Impact of Pregnancy on the Levels of Selected Polycyclic Aromatic Hydrocarbons

Table 6: Adjusted geometric means with 95% confidence intervals in ng/L for 9-hydroxyfluorene by pregnancy by smoking status. Data from National Health and Nutrition Examination Survey 2001-2010.

Variability by pregnancy status, smoking status and race/ ethnicity

Pregnant females had lower adjusted levels than non-pregnant females for FLU2 (p=0.03), FLU3 (p<0.01), and PHE3 (Table 2, p<0.01). On the other hand, pregnant females had higher adjusted levels of PHE1 (p<0.01), PHE4 (p<0.01), and PYE1 (p=0.04) than nonpregnant females. When interactions between pregnancy and iron storage status was taken into account, the levels of FLU9, PHE1, PHE2, and PHE4, and PYE1 were (i) higher among pregnant females with absent iron than pregnant females with replete iron (p ≤ 0.01, Table 5), and (ii) higher among pregnant females with absent iron than nonpregnant females with absent iron (p ≤ 0.01, Table 5). In addition, when interaction between pregnancy and smoking status is taken into account (Table 6), for FLU9, (i) both pregnant and non-pregnant nonsmokers had lower levels (p<=0.03) than pregnant and nonpregnant smokers, (ii) pregnant nonsmokers had higher levels than non-pregnant nonsmokers but non-pregnant smokers had higher levels than pregnant smokers (p<0.01, Table 6).

Smokers had higher adjusted levels of all ten PAH metabolites than nonsmokers (p<0.01, Table 2). Observed levels of certain PAH metabolites for smokers, as compared to nonsmokers, were more than 8-fold higher. For example for FLU3, the observed levels were 58.6 and 493.3 ng/mL (Table 2, p<0.01) for nonsmokers and smokers respectively. For NAP2, smokers had higher levels than nonsmokers irrespective of race/ethnicity but the observed differences between smokers and nonsmokers varied with race/ethnicity (p<0.01, Table 3, 2572.7 vs. 12192.3 ng/L for NHW for a difference of 9619.6 ng/L, 2980.6 vs. 7770.2 ng/L for NHB for a difference of 4789.6 ng/L, 4282.7 vs. 9685.8 ng/L for MA for a difference of 5403.1 ng/L, and 3513.6 vs. 8254.3 for OTH for a difference of 4740.7 ng/L). Thus, smoker-nonsmoker difference for NAP2 for NHW was almost double of what it is for NHB, MA, and OTH.

NHW had higher adjusted levels than NHB for NAP2 (p=0.049), FLU2 (p=0.02), and PHE1 (p<0.01, Table 2). NHB had higher adjusted levels than MA for FLU3 (p=0.03) but the reverse was true for NAP2 (p<0.01). However, when interaction between race/ethnicity was taken into account, the later difference was applicable for nonsmokers only (Table 3).

Model fit

R2 varied from a low of 43.6% for the model for NAP1 to a high of 71.7% for the model for FLU3 (Table 7). Actual sample sizes used in the model varied from 605 for the model for PHE4 to 1726 for the model for PHE1 (Table 7).

Table 7: Regression slopes for continuous variables with associated p-values for polycyclic aromatic hydrocarbon variables used in the analysis for females aged 20-44 years. Data from National Health and Nutrition Examination Survey 2001-2010.

