Previous studies through analyses of BPA in the serum of pregnant women and in cord blood collected at birth have indicated that BPA accumulates early in fetuses [5,6]. Schonfelder et al. [7] stated that BPA levels vary: from 0.3 to 18.9 ng/ml (median 3.1 ng/ml) in maternal plasma, from 0.2 to 9.2 ng/ml (median 2.3 ng/ml) in fetal plasma, and from 1.0 to 104.9 ng/g (median 12.7 ng/ml) in the placenta. BPA can readily cross the placenta [8], and some in vivo experiments have demonstrated that BPA can cause adverse birth outcomes in offspring. Pregnant rats were orally administered BPA at a dose of 10 mg/kg/day resulting in a decreased number of neonates and decreased survival rate [9]. Female genital tracts developed abnormally when the dams were exposed to BPA through gavage [10] or osmotic pumps [11]. Pregnant rats exposed to a low dose of BPA (1 mg/L) in drinking water showed increased adipogenesis in females at weaning [12].

In utero or neonatal exposure to BPA can alter offspring phenotype by stably altering the epigenome, an effect that can be counteracted by maternal dietary supplements [13]. Male offspring were orally exposed at lower dosages of BPA (0.05 mg/kg/day), which led to a significant decrease in weight gain; however, offspring exposed to BPA treatment at a higher dosage (50 mg/kg/day) showed higher body weights than the controls [14].

Table ​Table11 presented demographic characteristics, BPA levels, and lipid profiles of the 97 pregnant women and their newborns who participated in this study. The average (± S.D.) age, height, weight and BMI of pregnant women were 28.8 ± 3.7 years, 160.9 ± 5.2 cm, 65.3 ± 11.2 kg, and 25.2 ± 4.0 kg/m². The average values for serum BPA, adiponectin and leptin were 5.4 ± 6.3 ng/ml, 6.6 ± 4.7 μg/ml, and 17.9 ± 13.9 ng/ml in pregnant women, and 1.1 ± 2.2 ng/ml, 21.3 ± 8.2 μg/ml, and 4.6 ± 3.5 ng/ml in neonates. The neonates average weight and gestational age were 3109.6 ± 319.0 g and 38.9 ± 1.1 weeks, respectively. Gender distribution among neonates was 57.7% male and 42.3% female.

Based on the GM of maternal BPA levels, study subjects were divided into high- and low-BPA groups. The levels of TC and LDL were significantly higher in the low-BPA group than in the high-BPA group. Additionally, no significant differences in TRG, HDL, adiponectin and leptin levels were observed between these two groups. Neonates in the high BPA group were found to have lower birth weights than those in the low BPA group (p = 0.13). Some relevant differences between these two BPA groups were related to the gender of the infants.

To examine whether BPA exposure in pregnant women affected fetal BPA exposure and adverse outcomes, we analyzed the correlation between maternal BPA level, lipid profile, adipokines, birth weight, and gestational age (Table ​(Table2).2). The maternal BPA levels showed a significantly inverse relationship to BMI (r = -0.48, at 3rd tertile BPA level), TC (r = -0.67, at 2nd tertile BPA level), and LDL (r = -0.61, at 2nd tertile BPA level), but were positively associated with TRG (r = 0.44, at 1st tertile BPA level). Moreover, the level of leptin displayed a significant correlation coefficient with increased BPA levels (r = 0.39 at 1st tertile, r = 0.50 at 2nd tertile, and r = 0.59 at 3rd tertile BPA level). Conversely, maternal BPA exposure had a significant negative association with neonatal BPA level (r = -0.53 at 3rd tertile BPA level) and birth weight (r = -0.24 at total sample and r = -0.39 at 3rd tertile BPA level).

