Effect of Polycyclic Aromatic Hydrocarbon Compounds (PAH’s) on Missed Abortions in Tianjin, China

Chen et al. (2010) examined the potential impact of PAH exposure on in-utero fetal death during early pregnancy, specifically missed abortions. Missed abortion refers to an intrauterine pregnancy in which the fetus does not develop normally over a prolonged period of time (typically 6 weeks) or the fetus is already known to have died but the products of conception remain in-utero. Missed abortion is a complication of early pregnancy that occurs in up to 15% of all clinically recognized pregnancies. The scientists conducted a case–control study examining the influence of maternal exposure to polycyclic aromatic hydrocarbons (PAHs), specifically BaP, a five-ring PAH whose metabolites are mutagenic and highly carcinogenic, on missed vs. induced abortions in Tianjin, an industrial city in northern China. Maternal blood, but not aborted tissues, tested showed BaP-DNA adduct levels were strongly associated with the risk of missed abortions. The BaP-DNA adduct levels in maternal blood were found to be significantly and positively associated with environmental exposure, including proximity of the residence to the nearest roadway, commuting by walking, traffic congestion near the residence, and daily average time outdoors.  BaP-DNA adduct levels were found to be negatively associated with the consumption of grilled, smoked, or barbecued foods. Rosemary Kulp
Chen, Y. Hou, H. Ritz, B. Wu, J. 2010.  Exposure to polycyclic aromatic hydrocarbons and missed abortion in early pregnancy in a Chinese population. doi:10.1016/j.scitotenv.2010.02.028

