Information of Bisphenol A（2012） Close

No. Reference Species Stage Exposure Period Route Dose Endpoints Effects
1 Batista TM, Alonso-Magdalena P, Vieira E, Amaral ME, Cederroth CR, Nef S, Quesada I, Carneiro EM, Nadal A (2012). Short-term treatment with bisphenol-A leads to metabolic abnormalities in adult male mice. PLoS One. 7, e33814. OF1 mice　 3 months old［♂］ for 8 days twice a day Subcutaneous 100 µg/kg bw/day 【obesity】Plasma analysis, glucose, Insulin tolerance test, Insulin signaling assay, Whole-body energy homeostasis Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. BPA-treated mice had decreased food intake, lower body temperature and locomotor activity compared to control. In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptord b subunit was impaired in BPA-treated mice. This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr308 residue. Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein kinase (MAPK) signaling pathway was also impaired in the skeletal muscle from BPA-treated mice. In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor b subunit.
2 Bauer, S.M., Roy, A., Emo, J., Chapman, T.J., Georas, S.N., and Lawrence, B.P. (2012). The effects of maternal exposure to bisphenol A on allergic lung inflammation into adulthood. Toxicol Sci 130, 82-93. C57BL/6 mice Pregnant and lactating dams GD 6-PND 21 Oral 0.5, 5, 50, 500 µg/kg bw/day 【immune】Mucosal sensitization: PND 16-18, Peritoneal sensitization: PND 13, ［♂♀］ In the mucosal sensitization model, female offspring that were maternally exposed to 50, 500 µg BPA/kg bw/day displayed enhanced airway lymphocytic and lung inflammation, compared to offspring of control dams. Peritoneally sensitized, female offspring exposed to 0.5, 5, 50 µg BPA/kg bw/day presented dampened lung eosinophilia, compared to vehicle controls. These subtle, yet persistent changes due to developmental exposure to BPA did not
lead to significant differences in overall airway responsiveness.
3 Brannick, K.E., Craig, Z.R., Himes, A.D., Peretz, J.R., Wang, W., Flaws, J.A., and Raetzman, L.T. (2012). Prenatal exposure to low doses of bisphenol A increases pituitary proliferation and gonadotroph number in female mice offspring at birth. Biol Reprod 87, 82. mice on a mixed FVB, C57BL/6 background Pregnant dams E 10.5-18.5 Oral 0.5, 50 µg/kg bw/day 【pituitary, gonadotroph】Gonadotroph cell number or parameters of hormone synthesis in the pituitary: PND 1 ［♂♀］ Pituitaries from female offspring exposed in utero to either dose of BPA had increased proliferation, as assessed by mKi67 mRNA levels and immunohistochemistry. Gonadotroph number also increased in treated females. Females exposed to 0.5 µg/kg bw/day of BPA showed a significant increase in both luteinizing hormone (Lhb) and follicle stimulating hormone (Fshb) mRNA, females
exposed to the higher dose of 50 µg/kg bw/day of BPA showed a significant decrease in mRNA levels of both Lhb and Fshb. Female mice exposed to 0.5 µg/kg bw/day BPA had increased mRNA levels of gonadotropins and the GnRH receptor (Gnrhr), females treated with 50 µg/kg bw/day BPA had decreased gonadotropin mRNA levels, Gnrhr and Nr5a1. Male pituitaries showed no change in the parameters tested.
4 Cao J, Mickens JA, McCaffrey KA, Leyrer SM, Patisaul HB (2012). Neonatal Bisphenol A exposure alters sexually dimorphic gene expression in the postnatal rat hypothalamus. Neurotoxicology. 33, 23-36. Long-Evans rats Neonatal pups ［♂♀］ PND 0-2 Subcutaneous 50, 50,000 µg/kg bw/day 【brain】In situ hybridization in the anterior and mediobasal hypothalamus: PND 4, 10 ERb expression was significantly reduced in both BPA exposure groups by PND 10 with the Anteroventral periventricular nucleus (AVPV) expression virtually eliminated in both sexes. BPA had no effect on ER expression in females but the low dose resulted in elevated ERb expression in the male caudal hypothalamic ventromedial nucleus (VMNvl) by PND 10. Kiss1 expression was diminished by BPA in the anterior hypothalamus, especially in females.