Association with age, body mass index, number of live births, poverty income ratio, urine creatinine, and fasting time

There was a positive association between age and the adjusted levels of all 10 PAH metabolites except PHE4 and PYE1 (Table 7, p ≤ 0.02). Adjusted levels of NAP2 (β=0.00566, p<0.01), FLU2 (β=0.00506, p<0.01), FLU9 (β=0.00761, p<0.01), PHE1 (β=0.00447, p<0.01), PHE2 (β=0.00953, p<0.01), and PHE4 (β=0.00459, p<0.01, Table 8) increased with increase in body mass index. There was a decrease in the levels of PHE2 (β=-0.02603, p<0.01) with increase in number of live births (Table 3). Poverty income ratio was negatively associated with the adjusted levels of NAP2 (β=-0.02533, p<0.01), FLU2 (β=-0.02843, p<0.01), FLU3 (β=-0.02431, p<0.01), PHE2 (β=-0.02441, p<0.01), PHE3 (β=-0.01334, p=0.03), and PYE1 (β=-0.03155, p<0.01, Table 7). Urine creatinine was positively associated with the levels of all ten PAH metabolites (p<0.01, Table 7). Fasting time was negatively associated with NAP1 (p=0.01), FLU2 (p=0.03), FLU9 (p<0.01), PHE2, PHE3, and PHE4 (p ≤ 0.01).

Table 8: Regression slopes for continuous variables with associated p-values for polycyclic aromatic hydrocarbon variables used in the analysis for females aged 20-44 years. Data from National Health and Nutrition Examination Survey 2001-2010.

Time trends

Over the time period 2001-2010, there was an increasing trend in the adjusted levels of NAP2 (β=0.0465, p<0.01) and PYE1 (β=0.11145, p<0.01, Table 7) among females aged 20-44 years of age. However, there was a decreasing trend in the adjusted levels of FLU2 (β=-0.01842, p<0.01), PHE2 (β=-0.0233, p<0.01) and PHE3 (β=-0.04047, p<0.01) over the study period.

Discussion

One of the primary objectives of this study was to evaluate differences between pregnant and non-pregnant females for each of ten PAH metabolites. As described in the next section, pregnancy was associated with higher levels of two PAH metabolites and lower levels of three PAH metabolites.

Impact of pregnancy

During pregnancy, female hormones including different estrogens and progesterone rise steadily until they peak at term. Female hormones at high concentrations influence hepatic drug metabolizing enzyme (DME) expression. Increase in concentrations of both estrogen and progesterone “… can potentially lead to additive, synergistic or antagonistic effects of these hormones on CYP expression” [45]. Expression and activity levels of these DMEs determine clearance of various drugs from the body. This may be the reason why the observed levels of the metabolites of naphthalene and fluorine were lower among pregnant females as compared with non-pregnant females and the observed levels of the metabolites of phenanthrene and pyrene were higher among pregnant females than non-pregnant females. Thus, the observed levels of PAH metabolites among pregnant females exhibit the net effect of modified drug clearance as well as drug transfer to the developing fetus via placenta. As such, even relatively higher drug levels during pregnancy when compared with non-pregnant state does not rule out the possibility of drug transfer to the developing fetus. At least, based on the statistical significance, levels of FLU2, FLU3, and PHE3 were lower during pregnancy when compared with nonpregnant state which, most likely, translates to the transfer of these metabolites to the developing fetus.

Impact of smoking and race/ethnicity

The fact that smokers had statistically significantly higher levels of each of the ten PAH metabolites than nonsmokers indicates how important it may be for the pregnant females to quit smoking, at least during the pregnancy, in the interest of protecting the developing fetus from harm. The racial/ethnic differences seen in the observed levels of PAH metabolites may be due to differences in how PAHs are metabolized by different race/ethnicities.

Association between PAH levels and age, body mass index, and poverty income ratio

Positive association between age and the adjusted levels of four of the 10 PAH metabolites indicate somewhat higher risk of adverse birth outcomes for relatively older females. During pregnancy, throughout gestation, there is an increase in total body water and adipose tissue resulting in higher body mass index. Positive association between body mass index and the adjusted levels of six of the 10 PAH metabolites indicate higher risk of relatively higher PAH levels among pregnant females when compared non-pregnant females on the average. Poverty income ratio was inversely associated with the levels of six of the 10 PAH metabolites. This implies lifestyles associated with low socioeconomic status have higher risk of exposure to PAHs.

