General Health of Pregnant Sprague-Dawley Rats and Neonates’ Small Intestine Morphology Upon Maternal Bisphenol A Exposure: A Preliminary Study


  • Sarah Zulkifli Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Noor Shafina Mohd Nor Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Siti Hamimah Sheikh Abdul Kadir Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Norashikin Mohd Ranai Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Noor Kaslina Mohd Kornain Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Zatilfarihiah Rasdi Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Wan Nor I'zzah Wan Mohamad Zain Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Amirah Abdul Rahman Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Jesmine Khan Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia
  • Muhammad Yazid Jalaludin Universiti Malaya (UM), Kuala Lumpur



Bisphenol A, maternal exposure, pregnancy’s health, small intestine, histopathology


Associations between xenoestrogen bisphenol A (BPA) and multiple types of diseases, including metabolic syndrome, have been recorded in various studies. However, certain subsets of the human population are particularly more vulnerable to BPA repercussions, such as pregnant women, neonates, and children. This study was conducted to investigate the effects of BPA exposure during pregnancy on the general health of mothers and the histopathology of neonates’ small intestines. Eighteen Sprague-Dawley rats were divided into three groups: control, vehicle Tween-80, and 5mg/kg/day BPA after positive mating was confirmed. Physiological parameters consisted of body weight, waist circumference, water, and food intake, and blood pressures were measured at pregnancy day -1 or 2, 7, and 14 to see whether BPA exposure could exert obesogenic impacts on pregnant rats. Newborns were sacrificed to collect blood plasma for BPA analysis and intestinal samples for histopathological examination. Maternal BPA exposure did not affect the physiological parameters of pregnant rats. The number of pups delivered per litter and the sex ratio of BPA offsprings was not significantly different to those of control and vehicle groups (p>0.05). Likewise, the small intestine morphology of BPA neonates was comparable to those of controls and vehicles (preserved structure and absence of inflammatory cells infiltration). The nonsignificant difference in plasma BPA levels of control and BPA-exposed mothers and neonates may explain these findings. Future longitudinal studies which include the dose-dependent impacts of BPA on pregnant mothers’ health and neonates’ small intestine would be more beneficial.

Author Biography

Noor Shafina Mohd Nor, Universiti Teknologi MARA (UiTM) Kampus Sungai Buloh, Cawangan Selangor, Malaysia




Y. Q. Huang, C. K. Wong, J. S. Zheng, H. Bouwman, R. Barra, B. Wahlstrom, et al., Bisphenol A (BPA) in China: a review of sources, environmental levels, and potential human health impacts, Environ Int, 2012, vol. 42, no., pp. 91-9.

S. Flint, T. Markle, S. Thompson, E. Wallace, Bisphenol A exposure, effects, and policy: a wildlife perspective, J Environ Manage, 2012, vol. 104, no., pp. 19-34.

M. Ali, M. Jaghbir, M. Salam, G. Al-Kadamany, R. Damsees, N. Al-Rawashdeh, Testing baby bottles for the presence of residual and migrated bisphenol A, Environ Monit Assess, 2018, vol. 191, no. 1, pp. 7.

C. Liao, F. Liu, Y. Guo, H. B. Moon, H. Nakata, Q. Wu, et al., Occurrence of eight bisphenol analogues in indoor dust from the United States and several Asian countries: implications for human exposure, Environ Sci Technol, 2012, vol. 46, no. 16, pp. 9138-45.

T. Vasiljevic, T. Harner, Bisphenol A and its analogues in outdoor and indoor air: Properties, sources and global levels, Sci Total Environ, 2021, vol. 789, no. 148013, pp.

N. C. Maragou, A. Makri, E. N. Lampi, N. S. Thomaidis, M. A. Koupparis, Migration of bisphenol A from polycarbonate baby bottles under real use conditions, Food Addit Contam Part A Chem Anal Control Expo Risk Assess, 2008, vol. 25, no. 3, pp. 373-83.

H. H. Le, E. M. Carlson, J. P. Chua, S. M. Belcher, Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons, Toxicol Lett, 2008, vol. 176, no. 2, pp. 149-56.