5 Chao, H.H., Zhang, X.F., Chen, B., Pan, B., Zhang, L.J., Li, L., Sun, X.F., Shi, Q.H., and Shen, W. (2012). Bisphenol A exposure modifies methylation of imprinted genes in mouse oocytes via the estrogen receptor signaling pathway. Histochem Cell Biol 137, 249-259. CD-1 mice Neonatal pups ［♀］ Experiment 1: PND 7-14, Experiment 2: PND 5, 10, 15, 20 Subcutaneous 20, 40 µg/kg bw/day 【reproductive　system】Methylation of imprinted genes (sodium bisulfite genomic DNA sequencing) during oocyte growth and meiotic maturation: Experiment 1 (PND 15), Experiment 2 (PND 21) Hypomethylation of imprinted gene Igf2r and Peg3 during oocyte growth, and enhanced estrogen receptor (ER) expression at the levels of mRNA and protein.
6 D'Cruz SC, Jubendradass R, Mathur PP (2012). Bisphenol A induces oxidative stress and decreases levels of insulin receptor substrate 2 and glucose transporter 8 in rat testis. Reprod Sci. 19, 163-172. Wistar rats 90 days old ［♂］ for 45 days Oral 0.005, 0.5, 50, 500 µg/kg bw/day 【testis】 Glucose metabolism in testis, Oxidative stress The levels of plasma glucose and insulin were significantly increased, whereas the testicular glucose level significantly decreased following exposure to BPA. A dose-dependent increase in the level of hydrogen peroxide (H2O2) and a significant decline in the activities of hexokinase and phosphofructokinase was observed in the testis of rats treated with BPA. Western blot analyses of insulin receptor substrate 2 (IRS-2) and glucose transporter 8 (GLUT-8) in the testis showed a decline in the levels of these proteins following BPA administration. Immunolocalization of GLUT-8 protein in the testis revealed decreased expression of this protein in spermatocytes and developing spermatids of rats exposed to BPA.
7 D'Cruz SC, Jubendradass R, Jayakanthan M, Rani SJ, Mathur PP (2012). Bisphenol A impairs insulin signaling and glucose homeostasis and decreases steroidogenesis in rat testis: an in vivo and in silico study. Food Chem Toxicol. 50, 1124-1133. Wistar rats 90 days old ［♂］ for 45 days Oral 0.005, 0.5, 50, 500 µg/kg bw/day 【testis】Insulin signaling molecules, glucose transporter-2 (GLUT-2) Steroidogenesis in testis Decreased levels of insulin, insulin receptor, insulin receptor substrate-1, phosphoinositide 3-kinase and GLUT-2. Dose-dependent decrease in the activities of antioxidant enzymes, 3-b-hydroxysteroid dehydrogenase, 17-b-hydroxysteroid dehydrogenase, Steroidogenic Acute Regulatory Protein and testosterone were also observed.
8 Doshi, T., D'Souza, C., Dighe, V., and Vanage, G. (2012). Effect of neonatal exposure on male rats to bisphenol A on the expression of DNA methylation machinery in the postimplantation embryo. Journal of biochemical and molecular toxicology 26, 337-343. Holtzman rats Neonatal pups ［♂］ PND 1-5 Subcutaneous 400 µg/kg bw/day 【reproductive　system】Fertility assessment with normally cycling adult females: PND 75, Expression analysis of DNA methyltransferases of E 20 embryos sired by BPA-treated male A significant increase was observed in the time
taken for copulation in females mated with BPA-treated males. The number of copulated females showing resorptions significant increased, ultimately leading to subfertility. Neonatal exposure of male rats to BPA down regulates the gene expression of DNA methyltransferases and related transcription factors in resorbed embryos as compared with the viable embryo.
9 Eilam-Stock T, Serrano P, Frankfurt M, Luine V (2012). Bisphenol-A impairs memory and reduces dendritic spine density in adult male rats. Behav Neurosci. 126, 175-185. Sprague-Dawley rats 60 days old ［♂］ On the day of testing Subcutaneous 40 µg/kg bw 【brain】Object
recognition test, Object placement test, Golgi impregnation, Dendritic spine density analysis 		BPA significantly impaired both visual and spatial memory and decreased dendritic spine density on pyramidal cells in CA1 and the medial prefrontal cortex (mPFC). Additionally, BPA significantly decreased postsynaptic density-95 (PSD-95), a synaptic marker, in the hippocampus and increased cytosolic cAMP-responsive element-binding protein transcription factor (pCREB), a transcription factor, in mPFC.
