC:; a~ c: pharm,.,ucoiog;.cal significance.'-'-:° Each of these gases causes dssue hyg'oxla :hrough ~.ifferent mechanisms. The af.e.'ni~- of CO for hemog!obin is about .~C0 times that of ex'.:,='en.:" ~e:e.,'or=. CO displaces O: ~rom :ombinatien and forms carboxyhemoglobin .~ COHb). which is not capabie of respiratory, function. Carbon monoxide may also inhibit ~-.e ~-iac.*nta! "'t'acilitated oxygen :ransfer ~ystem'" ,*FOTS; and the placental cn.-bonic anhydrase.:".:° which r,-sults in an inc.-ease of the pCO:. The O: uptake by placenta .'armor be aw.dic:~" " . • ~, simv/e di,'guston or" O:. Therefore. a r'acilimted oxygen transfer system was proposed for placenta. This is a carv.e." system which does not require adenosine 5"-~.:'il:he~hate ).~,TP~.. It is irh~bited by CO. Nitrogen oxides oxidize me fe.-.ous ::vn of hemogiobin -:o :he fa."ric s:ate, r'orming methemogiobin IMHb. ~e.":ic hemoglobin), which is not capable of carrying ,:xygen. Cya- nides combine with me:hemoglobin..-'e,r:.-..ing cyanme:nemog!obin *.%tHb-CN:. ,vhich also ,:annct can:y oxygen.* F'ar:,ne:. cyanides :eversibly inhibit oxidative enzymes such as cytochrome oxidase ~,cy,'echrome ..~ 3) and dep.dve placental tissue of necessary oxygen. of these effects of gases in :obacco smoke are expected to cause, tissue hypoxia, which ~lepresses ceil function.

52 4. Metals About 30 metal.~, o( which special interest has be~n focussed on Ni. Cd. As. Ca. and Hg. have been identified ~n tobacco ~m~k¢ (Table I~. ~¢s¢ are present m [oh~cco pa~icula[es and are inhibitors of sulfahyd~'l ¢nzym¢~. All tbrms of Ni (m~tal and sanou. s~[~) are c=~no~en[cJ~.,~: Dudn~ ~mokin~. 10 ~o 20% o£ the Ni ~n the tobacco (~0 n~/ cig~ette) is t~nsfe~ed into mainstream smoke and is present in the gas phase ~ nickel carbonyl. Ni(COL. a carcinogen. [n mainstream smoke. 7 to 90 ng of Cd are present per cigarette.'s A heavy ~moker retains about 1.5 gg of C~ per day and ma~ accumulate up to 0.5 m~ through inhalation. Dependin~ on the smoking pa~tems of a smoker. 7 to I $% or" ~he total arsenic in cigarette tobacco * 12 ci~amtte~ is tmnsfe~ed imo the respiratory tract, and abou~ 50% or" this is deposited in the tissues.~ Due to ~eir cumu{ative natu~, all o~ ~ese m~mls ma~ accumulate in the placenta of a pmgn~t smoker ~d affect i~ Junction. II. METABOLISM OF NICOTINE AND ITS PLACENTAL TRANSFER Nicotine, the primary alkaloid of tobacco, has been extensively studied for its distribution. metabolism, and elimination both in animals-~`~ and man."z~: After its absorption into the blood (pH 7.4). about 69% of nicotine is ionized and 31% is nonionized. Less than 5% of the absorbed nicotine binds to plasma proteins.'-* Nicotine is distributed extensively to body tissues, with a steady-state volume of" distribution averaging 180 1 (2.5 times the body weight in kilograms). When nicotine concentrations have fully equilibrated, the amount of nicotine in the body tissues is 2.6 times the amount predicted by the product of the blood concentration and body weight. The. pattern of tissue uptake has been examined in tissues of rabbits by measuring concentrations of nicotine in various dssues after infusion of nicotine to a steady state. Spleen. liver, lungs, and brain have high concentrations of nicotine, whereas adipose tissue has a r~latively low concentration. After rapid intravenous (i.v.) injection, concentrations ot" nicotine decline rapidly because of its uptake by tissues. After i.v. injection, concentrations in arterial blood, lung. and brain are high, while concentrations in. tissues such as muscle and adipose (major storage tissues at steady state) are low. The uptake into the brain is rapid, occurring within 1 or 2 rain. and blood levels fail because of peripheral tlssde uptake for 20 or 30 rain after administration. Thereafter. blood concentrations decline slowly depending on rates ot" elimination and dismbution out of storage tissues. Nicotine is also secre~d into saliva."~ It is also identified in the freshly shampooed hair of smokers and of nonsmokers environmentally exposed to tobacco smoke,a-~ Nicotine is also secreted into breast milk. breast fluid of nonlactating women.-~.:: and cervical mucous.:" A. ELIMINATION AND METABOLISM OF NICOTINE Nicotine is metabolized primarily in the liver but also secondarily, to a small extent, in the lung."~ Renal excretion of unchanged nicotine depends on urinary pH and urine flow and may range from 2 to 35%. but typically accounts tbr 5 to 10% of total ellruination.:''-'~ The main metabolites of nicotine are eotinine, nicotine N'-oxide. and nomieotine (Figure 5). Codnine is formed in the liver in a two-step process: (I) oxidation or" position 5 or" the pyrrolidine ring in a cytochrome P450-mediated process to nicotine-.Av'r,iminium ionS: and I2) metabolism of iminium ion by a cytoplasmic aldehyde oxidase to cotinine2s Pan of the nicotine iminium ion (or intermediate carbinolamine) is convened stepwise into 7-3-pyridyl oxobutyric acid.