Time trends in the levels of PAHs

When adjusted for other factors that affect PAH levels, the levels of NAP2 and PYE1 increased over the study period of 2001-2010. However, based on unadjusted analysis (data not shown), levels of every PAH metabolite increased over the study period among both pregnant and non-pregnant females. The biennial year increase in the levels of NAP1 (p<0.01) and NAP2 (p<0.01) among pregnant females were 4.3 ng/L and 5.4 ng/L respectively. These increases for FLU2 (p<0.01), FLU3 (p<0.01), and FLU9 (p<0.01) among pregnant females were 2.4 ng/L, 1.5 ng/L, and 2.2 ng/L every two year respectively. For phenanthrene metabolites also, biennial increases in the levels of PHE1 (p<0.01), PHE2 (p<0.01), PHE3 (p<0.01), and PHE4 (p<0.01) were 2.2 ng/L, 1.6 ng/L, 1.6 ng/L, and 1.4 ng/L respectively. Finally, levels of PYE1 increased by 1.9 mg/L (p<0.01) every two years. This should be of concern since higher levels of these metabolites are associated with adverse birth outcomes like low birth weight (Table S1).

Table S1: Time trends in the levels of selected PAH metabolites over 2001-2010 for pregnant and non-pregnant females aged 20-44 years old. Data from National Health and Nutrition Examination Survey 2001-2010.

Variability in PAH levels across different countries among pregnant females

Polanska et al. [35] found mean PYE1 levels to be 0.4 μ g/g creatinine among pregnant females from a prospective cohort study conducted in 8 regions of Poland. In this study, mean PYE1 levels were found to be 0.09 μg/g creatinine (data not shown) or about 5 times lower than those found in Poland, an observation confirmed by Polanska et al [5]. Personal exposure to PAHs via air has also been reported to be about 10-fold higher in Krakow, Poland as compared to New York City, USA [46]. In a study of Brazilian pregnant females [34], the levels of PYE1 were reported to be 0.02, 0.05, and 0.15 μ mol/mol creatinine for non-smokers, passive smokers, and active smokers.

Limitations of the Study

Limitations of this study dilute the confidence that can be associated with the results obtained from this study. Exposure to PAHs is affected, among many other factors, for example, by the coal used for cooking and heating, food and food processing, vicinity of the place of residence to heavy traffic and housing density, and distance from the place of residence to the main road. The contribution of these factors was not taken into account on exposure levels to PAHs while analyzing data for this study because of non-availability and/or limited availability of data for these factors. It is unknown, in what way, this may have affected the conclusions arrived at in this study. Next, crosssectional nature of the NHANES data with no knowledge of the timing and ongoing levels of exposure to PAHs generates a level of uncertainty about the value that can be attached with the conclusions arrived at from this study. Only a longitudinal follow up study from prepregnancy to post-pregnancy can provide a definitive determination of how the observed levels of PAHs vary from pre-pregnancy to pregnancy period. However, a longitudinal study of the size of NHANES may not be possible for practical and financial reasons.

Summary and Conclusion

In summary, (i) pregnant females had lower levels of FLU2, FLU3, and PHE3 than non-pregnant females, (ii) pregnant females had higher levels of PHE1 and PHE4 than non-pregnant females (iii) smokers had higher levels of every PAH metabolite than non-smokers, and (iv) un-adjusted levels of every PAH metabolite increased over 2001-2010 for pregnant and non-pregnant females.