10 Ferguson, S.A., Law, C.D., and Abshire, J.S. (2012). Developmental treatment with bisphenol A causes few alterations on measures of postweaning activity and learning. Neurotoxicol Teratol 34, 598-606. Sprague-Dawley rats Pregnant dams-Pups GD 6-21 and PND 1-21 Oral 2.5, 25.0 µg/kg bw/day 【behavior】Open field test: PND 40-42, Startle response on the first trial block: PND 54, ［♂♀］ Males of the BPA groups were significantly more active in open field assessments. Males of both BPA groups exhibited a significantly decreased startle response
11 He Z, Paule MG, Ferguson SA (2012). Low oral doses of bisphenol A increase volume of the sexually dimorphic nucleus of the preoptic area in male, but not female, rats at postnatal day 21. Neurotoxicol Teratol. 34, 331-337. Sprague-Dawley rats Pregnant dams-Pups GD 6-21 and PND 1-21 Oral 2.5, 25.0　µg/kg bw/day 【brain】Volume of the rodent sexually dimorphic nucleus of the preoptic area (SDN-POA): PND 21［♂♀］ Males treated with 2.5 or 25.0 µg/kg bw/day BPA had significantly larger SDN-POA volumes than same-sex vehicle controls.
12 Inagaki, T., Frankfurt, M., and Luine, V. (2012). Estrogen-induced memory enhancements are blocked by acute bisphenol A in adult female rats: role of dendritic spines. Endocrinology 153, 3357-3367.
 Sprague- Dawley rats 3 months old［♀］ On the day of testing Subcutaneous 1, 4, 40, 120, 240, 400 µg/kg bw 【behavior, brain】Hippocampal-dependent memory: Object
placement test, Object recognition test, Golgi impregnation and spine density analysis 		BPA (1–400 µg/kg bw) did not alter recognition memory, but 1 and 40 µg/kg bw BPA, respectively, blocked 17b-E2-dependent increases in place and visual memory. When ovariectomized rats were tested with 17b-E2, 1 µg/kg bw BPA blocked place memory, but up to 40 µg/kg bw did not block visual memory. BPA, given to cycling rats at 40 µg/kg bw, blocked visual, but not place, memory during proestrus when 2 h intertrial delays were given. Spine density was assessed at times of memory consolidation (30 min) and retention (4 h) after 17b-E2 or BPA +17b-E2. In prefrontal cortex, BPA did not alter E2-dependent increases. In the hippocampus, BPA blocked E2 increases in basal spines at 4 h and was additive with E2 at 30 min.
13 Jones BA , Watson NV (2012). Perinatal BPA exposure demasculinizes males in measures of affect but has no effect on water maze learning in adulthood. Horm Behav. 61, 605-610. Long-Evans rats Pregnant and lactating dams GD 7-PND 14 Oral 5, 50, 500, and 5,000 µg/kg bw/day 【behavior】 Morris water maze test, Elevated plus maze test, Forced swim test: PND 90-150［♂♀］ No effect of BPA was observed in the Morris Water Maze, but on both the Elevated Plus Maze and Forced Swim Test, low doses (5 µg/kg bw/day) of BPA eliminated sex differences found between controls.
14 Kass, L., Altamirano, G.A., Bosquiazzo, V.L., Luque, E.H., and Munoz-de-Toro, M. (2012). Perinatal exposure to xenoestrogens impairs mammary gland differentiation and modifies milk composition in Wistar rats. Reprod Toxicol 33, 390-400.
 Wistar rats Pregnant and lactating F0 dams GD 9-PND 21 Drinking water 0.7, 64 µg/kg bw/day 【mammary gland】 Milk: nursing F1 dams on LD14, Mammary gland differentiation: pregnant F1 dams on GD 18, 21 The amount of b-casein in milk samples from F1 nursing mothers at LD 14 was lower in all of the experimental groups compared to the control group. On GD 21, F1 pregnant dams treated with BPA showed a reduced mammary gland histological differentiation score that did not differ from that of the control group on GD 18. The reduced scores on GD 21 were mostly due to the presence of less distended alveoli.