J. Lopez-Cervantes, P. Paseiro-Losada, Determination of bisphenol A in, and its migration from, PVC stretch film used for food packaging, Food Addit Contam, 2003, vol. 20, no. 6, pp. 596-606.

A. Cavazza, C. Bignardi, M. Grimaldi, P. Salvadeo, C. Corradini, Oligomers: Hidden sources of bisphenol A from reusable food contact materials, Food Res Int, 2021, vol. 139, no., pp. 109959.

J. Lee, K. Choi, J. Park, H. B. Moon, G. Choi, J. J. Lee, et al., Bisphenol A distribution in serum, urine, placenta, breast milk, and umbilical cord serum in a birth panel of mother-neonate pairs, Sci Total Environ, 2018, vol. 626, no., pp. 1494-501.

L. N. Vandenberg, I. Chahoud, J. J. Heindel, V. Padmanabhan, F. J. Paumgartten, G. Schoenfelder, Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A, Environ Health Perspect, 2010, vol. 118, no. 8, pp. 1055-70.

X. Chen, S. Zhong, M. Zhang, W. Zhong, S. Bai, Y. Zhao, et al., Urinary parabens, bisphenol A and triclosan in primiparas from Shenzhen, China: Implications for exposure and health risks, J Environ Health Sci Eng, 2021, vol. 19, no. 1, pp. 251-9.

D. A. Crain, M. Eriksen, T. Iguchi, S. Jobling, H. Laufer, G. A. LeBlanc, et al., An ecological assessment of bisphenol-A: evidence from comparative biology, Reprod Toxicol, 2007, vol. 24, no. 2, pp. 225-39.

F. Ranciere, J. G. Lyons, V. H. Loh, J. Botton, T. Galloway, T. Wang, et al., Bisphenol A and the risk of cardiometabolic disorders: a systematic review with meta-analysis of the epidemiological evidence, Environ Health, 2015, vol. 14, no., pp. 46.

B. Sunman, K. Yurdakok, B. Kocer-Gumusel, O. Ozyuncu, F. Akbiyik, A. Balci, et al., Prenatal bisphenol a and phthalate exposure are risk factors for male reproductive system development and cord blood sex hormone levels, Reprod Toxicol, 2019, vol. 87, no., pp. 146-55.

Y. Malaise, S. Menard, C. Cartier, E. Gaultier, F. Lasserre, C. Lencina, et al., Gut dysbiosis and impairment of immune system homeostasis in perinatally-exposed mice to Bisphenol A precede obese phenotype development, Sci Rep, 2017, vol. 7, no. 1, pp. 14472.

V. Braniste, A. Jouault, E. Gaultier, A. Polizzi, C. Buisson-Brenac, M. Leveque, et al., Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats, Proc Natl Acad Sci U S A, 2010, vol. 107, no. 1, pp. 448-53.

H. Liu, J. Wang, D. Mou, L. Che, Z. Fang, B. Feng, et al., Maternal Methyl Donor Supplementation during Gestation Counteracts the Bisphenol A-Induced Impairment of Intestinal Morphology, Disaccharidase Activity, and Nutrient Transporters Gene Expression in Newborn and Weaning Pigs, Nutrients, 2017, vol. 9, no. 5, pp.

B. Balakrishnan, K. Henare, E. B. Thorstensen, A. P. Ponnampalam, M. D. Mitchell, Transfer of bisphenol A across the human placenta, Am J Obstet Gynecol, 2010, vol. 202, no. 4, pp. 393 e1-7.

M. Nishikawa, H. Iwano, R. Yanagisawa, N. Koike, H. Inoue, H. Yokota, Placental transfer of conjugated bisphenol A and subsequent reactivation in the rat fetus, Environ Health Perspect, 2010, vol. 118, no. 9, pp. 1196-203.

J. J. Heindel, F. S. vom Saal, Role of nutrition and environmental endocrine disrupting chemicals during the perinatal period on the aetiology of obesity, Mol Cell Endocrinol, 2009, vol. 304, no. 1-2, pp. 90-6.