It is of public health importance to develop educational and other medical/non-medical programs to enable general public to limit exposure to PAHs but these efforts should be made with additional vigor and resources for pregnant females because of the harms the exposures to PAHs can cause to the developing fetus. The harm to the developing fetus is not limited to the adverse birth outcomes like low birth weight, pre-term birth, and others but also the concomitant consequences like neurological deficiencies during early and late childhood. In the opinion of this author, education is the best tool to enable behavioral modifications as long as these programs focus on “what is right” and not “what is wrong and what can go wrong”. Consequently, future research efforts to minimize exposures to PAHs among pregnant females should focus on developing educational modules that can advise pregnant females on ways to modify day-today behavior (to minimize exposure to PAHs and other environmental contaminants) at home and outside home that is in the best interests of a healthy full-term live birth. Recently developed group prenatal counseling programs called centering pregnancy are very well suited to administer and use such educational modules. In a centering pregnancy prenatal counseling program, eight to twelve females with similar due dates meet regularly with a midwife or doctor trained as a facilitator monthly in the second trimester and every two weeks in the third trimester [47]. Usually, there are 10 counseling sessions each lasting about two hours. Topics discussed during these sessions include breastfeeding, nutrition, and childbirth. These sessions could be very useful for mutual support and sharing individual experiences with other pregnant females. This is the recommendation of this author that these counseling sessions be used to include 20-30 minute educational modules that provide guidance on how to make adjustments in day-today behavior that could make it possible to have full-term healthy live births by avoiding exposure to unnecessary environmental contaminants. It may be even more productive if one of the pregnant females in the group administers these modules.