 Human exposure to PAHs occurs largely through inhalation and diet. PAHs adversely impact birth outcomes and cognitive development in early childhood; including decreased head circumferences, birth length, and birth weight.  In animal studies transplacental exposure to benzo[a]pyrene (BaP), a specific type of PAH, has been associated with an increase in xenobiotic (a chemical found in an organism but not normally produced or expected to be present in it, or a substances present in much higher concentrations than usual) metabolism in the placental tissues, fetal loss and a decrease in plasma hormone levels of progesterone; a steroid hormone involved in the female menstrual cycle, which supports gestation and embryogenesis of humans and other species. BaP has also been found to negatively affect estrogen levels and prolactin peptides; which control lactation during breastfeeding. It is hypothesized that fetuses may be particularly sensitive to the impact of toxic PAHs during early pregnancy (e.g. the 1st trimester) because of the rapid development of fetal organs and the higher exposure per body weight of the fetus.
The biologic mechanisms through which parental exposures to PAHs might affect early pregnancy loss are not well understood but may involve the induction of apoptosis (the process of programmed cell death that can occur in multicellular organisms) after DNA damage from PAHs, antiestrogenic effects of PAHs, and binding to the human aryl hydrocarbon hydroxylase to induce P450 enzymes or to receptors for placental growth factors, altering trophoblast (cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg proliferation as well as its endocrine function and decreasing exchange of oxygen and nutrients between the fetus and the mother. The endocrine system is a system of glands, each of which secretes a type of hormone into the bloodstream to regulate the body’s homeostasis.
This study was conducted in Tianjin, the second largest city in northern coastal China. It is an important industrial center and contains a developed sea–land–air transportation network. As one of the fastest growing areas in coastal China, the PAH’s levels are considered much higher than in rural areas. This study was conducted during a relatively warm period (April– November), reducing the potential for high PAH exposures from coal combustion during home heating. Data from the Tianjin Environmental Protection Agency showed BaP concentrations to be as high as 14.5 ng/m3 in January compared to only 1.3 ng/m3 in July of 2006.
All study participants were screened to exclude smokers, women with chronic diseases (e.g. hypertension, heart disease, and diabetes), pregnancy complications, women with potentially high occupational exposures to PAH’s like bus or taxi drivers, traffic police officers, coal plant workers, coke oven workers, cooks, etc, and those who had resided in the city for less than a year. After scrrening, aproximatly 80 control subjects and 90 test cases were used. Cases with missed abortions and controls seeking induced abortion services were gathered and recorded from four hospitals, including the Main Hospital of Tianjin Medical University, the 2nd Hospital of Tianjin Medical University, the Hospital of Chinese People’s Armed Police Forces, and Dongli Hospital. All four hospitals allowed the collection of aborted tissues, but only two of the hospitals gave permission for maternal blood drawings. Thus, maternal blood samples were collected for only a subset of the matched case–control pairs. However the other two hospitals were within a close distance (6 km) of the other two hospitals, and so were not adjusted for in the calculations.
Test cases were pregnant women carrying an in-utero fetus that was confirmed dead by ultrasound measurements before 14 weeks of gestation. Control cases were women with normal pregnancies who requested an induction of an abortion due to an unplanned and unwanted pregnancy. BaP levels were measured via biomarker in maternal blood and aborted tissues.
One hour after the abortion procedure the aborted tissues and maternal blood were collected and a standardized twenty minute interview was administered by trained personnel to the recipient of the procedure. During the interview the demographics and socioeconomic information was collected, as well as the reproductive history (e.g. previous abortion history, and number of previous birth to a fetus with a gestational age of 24 weeks or more); and any factors that may have lead to increased  exposure to PAHs during pregnancy, such as time spent outdoors and intransit (commuting), proximity to nearby industrial facilities, traffic activities near residence, cooking activities and fuels used, dietary PAH exposure via grilled, smoked, or barbecued foods, exposure to environmental tobacco smoke, etc.
Two ml of maternal blood were drawn from consenting women by syringe. The aborted tissue was analyzed in total because it is difficult to separate the villous (gastrointestinal polyps) from the embryo early in pregnancy, so all samples contained both embryo and villous materials together. Two different purification kits were used for the aborted tissue and the maternal blood in order to determine the levels of BaP in the aborted tissue and maternal blood.  BaP-DNA adducts (the places where BaP is taken up into the neurons) in extracted DNA were analyzed using the high-performance liquid chromatography-fluorescence method, a technique that can separate a mixture of compounds out so that certain compounds can be analyzed for concentration. This specific test detects benzo[a] pyrene diol-epoxide (BPDE) tetrols (a type of PAH) in the DNA adducts and from these concentrations BaP-DNA adduct levels were calculated by dividing the BPDE concentrations by the total DNA concentrations.
A set of multivariate conditional logistic regression models was used to examine the influence of the PAH adduct levels in maternal blood and aborted tissue on the risk of missed abortions. BaP-DNA adduct levels were modeled as a continuous exposure, and compared to subjects with higher adduct levels and those with lower adduct levels using the median adduct level in the control group as the cut point.
Approximately ninety percent (90.1%) of the study participants were between 20 and 35 years of age. Missed abortion subjects were less educated, reported lower monthly household income, and were somewhat younger than the control subjects seeking induced abortions. After controlling for maternal education and household income, maternal blood BaP-DNA level (per adduct/108 nucleotides) increased the risk of having experienced a missed abortion, and when the number of BaP-DNA adducts was categorized according to the median in the control group, the risk of a missed abortion was more than four times higher for those exposed above the fifty percent marker. 
BaP-DNA adducts in maternal blood correlated poorly and slightly negatively with the levels measured in aborted tissues (overall r=−0.12, n=102; cases r=−0.02, n=51; controls r=−0.21, n=51). BaP-DNA adduct levels in maternal blood were significantly higher in the case group.  The mean number of BaP-DNA adducts in the aborted tissues was somewhat lower in the case (4.8 adducts/108 nucleotides) than in the control group (6.0 adducts/108 nucleotides), however, this difference was not statistically significant (p=0.29).  Missed abortions were not associated with the BaP-DNA adducts in aborted tissues regardless of whetherthe adduct levels were treated as a continuous variable or not. 
There was an observed risk of increase for missed abortion in women who reported commuting by walking (adjusted OR=3.52; 95% CI, 1.44–8.57), traffic congestion near their residence (adjusted OR=3.07; 95% CI, 1.31–7.16), living near an industrial site (adjusted OR=3.21; 95% CI, 0.98– 10.48), and frequent cooking activities during pregnancy (adjusted OR=3.78; 95% CI, 1.11–12.87). Living close to a roadway and spending more time outdoors was also positively associated with missed abortion. Surprisingly, reporting the consumption of grilled, smoked, or barbecued foods seemed to decrease the risk of missed abortion even after adjustmant for socioeconomic factors (OR=0.22; 95% CI, 0.06–0.86). However, these foods were mostly consumed by women who reported cooking never, or occasionally, rather than routinely.
The lack of an association between missed abortion and PAH adduct levels in aborted tissue, as well as the absence of any correlation between maternal blood and aborted tissues DNA adduct levels in both cases and controls could be due to the more active and complex metabolism taking place in the rapidly developing placental and fetal cells of early pregnancy compared to the fully differentiated lymphocytes of the mother.
Other scientists have proposed that the placenta might act as a protective barrier against some genotoxic components between the circulation of mother and child. PAH-DNA adduct levels in placental tissues have been found to be influenced by the activity of the enzymes cytochrome P450-1A1 and glutathione Stransferases.  The overall average BaP-DNA adduct levels (including cases and controls) were about 26% higher in the aborted tissue than in maternal blood. The higher levels measured in aborted tissues in comparison to the maternal blood in this study might be due to the aborted tissues having been collected early in pregnancy when the fetal/villous tissues exhibit a very high metabolism rate in order to form a fully functional placenta.
This study shows that it cannot be assumed that PAH exposures preferentially effect missed abortions. It is even conceivable that the highest exposures lead to earlier spontaneous abortions that may or may not be clinically recognized by women.
The consumption of grilled, smoked, or barbecued foods seemed to decrease the risk of missed abortions while cooking frequently at home increased risk. However, intake of possibly high PAH food items was found to be associated with a low frequency of cooking at home, i.e. the less a woman reported cooking at home the more she may have eaten outside the home; and while this Chinese population seldom cooks, grills, smokes, or barbecues food at home, such foods are easily available from vendors outside the home. While missed abortions were associated with frequent cooking activities, statistically significant correlation were not found between cooking frequency and maternal blood PAH-DNA adduct levels. 

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