As BPA recently has been clinically shown in human and animals to cross the placental barrier, the potential effects of maternal BPA exposure on prenatal development has become a more focal area of research [10, 25]. Previous studies have shown that prenatal BPA exposure in rodents and human is associated with fetal developmental and metabolic adverse effects, for example, increased birth weight [19, 26], reduced gestational age , and disrupted thyroid function . These findings raise concerns as to the developmental toxicity since the active BPA dose is considerably lower than the reported concentrations in the serum of pregnant women in the U.S. (5.9 ng/ml) and in South Korea (2.7 ng/ml) [29, 30]. This study is the first to show the correlation between maternal BPA exposure and birth outcomes in Taiwan. We analyzed BPA levels in blood samples obtained from pregnant women and umbilical cords. The levels of BPA ranged from 0.3 to 29.4 ng/ml (GM 2.5 ng/ml) and 0.3 to 18.5 ng/ml (GM 1.1 ng/ml) in pregnancy and cord serum, respectively. A recent study indicated that approximately 27% of BPA can readily cross a placenta  and that maternal BPA exposure transferred to the fetus can cause developmental abnormalities and other adverse health effects in the offspring [10–13]. This study found a 13% transfer of BPA from maternal blood to fetal cord blood. The results indicated that fetuses can be exposed to BPA in utero despite differences in the placental transfer percentage of BPA in a previous study . In male neonates, this study found a significantly negative correlation between fetal birth weight and maternal BPA level. Additionally, the risks of LBW and SGA and higher fetal leptin and adiponectin levels increased with maternal BPA levels in the highest tertile. That prenatal exposure to BPA seems to cause adverse effects on fetal growth and development is an important concern.
The present study revealed several important findings. First of all, we found a correlation between maternal BPA exposure and birth outcomes. Prenatal BPA exposure in the highest quartile (> 7.04 ng/ml) was inversely associated with birth weight, whereas it was not significantly correlated at the lowest and second quartiles of BPA concentrations. Some animal studies supported our finding that the reduction in weight of both male and female offspring is associated with prenatal or postweaning exposure to BPA [12, 31]. Kim et al.  reported that administration of a high BPA level (300 mg/kg) during the entire gestational period in Sprague-Dawley rats reduced the weight of the fetuses. Maternal exposure in sheep at BPA levels of 30 to 50 ng/ml during days 30 to 90 of gestation resulted in low birth weight in offspring . However, certain studies provided conflicting results, reporting an increased weight in offspring whose mothers were exposed to BPA during gestation [26, 34, 35]. Moreover, mice embryos cultured at the two-cell stage in 1 nM or 100 μM BPA showed no noted differences in pup weight at birth . However, at the time of weaning on postnatal Day 21, offspring from embryos exposed to either dose of BPA were significantly heavier than the control offspring. Although this study showed that male fetal birth weight was negatively correlated with a high level of maternal BPA exposure, the BPA treatment level of animal models compared to human exposure should be considered. Lee et al.  also indicated that maternal BPA levels have more marked effect on male fetuses than female fetuses, but they found a significant positive correlation between maternal serum BPA levels and fetal birth weight.
Estrogen is known to stimulate cell proliferation for growth and development. Troisi et al.  indicated that the serum estrogen level of pregnant women is positively correlated with fetus weight, fetus length, and head circumference, but with no existing correlation between the estrogen level of the umbilical cord and fetus weight. Nagata et al.  also found a positive association between birth weight and maternal serum estradiol and estriol levels. Aromatase converts testosterone to estradiol . Prenatal testosterone treatment leads to growth retardation and compromised estradiol-positive feedback, as illustrated by Manikkam et al. , leading to growth retardation and consequently resulting in low birth weight in sheep. Savabieasfahani et al.  reported low birth weight in offspring because of prenatal exposure to BPA and suggested that the effect may be facilitated through a conversion of testosterone to estradiol. In the present study, the prenatal BPA exposure in male fetuses with low birth weight suggested a response to testosterone feedback. Thus, the magnitude of BPA effect on weight may be influenced by subtle changes of hormones in utero.