References

1. ATSDR (2015) Agency for toxic substances and disease registry.
2. Boström C, Gerde P, Hanberg A, Jernström B, Johansson C,et al. (2002) Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient. Environ Health Perspect 110: 451-488.
3. Rehwagen M, Müller A, Massolo L, Herbarth O, Ronco A (2005) Polycyclic aromatic hydrocarbons associated with particles in ambient air from urban and industrial areas. Sci Total Environ 348: 199-210.
4. CDC (2015) Polycyclic aromatic hydrocarbons overview. Centers for disease control and prevention.
5. Polanska K, Hanke W, Dettbarn G, Sobala W, Gromadzinska J, et al. (2014) The determination of polycyclic aromatic hydrocarbons in the urine of non-smoking Polish pregnant women. Sci Total Environ 487: 102-109.
6. Perera FP, Tang D, Wang S, Vishnevetsky J, Zhang B, et al. (2012) Prenatal polycyclic aromatic hydrocarbon (PAH) exposure and child behavior at age 6-7 years. Environ Health Perspect 120: 921-926.
7. Adetona O, Li Z,Sjodin A, Romanoff LC, Aguilar-Villalobos M (2013) Biomonitoring of polycyclic aromatic hydrocarbon exposure in pregnant women in Trujillo, Peru – compaiosn of different fuel types used for cooking. Environ Int 53:1-8.
8. PolaÅ?ska K, Hanke W, Gromadzinska J, Ligocka D, Gulczynska E, et al. (2009)Ploisk mother and child cohort study – defining the problem, the aim of the study and methodological assumption. Int J Occup Med Environ Health 22: 383-391.
9. Jedrychowski W, Whyatt RM, Camman DE, Bawle UV, Peki K,et al. (2003) Effect of prenatal PAH exposure on birth outcomes and neurocognitive development in a cohort of newborns in Poland. Study design and preliminary ambient data. Int J Occup Med Environ Health16: 21-29.
10. Magnus P (2007) The nowegian mother and child cohort study (moba) – new research possibilities. NorskEpid 17: 107-110.
11. CDC (2015) National birth defects prevention study. Centersfor disease control and prevention.
12. Jedrychowski W, Perera FP, Tang D, Stigter L, Mroz E, et al. (2012) Impact of barbecued meat consumed in pregnancy on birth outcomes accounting for personal prenatal exposure to airborne polycyclic aromatic hydrocarbons: birth cohort study in Poland. Nutrition 28: 372-377.
13. PolaÅ?ska K, Hanke W, Sobala W, Brzeźnicki S, Ligocka D (2012) Exposure to polycyclic aromatic hydrocarbons and newborn biometric indicators. Int J Occup Med Environ Health 23: 339-346.
14. Salles DT, Mendez MA, Pessoa V, Guxens M, Aguilera I, et al. (2010) Smoking during pregnancy is associated with higher dietary intake of polycyclic aromatic hydrocarbons and poor diet quality. Pub Health Nutri13: 2034-2043.
15. Salles DT, Mendez MA, Meltzer HM, Alexander J, Haugen M (2013) Dietary benzo(a)pyrene intake during pregnancy and birth weight: associations modified by vitamin C intakes in the Norwegian mother and child cohort study (MoBa). Environ Int 60: 217-223.
16. Choi H, Perera FP (2012) Sources of greater fetal vulnerability to airborne polycyclic aromatic hydrocarbons among African Americans. J Epidemiol Community Health.66: 121-126.
17. Choi H, Wang L, Lin X, Spengler JD, Perera FP (2012) Fetal window of vulnerability to airborne polycyclic aromatic hydrocarbons on proportional intrauterine growth restriction. PLoS One 7: e35464.
18. Jedrychowski WA,Perera FP, Majewska R, Budzyn MD, Mroz E,et al. (2015) Depressed height gain of children associated with intrauterine exposure to polycyclic aromatic hydrocarbons (PAH) and heavy metals: the cohort prospective study. Environ Res 136: 141-147.
19. Langlois PH, Hoyt AT, Desrosiers TA, Lupo PJ, Lawson CC,et al. (2014) National birth defects prevention study. maternal occupational exposure to polycyclic aromatic hydrocarbons and small for gestational age offspring. Occup Environ Med 71: 529-35.
20. Wilhelm M, Ghosh JK, Su J, Cockburn M, Jerrett M, Ritz B (2011) Traffic-related air toxics and preterm birth: a population-based case-control study in Los Angeles County, California. Environ Health 10: 89.
21. Jedrychowski WA,Perera FP, Maugeri U, Majewska R, Mroz E, et al. (2015) Long term effects of prenatal and postnatal airborne PAH exposures on ventilatory lung function of non-asthmatic preadolescent children. Prospective birth cohort study in Krakow. Sci Total Environ 502: 502-509.
22. Jedrychowski WA, Perera FP, Camann D, Spengler J, Butscher M, et al. (2015) Prenatal exposure to polycyclic aromatic hydrocarbons and cognitive dysfunction in children. Environ SciPollut Res Int 22: 3631-3639.
23. Perera FP, Li Z, Whyatt R, Hoepner L, Wang S, et al. (2009) Prenatal airborne polycyclic aromatic hydrocarbon exposure and child IQ at age 5 years. Pediatrics 124: e195-e202.