15 Kendziorski JA, Kendig EL, Gear RB, Belcher SM (2012). Strain specific induction of pyometra and differences in immune responsiveness in mice exposed to 17a-ethinyl estradiol or the endocrine disrupting chemical bisphenol A. Reprod Toxicol. 34, 22-30. C57BL/6 mice, CD-1 mice 6-7 weeks old ［♂♀］ from 6-7 weeks old till the end of testing Diet 4.0, 32.8, 4,168 (C57BL/6), 4.1, 41.7, 4,182 (CD1) µg/kg bw/day 【uterus】Fertility and Fecundity, Uterine pathology: 19-23 weeks old［♀］ No effect on fertility or fecundity in the C57BL/6 strain for any dose of BPA was observed. In the CD1 strain 4 µg/kg bw/day and 41 µg/kg bw/day BPA treatment groups, an increase in latency
of mating and a decrease in productive mating was noted. In the C57BL/6 strain, pyometra occurred in the 33 µg/kg bw/day BPA treatment groups. At the effective concentration of BPA, histological analysis revealed pathological alterations of uterine morphology associated with a >5.3-fold increase in macrophage numbers in non-pyometra uteri of C57BL/6 mice exposed to BPA. Pyometra did not occur in CD1 mice exposed to different dietary doses of BPA.
16 Komada M, Asai Y, Morii M, Matsuki M, Sato M , Nagao T (2012). Maternal bisphenol A oral dosing relates to the acceleration of neurogenesis in the developing neocortex of mouse fetuses. Toxicology. 295, 31-38. C57BL/6J mice Pregnant dams E 8.5-13.5 Oral 20, 200 µg/kg bw/day 【brain】Histopathological analysis: E 14.5［♀］ 200 µg/kg bw/day: Cortical plate was hyperplastic and the number of neural stem/progenitor cells was decreased after the exposure to BPA. In particular, the maternal BPA oral dosing related to the effects on intermediate progenitor cells (IPCs, neural progenitor cells) in the subventricular zone (SVZ) of dorsal telencephalon. Exposure to BPA associated the promotion of the cell cycle exit in radial glial cells (RGCs, neural stem cells) and IPCs, and decreased the proliferation resulting from the prolong cell cycle length of IPCs in the SVZ.
17 Losa-Ward, S.M., Todd, K.L., McCaffrey, K.A., Tsutsui, K., and Patisaul, H.B. (2012). Disrupted organization of RFamide pathways in the hypothalamus is associated with advanced puberty in female rats neonatally exposed to bisphenol A. Biol Reprod 87, 28. Wistar rats Neonatal pups ［♂♀］ PND 0-3 Subcutaneous 50, 50,000 µg/kg bw/day 【gonadotropic】Gonadotropin releasing hormone (GnRH) in neurons, ［♀］: PND 17, 21, 24, 28, 33, ［♂］: PND 21, 33 Neonatal low dose BPA exposure to females was accompanied by advanced vaginal opening and decreased RFamide related peptide 3 (RFRP3) cell numbers, fiber density and gonadotropin releasing
hormone (GnRH) innervation.
18 Marmugi A, Ducheix S, Lasserre F, Polizzi A, Paris A, Priymenko N, Bertrand-Michel J, Pineau T, Guillou H, Martin PG , Mselli-Lakhal L (2012). Low doses of bisphenol A induce gene expression related to lipid synthesis and trigger triglyceride accumulation in adult mouse liver. Hepatology. 55, 395-407. CD-1 mice 6 weeks old ［♂］ for 28 days Diet 5, 50, 500, 5,000 µg/kg bw/day 【obesity】Plasma Insulin, Liver Transcriptome, Histopathological analysis of liver［♂］ Data analysis revealed a specific impact of low doses of BPA on the hepatic transcriptome, more particularly on genes involved in lipid synthesis. The effect of BPA on the expression of de novo lipogenesis followed a nonmonotonic dose-response curve, with more important effects at lower doses than at the higher dose. In addition to lipogenic enzymes (Acc, Fasn, Scd1), the expression of transcription factors such as liver X Receptor, the sterol regulatory element binding protein-1c, and the carbohydrate responsive element binding protein that govern the expression of lipogenic genes also followed a nonmonotonic dose-response curve in response to BPA. Consistent with an increased fatty acid biosynthesis, determination of fat in the liver showed an accumulation of cholesteryl esters and of triglycerides.