As shown in Table ​Table3,3, the crude ORs showed that maternal BPA exposure was associated with LBW (OR 2.65, 95% CI 1.43-3.47) and SGA (OR 1.93, 95% CI 1.44-2.56) for male neonates but was not significantly associated with fetal adiponectin and leptin. Further adjustment for BMI, TC, TRG, HDL, LDL and adipokines attenuated this association, but maternal BPA exposure was still significantly related to an increased risk of fetal LBW (OR 2.12, 95% CI 1.05-2.38) and SGA (OR 1.34, 95% CI 1.13-2.83) in males. Additionally, the ORs of fetal adverse outcomes and the maternal BPA level were not observed in female neonates.

The risks of fetal LBW, SGA, LAD, and HLP were plotted by quartiles based on maternal BPA exposure levels in Figure ​Figure2.2. Among male infants, the multivariable adjusted ORs of LBW of the second (OR 2.75, 95% CI 1.52-4.22) and fourth quartile (OR 2.42, 95% CI 1.72-3.36) of maternal BPA exposure, in contrast to the first quartile of BPA levels, showed that maternal BPA levels were significantly associated with an increased risk of LBW. The adjusted ORs of SGA of the second (OR 0.24, 95% CI 0.17-0.32) and the third quartile (OR 0.44, 95% CI 0.20-0.53) of maternal BPA level were significantly decreased, but increased in the fourth quartile (OR 2.01, 95% CI 0.99-0.62) (Figure ​(Figure2A).2A). The dose- response curve at SGA in male infants illustrated a U-shaped curve, but showed adverse effects at the highest BPA exposure (4th quartile). Additionally, significantly increased risks of LAD (OR 1.67, 95% CI 1.12-2.25) and HLP (OR 3.03, 95% CI 2.09-4.54) were observed for male neonates at the highest BPA exposure quartile (Figure ​(Figure2A).2A). In female neonates, BPA levels in the second (OR 2.99, 95% CI 1.47-4.11) and the fourth quartile (OR 2.17, 95% CI 1.19-3.12) were positively correlated with an increased risk of SGA presenting a Z-shaped curve and adverse effects (Figure ​(Figure2B).2B). Otherwise, the ORs of LAD were significantly decreased in the second (OR 0.21, 95% CI 0.10-0.21) and the fourth exposure quartiles (OR 0.55, 95% CI 0.34-0.56). The ORs of HLP at the second (OR 0.18, 95% CI 0.12-0.18) and third quartile (OR 0.11, 95% CI 0.06-0.11) of maternal BPA exposure were significantly decreased, but increased in the fourth quartile (OR 1.75, 95% CI 1.04-1.85) (Figure ​(Figure2B).2B). The dose-response curve of HLP in female infants showed a U-shape, but adverse effects were observed at the highest exposure quartile of BPA.

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. [32] 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 [33]. 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 [36]. 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. [30] 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. [37] 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. [38] also found a positive association between birth weight and maternal serum estradiol and estriol levels. Aromatase converts testosterone to estradiol [39]. Prenatal testosterone treatment leads to growth retardation and compromised estradiol-positive feedback, as illustrated by Manikkam et al. [40], leading to growth retardation and consequently resulting in low birth weight in sheep. Savabieasfahani et al. [33] 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 ​(Table3).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 ​(Figure2A).2A). This finding produced a non-monotonic or a U-shaped dose-response curve consistent with the previous report [41]. Additionally, male neonates suffered an approximately 34% higher risk of SGA from a maternal BPA level higher than 2.5 ng/ml (Table ​(Table3).3). A linear dose-dependent response was noted at increased quartiles of BPA levels (Figure ​(Figure2).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 ​(Figure2).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 [35]. Prenatal or neonatal exposure to BPA was correlated with adverse effects on fetal growth parameters such as LBW and SGA. Manikkam et al. [40] 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. [44] 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 [12]. Moreover, BPA was reported to inhibit adiponectin secretion from human adipocyte explants in a dose-dependent manner [45]. An in vivo study suggested that neonatal estrogenization can influence fetal development including fetus weight [28]. 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.