T. T. Schug, A. Janesick, B. Blumberg, J. J. Heindel, Endocrine disrupting chemicals and disease susceptibility, J Steroid Biochem Mol Biol, 2011, vol. 127, no. 3-5, pp. 204-15.

D. L. Almeida, A. Pavanello, L. P. Saavedra, T. S. Pereira, M. A. A. de Castro-Prado, P. C. de Freitas Mathias, Environmental monitoring and the developmental origins of health and disease, J Dev Orig Health Dis, 2019, vol. 10, no. 6, pp. 608-15.

M. Garcia-Arevalo, P. Alonso-Magdalena, J. M. Servitja, T. Boronat-Belda, B. Merino, S. Villar-Pazos, et al., Maternal Exposure to Bisphenol-A During Pregnancy Increases Pancreatic beta-Cell Growth During Early Life in Male Mice Offspring, Endocrinology, 2016, vol. 157, no. 11, pp. 4158-71.

S. M. MohanKumar, T. D. Rajendran, A. K. Vyas, V. Hoang, N. Asirvatham-Jeyaraj, A. Veiga-Lopez, et al., Effects of prenatal bisphenol-A exposure and postnatal overfeeding on cardiovascular function in female sheep, J Dev Orig Health Dis, 2017, vol. 8, no. 1, pp. 65-74.

S. Zulkifli, A. A. Rahman, S. Kadir, N. S. M. Nor, Bisphenol A and its effects on the systemic organs of children, Eur J Pediatr, 2021, vol. 180, no. 10, pp. 3111-27.

D. R. Doerge, N. C. Twaddle, M. Vanlandingham, J. W. Fisher, Pharmacokinetics of bisphenol A in neonatal and adult Sprague-Dawley rats, Toxicol Appl Pharmacol, 2010, vol. 247, no. 2, pp. 158-65.

A. B. Javurek, W. G. Spollen, S. A. Johnson, N. J. Bivens, K. H. Bromert, S. A. Givan, et al., Effects of exposure to bisphenol A and ethinyl estradiol on the gut microbiota of parents and their offspring in a rodent model, Gut Microbes, 2016, vol. 7, no. 6, pp. 471-85.

A. Ko, M. S. Hwang, J. H. Park, H. S. Kang, H. S. Lee, J. H. Hong, Association between Urinary Bisphenol A and Waist Circumference in Korean Adults, Toxicol Res, 2014, vol. 30, no. 1, pp. 39-44.

K. Y. Kim, E. Lee, Y. Kim, The Association between Bisphenol A Exposure and Obesity in Children-A Systematic Review with Meta-Analysis, Int J Environ Res Public Health, 2019, vol. 16, no. 14, pp.

J. Wei, Y. Lin, Y. Li, C. Ying, J. Chen, L. Song, et al., Perinatal exposure to bisphenol A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet, Endocrinology, 2011, vol. 152, no. 8, pp. 3049-61.

S. Bae, J. H. Kim, Y. H. Lim, H. Y. Park, Y. C. Hong, Associations of bisphenol A exposure with heart rate variability and blood pressure, Hypertension, 2012, vol. 60, no. 3, pp. 786-93.

F. R. Cagampang, C. Torrens, F. W. Anthony, M. A. Hanson, Developmental exposure to bisphenol A leads to cardiometabolic dysfunction in adult mouse offspring, J Dev Orig Health Dis, 2012, vol. 3, no. 4, pp. 287-92.

K. M. Junge, B. Leppert, S. Jahreis, D. K. Wissenbach, R. Feltens, K. Grutzmann, et al., MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development, Clin Epigenetics, 2018, vol. 10, no., pp. 58.

H. Inoue, A. Tsuruta, S. Kudo, T. Ishii, Y. Fukushima, H. Iwano, et al., Bisphenol a glucuronidation and excretion in liver of pregnant and nonpregnant female rats, Drug Metab Dispos, 2005, vol. 33, no. 1, pp. 55-9.