Second, our data demonstrated that pregnant women exposed to BPA levels greater than 2.51 ng/ml had a higher risk of giving birth to males with LBW (OR 2.12, 95% CI 1.05-2.38) (Table 3). Moreover, in the male offspring, the lower and highest quartiles of BPA levels conferred a greater risk of LBW than the lowest quartile of BPA level (Figure 2A). This finding produced a non-monotonic or a U-shaped dose-response curve consistent with the previous report . Additionally, male neonates suffered an approximately 34% higher risk of SGA from a maternal BPA level higher than 2.5 ng/ml (Table 3). A linear dose-dependent response was noted at increased quartiles of BPA levels (Figure 2). Conversely, the secretion of leptin and adiponectin was used as a predictor to assess the potential risk of developing metabolic syndrome in newborns. Additionally, a higher relative risk of increased leptin secretion in both male and female infants corresponding to pregnant women exposed to the highest quartile BPA level (Figure 2). As mentioned earlier, our results implied that the effects of maternal BPA exposure produced a U-shaped dose and gender dependence on fetal birth outcomes. These results were consistent with several published studies. Differential processing of high dose BPA relative to low dose contributes to the U-shaped, non-monotonic dose-response curve and gender-difference effects [42, 43]. Sex- and dose-dependent differences in weight in response to early postnatal exposure to diethylstilbestrol, a synthetic estrogen similar to the BPA structure, have been reported . Prenatal or neonatal exposure to BPA was correlated with adverse effects on fetal growth parameters such as LBW and SGA. Manikkam et al.  reported that exposure to endocrine-disrupting compounds in utero caused fetal growth retardation in sheep. Our data suggests that BPA mimics estrogen in its action, and continued exposure to BPA during gestation is likely to have an impact on the fetus' developmental trajectory. In fact, a growing body of evidence, in addition to our data, had considered LBW and SGA to be a potential outcome of fetal exposure to BPA or endocrine-disrupting compounds [33, 35].
Thirdly, our data showed that prenatal exposure to BPA may lead to a potential risk of altering metabolic features in the fetus such as increasing adverse secretion of letpin and adiponectin. Phrakonkham et al.  suggested that BPA increases gene expression of adipogenic transcription factors in 3T3-L1 preadipocytes. Perinatal BPA exposure is associated with the over-expression of adipocyte hypertrophy and of lipogenic genes in rats . Moreover, BPA was reported to inhibit adiponectin secretion from human adipocyte explants in a dose-dependent manner . An in vivo study suggested that neonatal estrogenization can influence fetal development including fetus weight . These studies provided indirect evidence supporting our observation of BPA altering the secretion of fetal adipokines. However, more information about the adipogenic effect of BPA in fetuses is required for confirmation.
This study has several limitations. First, the level of plasma BPA was only detected at a single time in connection with delivery. Some imprecision exists because BPA exposure is variable over time . Thus, this study assumed that the BPA exposure sources, for example, living environment, consumption habits, and exposure routes, were sustained, and that the exposure level of BPA influencing fetal development and health would be persistent in maternal plasma, though the half-life of BPA is relatively short. Second, the statistical modeling included only maternal age, BMI, and metabolic parameters as control variables to adjust for birth outcomes (LBW and SGA), but parity, a potential confounding factor for birth weight, was not considered. Additionally, it would be reasonable to concede from the results of this study that maternal BPA levels were not significantly correlated with fetal BPA levels. Nishikawa et al.  reported that maternal BPA-glucuronide (BPA-GA) may cross through the placenta and deconjugate to BPA in the fetus. Our results suggest that prenatal exposure to BPA might influence fetal development even though we found no significant correlation was present between maternal and fetal BPA levels due to the differences in the drug-metabolizing system of mother and fetus. However, these inferences still require further confirmation.