19 Matsuda, S., Matsuzawa, D., Ishii, D., Tomizawa, H., Sutoh, C., Nakazawa, K., Amano, K., Sajiki, J., and Shimizu, E. (2012). Effects of perinatal exposure to low dose of bisphenol A on anxiety like behavior and dopamine metabolites in brain. Progress in neuro-psychopharmacology & biological psychiatry 39, 273-279. C57BL/6J mice Pregnant dams GD 10–20 Subcutaneous 0.25 µg/kg bw/day 【behavior, brain】Open field test: P4W, P8W［♂♀］, Dopamine and DOPAC in dorsal
hippocampus, amygdala, medulla oblongata: P9W［♂♀］ 		In males, BPA decreased the time spent in the center area of the open field in both juveniles and adults. BPA increased dopamine levels in the dorsal hippocampus and medulla oblongata and decreased the DOPAC/Dopamine ratio in the dorsal hippocampus amygdala and medulla oblongata in adults. The activity of monoamine oxidase-B, the enzyme that metabolizes dopamine into DOPAC, was reduced in the medulla oblongata. In females, those changes were not observed.
20 Nakamura K, Itoh K, Dai H, Han L, Wang X, Kato S, Sugimoto T, Fushiki S (2012). Prenatal and lactational exposure to low-doses of bisphenol A alters adult mice behavior. Brain Dev. 34, 57-63. ICR/jcl mice Pregnant and lactating dams GD 0-PND 21 Subcutaneous 20 µg/kg bw/day 【behavior】Open field test, Elevated plus maze test, Morris water
maze test: P3W, P10W-P13W, ［♂♀］ 		The total distance in the elevated plus maze test at PND 21 and in the open-field test at PND 70 was significantly decreased in the BPA-exposed males group.
21 Nanjappa MK, Simon L , Akingbemi BT (2012). The Industrial Chemical Bisphenol A (BPA) Interferes with Proliferative Activity and Development of Steroidogenic Capacity in Rat Leydig Cells. Biol Reprod. 86, 135 Long-Evans rats Pregnant and lactating dams GD 12-PND 21 Oral 2.5, 25 µg/kg bw/day 【testis】Leydig cell differentiation: PND 21, 35, 90, Primary Leydig cultures: progenitor Leydig cells (PLCs) at PND 21 Perinatal exposure of male rats to BPA (2.5, 25 µg/kg bw/day) increased Leydig cell numbers at PND 90. Exposure of male rats to BPA (2.5, 25 µg/kg bw/day) induced proliferative activity in PLCs. Perinatal exposure of male rats to BPA increased PCNA, cyclin D3, IGF1RB, EGFR, AMHR2 protein, phosphorylation (p-MAPK3/1) in PLCs. Exposure to BPA (2.5, 25 µg/kg bw/day) caused greater LHCGR, ERa and AR protein levels in PLCs. Leydig cell (PND 21, 35, 90) testosterone production was decreased exposure to BPA (2.5, 25 µg/kg bw/day). LHCGR and HSD17B3 protein were decreased in BPA (2.5, 25 µg/kg bw/day)-exposed adult Leydig cells at PND 90.
22 Pant, J., Pant, M.K., and Deshpande, S.B. (2012). Bisphenol A attenuates phenylbiguanide-induced cardio-respiratory reflexes in anaesthetized rats. Neurosci Lett 530, 69-74. Charles Foster strain rats adult ［♀］ for 30 days Oral 2 µg/kg bw/day 【cardio, respiratory】Effect on cardio-respiratory parameters In BPA treated group, the phenylbiguanide-induced heart rate and respiratory frequency changes were attenuated significantly.