R. Kamaludin, Z. Rasdi, M. H. D. Othman, S. H. S. Abdul Kadir, N. S. Mohd Nor, J. Khan, et al., Visible-Light Active Photocatalytic Dual Layer Hollow Fiber (DLHF) Membrane and Its Potential in Mitigating the Detrimental Effects of Bisphenol A in Water, Membranes (Basel), 2020, vol. 10, no. 2, pp.

W. Xi, H. T. Wan, Y. G. Zhao, M. H. Wong, J. P. Giesy, C. K. Wong, Effects of perinatal exposure to bisphenol A and di(2-ethylhexyl)-phthalate on gonadal development of male mice, Environ Sci Pollut Res Int, 2011, vol. 19, no. 7, pp. 2515-27.

A. P. Santos-Silva, E. G. de Moura, C. R. Pinheiro, E. Oliveira, P. C. Lisboa, Short-Term and Long-Term Effects of Bisphenol A (BPA) Exposure During Breastfeeding on the Biochemical and Endocrine Profiles in Rats, Horm Metab Res, 2018, vol. 50, no. 6, pp. 491-503.

E. Panagiotidou, S. Zerva, D. J. Mitsiou, M. N. Alexis, E. Kitraki, Perinatal exposure to low-dose bisphenol A affects the neuroendocrine stress response in rats, J Endocrinol, 2014, vol. 220, no. 3, pp. 207-18.

B. M. Angle, R. P. Do, D. Ponzi, R. W. Stahlhut, B. E. Drury, S. C. Nagel, et al., Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation, Reprod Toxicol, 2013, vol. 42, no., pp. 256-68.

T. Aiba, T. Saito, A. Hayashi, S. Sato, H. Yunokawa, T. Maruyama, et al., Does the prenatal bisphenol A exposure alter DNA methylation levels in the mouse hippocampus?: An analysis using a high-sensitivity methylome technique, Genes Environ, 2018, vol. 40, no., pp. 12.

Q. Li, J. Davila, A. Kannan, J. A. Flaws, M. K. Bagchi, I. C. Bagchi, Chronic Exposure to Bisphenol A Affects Uterine Function During Early Pregnancy in Mice, Endocrinology, 2016, vol. 157, no., pp. 1764-74.

D. Caserta, F. Costanzi, M. P. De Marco, L. Di Benedetto, E. Matteucci, C. Assorgi, et al., Effects of Endocrine-Disrupting Chemicals on Endometrial Receptivity and Embryo Implantation: A Systematic Review of 34 Mouse Model Studies, Int J Environ Res Public Health, 2021, vol. 18, no. 13, pp.

N. Jalal, A. R. Surendranath, J. L. Pathak, S. Yu, C. Y. Chung, Bisphenol A (BPA) the mighty and the mutagenic, Toxicol Rep, 2018, vol. 5, no., pp. 76-84.

A. L. Heffernan, L. L. Aylward, L. M. Toms, G. Eaglesham, P. Hobson, P. D. Sly, et al., Age-related trends in urinary excretion of bisphenol A in Australian children and adults: evidence from a pooled sample study using samples of convenience, J Toxicol Environ Health A, 2013, vol. 76, no. 18, pp. 1039-55.

A. M. Calafat, X. Ye, L. Y. Wong, J. A. Reidy, L. L. Needham, Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004, Environ Health Perspect, 2008, vol. 116, no. 1, pp. 39-44.

M. Tanaka, S. Nakaya, M. Katayama, H. Leffers, S. Nozawa, R. Nakazawa, et al., Effect of prenatal exposure to bisphenol A on the serum testosterone concentration of rats at birth, Hum Exp Toxicol, 2006, vol. 25, no. 7, pp. 369-73.

C. Tonini, M. Segatto, S. Bertoli, A. Leone, A. Mazzoli, L. Cigliano, et al., Prenatal Exposure to BPA: The Effects on Hepatic Lipid Metabolism in Male and Female Rat Fetuses, Nutrients, 2021, vol. 13, no. 6, pp.