24. Jedrychowski WA, Perera FP, Maugeri U, Budzyn MD, Mroz E, et al. (2010) Intrauterine exposure to polycyclic aromatic hydrocarbons, fine particulate matter and early wheeze. Prospective birth cohort study in 4-year olds. Pediatr Allergy Immunol 21: e723-e732.
25. Jedrychowski, WA,Perera FP, Majewska R, Camman D, Spengler JD, et al. (2014) Separate and joint effects of tranplacental and postnatal inhalatory exposure to polycyclic aromatichydrocarbons: prospective birth cohort study on wheezing events. PediatrPulmonol 49: 162-172.
26. Perera F, Li TY, Lin C, Tang D (2012) Effects of polycyclic aromatic hydrocarbon exposure and environmental tobacco smoke on child IQ in a Chinese cohort. Environ Res 114: 40-46.
27. Jurewicz J, PolaÅ?ska K, Hanke W (2013) Exposure to widespread environmental toxicants and children's cognitive development and behavioral problems. Int J Occup Med Environ Health 26: 185-204.
28. Parodi S, Merlo DF, Ranucci A, Miligi L, Benvenuti A, et al. (2014) Risk of neuroblastoma, maternal characteristics and perinatal exposures: the SETIL study. Cancer Epidemiol 38: 686-694.
29. Heck JE, Park AS, Qiu J, Cockburn M, Ritz B (2013) An exploratory study of ambient air toxics exposure in pregnancy and the risk of neuroblastoma in offspring. Environ Res 127: 1-6.
30. Wang B, Jin L, Ren A, Yuan Y, Liu J, et al. (2015) Levels of polycyclic aromatic hydrocarbons in maternal serum and risk of neural tube defects in offspring. Environ SciTechnol 49: 588-596.
31. Rundle A, Hoepner L, Hassou A, Oberfield S, Freyer G, et al. (2012) Association of childhood obesity with maternal exposure to ambient air polycyclic aromatic hydrocarbons during pregnancy. Am J Epidemiol 175: 1163-1172.
32. Lupo PJ, Langlois PH, Reefhuis J, Lawson CC, Symanski E, et al. (2012) Maternal occupational exposure to polycyclic aromatic hydrocarbons: effects on gastroschisis among offspring in the national birth defects prevention study. Environ Health Perspect 120: 910-915.
33. Langlois PH, Hoyt AT, Lupo PJ, Lawson CC, Waters MA (2013) Maternal occupational exposure to polycyclic aromatic hydrocarbons and risk of oral cleft-affected pregnancies. Cleft Palate Craniofac J 50: 337-346.
34. Jde BM, Chatkin JM, Zimmer AR, Goulart AP, Thiesen FP (2014) Cotinine and polycyclic aromatic hydrocarbons levels in the amniotic fluid and fetal cord at birth and in the urine from pregnant smokers. PLoS One 9: e116293.
35. Polanska K, Hanke W, Sobala W, Brzeznicki S, Ligocka D (2011) Predictors of environmental exposure to polycyclic aromatic hydrocarbons among pregnant women - prospective cohort study in Poland. Int J Occup Med Environ Health 24: 8-17.
36. Polanska K, Dettbarn G, JurewiczJ, Sobala W, Magnus P, et al. (2014) Effect of prenatal polycyclic aromatic hydrocarbons exposure on birth outcomes: the Polish mother and child cohort study. Biomed Res Int 2014: 408939.
37. Perera FP, Tang D, Rauh V, Lester K, Tsai WY, et al. (2005). Relationships among polycyclic aromatic hydrocarbon-DNA adducts, proximity to the world trade center, and effects on fetal growth. Environ Health Perspect 113: 1062-1070.
38. Perera FP, Rauh V, Whyatt RM, Tang D, Tsai WY, et al. (2005) A summary of recent findings on birth outcomes and developmental effects of prenatal ETS, PAH, and pesticide exposures. Neurotoxicology 26: 573-587.
39. Perera FP, Tang D, Rauh V, Tu YH, Tsai WY, et al. (2007) Relationships among polycyclic aromatic hydrocarbon-DNA adducts, environmental tobacco smoke, and child development in the World Trade Center cohort Environ Health Perspect 115: 1497-1502.
40. CDC (2015) National health and nutrition examination survey. Centers for disease control and prevention.
41. National Health and Nutrition Examination Survey (2009) pregnancy test - urine, 2009-2010 Data Documentation, Codebook, and Frequencies
42. CDC (2015) Description of laboratory methodology. Centers for disease control and prevention.
43. Jain RB (2013) Effect of pregnancy on the levels of blood cadmium, lead, and mercury for females aged 17-39 years old: data from national health and nutrition examination survey 2003-2010. J Toxicol Environ Health 76: 58-69.
44. CDC (2015) National center for health statistics. Centers fordisease control and prevention.
45. Jeong H (2010) Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes. Expert Opin Drug MetabToxicol 6: 689-699.
46. Choi H, Jedrychowski W, Spengler J, Camann DE, Whyatt RM, et al. (2006) International studies of prenatal exposure to polycyclic aromatic hydrocarbons and fetal growth. Environ Health Perspect 114: 1744-1750.
47. Department of obstetrics and gynecology (2016) Virginia Commonwealth University, Centering Pregnancy® at VCU.