23 Patisaul, H.B., Sullivan, A.W., Radford, M.E., Walker, D.M., Adewale, H.B., Winnik, B., Coughlin, J.L., Buckley, B., and Gore, A.C. (2012). Anxiogenic effects of developmental bisphenol a exposure are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy. PLoS One 7, e43890. Wistar rats Pregnant and lactating dams-Pups GD 6-PND 20 and PND 21-40 Drinking water 18.2(♂), 22.4(♀) µg/day (1 mg/L) 【behavior】Light/dark box test, Elevated plus maze test: PND 24–28, PND 60–70, Gene Expression Analysis in amygdalar: PND 34, ［♂♀］ BPA induced anxiogenic behavior in juveniles and loss of sexual dimorphisms in adult exploratory behavior, but only in the animals reared on the soy-free diet. Expression analysis revealed a suite of genes, including a subset known to mediate sociosexual behavior, associated with BPA-induced juvenile anxiety. Esr2 (ERb) and Gad2 expression were significantly down-regulated by BPA in both sexes compared to Soy-free controls. Tac2 and Mc4r were significantly down-regulated by BPA exposure in females.
24 Pelch KE, Carleton SM, Phillips CL , Nagel SC (2012). Developmental exposure to xenoestrogens at low doses alters femur length and tensile strength in adult mice. Biol Reprod. 86, 69. C57BL/6 mice Pregnant and lactating dams GD 11-PND 12 Pumps s.c. 10 µg/kg bw/day 【bone】Bone geometry, Torsional strength: P10W［♀］, P13W［♀］, P23 W［♂］ Increased adult femur length in males (P23W). Developmental exposure to BPA tended to decrease energy to failure in females (P13W), but had no effect on energy to failure in males.
25 Roy A, Bauer SM , Lawrence BP (2012). Developmental exposure to bisphenol A modulates innate but not adaptive immune responses to influenza A virus infection. PLoS One. 7, e38448. C57BL/6 mice Pregnant and lactating dams GD 6-PND 21 Oral 50 µg/kg bw/day 【immune】Immune response to infection with influenza A virus, Pulmonary inflammation,
Cytokine/chemokine gene expression levels in lung tissues: P6W–P8W［♂♀］ 		Significantly less severe pulmonary inflammation 7 days after infection (during early virus clearance phase) in mice exposed to BPA. A general pattern of reduced expression of genes for the cytokine TNF-a and the chemokines RANTES (CCL5), IP-10 (CXCL10), and MCP-1 (CCL2) in lungs of infected mice exposed to BPA, however, statistical significance of this reduction was only found for some of these genes. Reduced expression levels of genes for interferon (IFN)-g and inducible nitric oxide synthase (iNOS) in the lungs of BPA exposed mice.
26 Tang WY, Morey LM, Cheung YY, Birch L, Prins GS, Ho SM (2012). Neonatal exposure to estradiol/bisphenol A alters promoter methylation and expression of Nsbp1 and Hpcal1 genes and transcriptional programs of Dnmt3a/b and Mbd2/4 in the rat prostate gland throughout life. Endocrinology. 153, 42-55. Sprague-Dawley rats Neonatal pups［♂］ PND 1, 3, 5 Subcutaneous 10 µg/kg bw/day 【prostate】Estrogen-reprogrammable epigenetic marks, methylation changes in the prostate gland: Bisulfite genomic sequencing, Methylation-specific PCR: PND 10, 90, 200 Hypomethylation of the promoter of nucleosome binding protein-1 (Nsbp1), unlike Pde4d4, is an early and permanent epigenetic mark of neonatal exposure to BPA that persists throughout life, unaffected by events during adulthood. In contrast, hippocalcin-like 1 (Hpcal1) is a highly plastic epigenetic mark whose hypermethylation depends on both type of early-life exposure and adult-life events. Four of the eight genes involved in DNA methylation/demethylation showed early and persistent overexpression that was not a function of DNA methylation at their promoters, including genes encoding de novo DNA methyltransferases (Dnmt3a/b) and methyl-CpG binding domain proteins (Mbd2/4) that have demethylating activities.
27 Tharp, A.P., Maffini, M.V., Hunt, P.A., VandeVoort, C.A., Sonnenschein, C., and Soto, A.M. (2012). Bisphenol A alters the development of the rhesus monkey mammary gland. Proc Natl Acad Sci U S A 109, 8190-8195. Rhesus monkey (Macaca mulatta) Pregnant mothers GD 100–165 Oral 400 µg/kg bw/day 【mammary gland】Histopathological analysis, Morphometric analysis of mammary gland： PND 1-3 The density of mammary buds was significantly increased in BPA-exposed monkeys, and the overall development of their mammary gland was more advanced compared with unexposed monkeys.
