The identification of a “window of critical vulnerability” to ubiquitous air pollutants such as PAHs is a particularly important, yet challenging, question. Critical hurdle with answering this question regards the dose-response relationship of the xenotoxicant during a given age, which is inherently related to the host's susceptibility as well as the host's adaptiveness. Such exquisite sensitivity of the fetus and newborn to xenotoxicants is thought to be related to the immaturity of the developing immune systems; the rapid development of fetal organs; epigenetic mediation; and the fact that exposure per body weight is much higher than for adult exposure 
. Thus, the age-specific measurement of PAH exposure is critical for the clarification of the severity and the type of IUGR 
The present analysis supports the hypothesis that PAH exposure during the first trimester imparts the largest reduction in the markers of symmetric fetal growth restriction. Furthermore, we originally posited that elevated Cephalization Index represents a marker of asymmetric growth. However, our results suggest that it is, in fact, correlated with a symmetric fetal growth restriction. Prenatal PAH exposure during the earliest gestational months was associated with a consistent effect on Cephalization Index and FGR. Also, we saw no evidence that PAH exposure increases the likelihood of acute fetal growth restriction, as indicated by the Ponderal Index.
The strong inverse correlation between FGR and Cephalization Index in our results is also supported by similar results in the murine model 
]P administration during organogenesis interfered with preliminary synapse formation during the earliest weeks of gestation and induced the largest disproportionate increase in Cephalization Index 
. Furthermore, gestational B[a
]P exposure postnatally inhibited the cortical region for learning and memory 
Our present observation of the largest unit effect during the first trimester suggests that PAHs might influence the rate of fetal growth. Other epidemiologic investigations independently observed that fetal growth rate is programmed during the earliest gestational period, resulting in a progressively larger deficit as gestation matures 
An adverse intrauterine environment, particularly during the early pregnancy period, is hypothesized to switch on the survival mechanism of the fetus by protecting vital organs such as brain and heart while suppressing the development of other systems 
. Recent clinical examinations in various populations have demonstrated that a significantly slower growth rate begins in the earliest gestational weeks for growth restricted newborns 
. Among a group of singleton newborns who were longitudinally followed from the 12th
week of gestation to delivery by ultrasound, a significant difference in inter-individual rate of fetal growth was evident in terms of fetal abdominal and head circumference, as well as femur diaphysis length 
. Starting around the 13th
week, significantly slower fetal growth velocity was evident for those who were born in the lowest third percentile of birth weight. This difference in fetal growth velocity remained constant throughout gestation after maternal anthropomorphic characteristics (including pre-pregnancy weight, height and weight gain) were accounted for 
In some populations, fetuses that are born small-for-gestational age or with low birthweight, are at greater risk of neurodevelopmental delays 
, impaired lung function 
, asthma symptoms 
throughout childhood, as well as cardiopulmonary diseases 
during adulthood, including hypertension, and atherosclerosis, as well as diabetes 
. Our personal, indoor, and outdoor air monitoring of 344 women represents one of the largest and most comprehensive PAH exposure assessment campaigns to date. The airborne PAH exposure in Krakow, Poland, represents a typical exposure scenario in countries dependent on coal-burning for heat and power generation 
. Ambient PAH concentrations differ by more than two orders of magnitude between summer and winter with overall spatial homogeneity in concentration during given season 
. The extreme seasonal fluctuation of ambient PAH levels was instrumental in obtaining valid and precise predicted personal PAH exposure concentrations during the unmonitored months. Spearman's coefficients for concurrent personal, indoor and outdoor measurements ranged between 0.96–0.98 
. Thus, the spatial variability in personal, indoor and outdoor PAH concentration (within a given household) was very small during a typical air pollution episode (). For example, the maximum values for personal B[a
]P exposure concentration (42.23 ng/m3
) in our cohort and ambient B[a
]P level (200 ng/m3
), as reported by Junninen et al. (2009), represent two of the highest values of the compound that have ever been documented. Accordingly, the cohort's mean exposure over the monitoring period was weighed heavily in estimating the personal exposure of other newborns during their unmonitored months. Pearson's correlation coefficients between observed vs. predicted personal exposure concentration were 0.91, 0.98, and 0.96 at the 3rd
, and 8th
gestational month, respectively.
Another key strength of the study is the application of stringent enrollment criteria. Only young Polish women (18–35 years of age), non-smoking, healthy (i.e., free of diabetes, hypertension, or known HIV, nonusers of other tobacco products or illicit drugs) were targeted. In addition, only those who received adequate prenatal care (i.e. enrolled in the clinic between 8th to 13th week of pregnancy) were included. Thus, several important confounders have been precluded. At the same time, several study limitations warrant consideration. As our strict enrollment criteria precluded notable sources of confounding, our mothers and newborns cohort is not representative of the general population. Furthermore, only those fetuses who survived beyond the 8–13th gestational weeks were recruited into the study. Thus, PAH effects in the general population might be different than in the present cohort.
It is currently unknown whether other constituents of coal combustion by-products, including Cadmium (Cd), Nickel (Ni), Arsenic (As), and Lead (Pb) affect birth outcomes through a mechanism common with PAHs. Thus, our results cannot rule out confounding effects from other airborne correlates of PAHs, particularly during the winter. Another limitation of the study is the fact that we did not consider the genetic polymorphisms of the developing fetus and/or the mothers for the risk of IUGR. In our earlier analyses, both maternal and newborn haplotypes of the cytochrome 450 genes CYP1A1 significantly augmented PAH effects on children's neurocognitive development once they reached the age of 1, 2, and 3 respectively 
. It is plausible that the genes involved in PAH metabolic activation or detoxification may also modify PAH exposure risks on IUGR.
Cyclic fluctuation in ambient PAH concentration influenced the mean personal exposure during the first gestational month so that it was positively correlated with exposure during the ninth gestational month. While we statistically adjusted for this correlation in exposure, future research should quantify the fetal growth rate in real-time during gestation, rather than determine the absolute size decrement at birth. Such a measurement would also be useful in early detection of IUGR cases.
The identification of a “window of critical vulnerability” to ubiquitous air pollutants such as PAHs is a particularly important, yet challenging, question. The challenge surrounding this question stems, at least partly, from the fact that the dose-response relationship of the xenotoxicant during a given age is inherently related to the host's susceptibility as well as the host's adaptiveness. Furthermore, exposure duration is chronic, yet variable. Our results based on several alternate exposure estimation approaches suggest that one ln-unit PAH exposure during the first trimester, and the first gestational month in particular, increases the risk of FGR reduction and Cephalization Index elevation, respectively. On the other hand, no gestational period was associated with a marked reduction in Ponderal index. Reduction in birthweight, birth length and FGR, as well as an elevated CI predict mortality and morbidity risks in newborns and compromised cognitive development in children. In addition, ambient PAH concentrations in Krakow are typical of regions dependent on coal-burning for heat and power generation 
. The present data support the need for a multinational coal-combustion abatement strategy for the protection of pregnant women and the embryo/fetus, particularly during the earliest stage of pregnancy.