28 Wolstenholme, J.T., Edwards, M., Shetty, S.R., Gatewood, J.D., Taylor, J.A., Rissman, E.F., and Connelly, J.J. (2012). Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. Endocrinology 153, 3828-3838. C57BL/6J (B6) mice Dams from 7–10 days before pairing with a male, over the last 10 days of gestation Diet 20 µg/day 【behavior】Transgenerational alterations ( F1, F2 and F4) of behavior and gene expression, Juvenile social interactions: PND 20, Elevated plus maze test: PND 24, Microarray analysis of brain : E 18.5, ［♂♀］ Juveniles in the first generation exposed to BPA in utero displayed fewer social interactions as compared with control mice, whereas in later generations (F2 and F4), the effect of BPA was to increase these social interactions. Brains from embryos (E 18.5) exposed to BPA had lower gene transcript levels for several estrogen receptors, oxytocin, and vasopressin as compared with controls; decreased vasopressin mRNA persisted into the F4 generation, at which time oxytocin was also reduced but only in males.
29 Xu, X., Hong, X., Xie, L., Li, T., Yang, Y., Zhang, Q., Zhang, G., and Liu, X. (2012). Gestational and lactational exposure to bisphenol-A affects anxiety- and depression-like behaviors in mice. Horm Behav 62, 480-490. ICR m ice Pregnant dams or Lactating dams GD 7-20 or PND 1-14 Oral 400, 4,000 µg/kg bw/day 【behavior】Open field test, Dark/light transition test, Elevated plus maze test, Forced swim test: PND 56［♂♀］ The results indicated that both gestational and lactational exposures to BPA at low levels increased anxiety- and depression-like behavior in mice of both sexes. Western blot analyses showed that both gestational and lactational exposures inhibited the expression of the AMPA receptor subunit GluR1 in the hippocampus and amygdala in mice of both sexes.
30 Zhang HQ, Zhang XF, Zhang LJ, Chao HH, Pan B, Feng YM, Li L, Sun XF, Shen W (2012). Fetal exposure to bisphenol A affects the primordial follicle formation by inhibiting the meiotic progression of oocytes. Mol Biol Rep. 39, 5651-5657. CD-1 mice Pregnant dams 12.5-18.5 dpc Oral 20, 40, 80 µg/kg bw/day 【germ cell】 Oocyte cyst breakdown, Primordial follicle
assembly, Follicle development:
PND 3, 5, 7. Meiosis prophase I assay: 15.5, 17.5, 19.5 dp., DNA methylation ( bisulfite sequencing) analysis of oocytes: 13.5, 15.5, 17.5 dpc［♀］ 		A dose-response relationship was observed with increased BPA exposure level associated with more oocytes in germ cell cyst and less primordial follicle at PND 3. Progression to meiosis prophase I of oocytes was delayed in the 80 µg/kg bw/day treated group. Decreased mRNA expression of specific meiotic genes including Stra8, Dmc1, Rec8 and Scp3 were observed.
31 Zhang, X.F., Zhang, L.J., Feng, Y.N., Chen, B., Feng, Y.M., Liang, G.J., Li, L., and Shen, W. (2012). Bisphenol A exposure modifies DNA methylation of imprint genes in mouse fetal germ cells. Mol Biol Rep. 39(9): 8621-8628. CD-1 mice Pregnant dams 0.5-12.5 dpc Oral 40, 80, 160 µg/kg bw/day 【germ cell】 DNA methylation of imprinting genes, the expression of specific
genes in fetal germ cells: 12.5 dpc ［♂♀］ 		DNA methylation of imprinting genes, Igf2r, Peg3 and H19, was decreased with the increase of BPA concentration in fetal mouse germ cells. The relative mRNA levels of Nobox were lower in BPA-treated group compared to control in female fetal germ cells, but in male fetal germ cells, a significant higher in Nobox expression was observed in BPA-treated group compared to control. After BPA exposure, the mRNA expression of specific meiotic genes (Stra8, Dazl) in 160 µg/kg bw/day group were significantly lower than that of the control group.

BPA: bisphenol A
dpc: days post coitum
E: embryonic day
GD: gestational day
LD: lactatinal day
PND: postnatal day
PW: postnatal week
s.c. : subcutaneous

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