V. Braniste, M. Audebert, D. Zalko, E. Houdeau, Bisphenol A in the Gut: Another Break in the Wall? Multi-System Endocrine Disruption. Research and Perspectives in Endocrine Interactions2011. p. 127-44.

C. Chelakkot, J. Ghim, S. H. Ryu, Mechanisms regulating intestinal barrier integrity and its pathological implications, Exp Mol Med, 2018, vol. 50, no. 8, pp. 1-9.

C. Li, Y. Zhou, P. Rychahou, H. L. Weiss, E. Y. Lee, C. L. Perry, et al., SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation, Cell Mol Gastroenterol Hepatol, 2020, vol. 10, no. 1, pp. 43-57.

L. Reddivari, D. N. R. Veeramachaneni, W. A. Walters, C. Lozupone, J. Palmer, M. K. K. Hewage, et al., Perinatal Bisphenol A Exposure Induces Chronic Inflammation in Rabbit Offspring via Modulation of Gut Bacteria and Their Metabolites, mSystems, 2017, vol. 2, no. 5, pp.

S. Ambreen, T. Akhtar, N. Hameed, I. Ashfaq, N. Sheikh, In Vivo Evaluation of Histopathological Alterations and Trace Metals Estimation of the Small Intestine in Bisphenol A-Intoxicated Rats, Can J Gastroenterol Hepatol, 2019, vol. 2019, no. 9292316, pp. 9292316.

L. N. Vandenberg, T. Colborn, T. B. Hayes, J. J. Heindel, D. R. Jacobs, Jr., D. H. Lee, et al., Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses, Endocr Rev, 2012, vol. 33, no. 3, pp. 378-455.

L. N. Vandenberg, S. Ehrlich, S. M. Belcher, N. Ben-Jonathan, D. C. Dolinoy, E. R. Hugo, et al., Low dose effects of bisphenol A: An integrated review of in vitro, laboratory animal, and epidemiology studies, Endocrine Disruptors, 2014, vol. 1, no. 1, pp.

G. L. Raja, C. Lite, K. D. Subhashree, W. Santosh, S. Barathi, Prenatal bisphenol-A exposure altered exploratory and anxiety-like behaviour and induced non-monotonic, sex-specific changes in the cortical expression of CYP19A1, BDNF and intracellular signaling proteins in F1 rats, Food Chem Toxicol, 2020, vol. 142, no., pp. 111442.

Z. Awada, F. Sleiman, A. Mailhac, Y. Mouneimne, H. Tamim, N. K. Zgheib, BPA exposure is associated with non-monotonic alteration in ESR1 promoter methylation in peripheral blood of men and shorter relative telomere length in peripheral blood of women, J Expo Sci Environ Epidemiol, 2019, vol. 29, no. 1, pp. 118-28.

J. H. Kim, M. A. Sartor, L. S. Rozek, C. Faulk, O. S. Anderson, T. R. Jones, et al., Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome, BMC Genomics, 2014, vol. 15, no. 30, pp.

M. Thoene, L. Rytel, E. Dzika, A. Wlodarczyk, E. Kruminis-Kaszkiel, P. Konrad, et al., Bisphenol A Causes Liver Damage and Selectively Alters the Neurochemical Coding of Intrahepatic Parasympathetic Nerves in Juvenile Porcine Models under Physiological Conditions, Int J Mol Sci, 2017, vol. 18, no. 12, pp.

K. Szymanska, K. Makowska, S. Gonkowski, The Influence of High and Low Doses of Bisphenol A (BPA) on the Enteric Nervous System of the Porcine Ileum, Int J Mol Sci, 2018, vol. 19, no. 3, pp.

L. Feng, S. Chen, L. Zhang, W. Qu, Z. Chen, Bisphenol A increases intestinal permeability through disrupting intestinal barrier function in mice, Environ Pollut, 2019, vol. 254, no. Pt A, pp. 112960.

J. A. DeLuca, K. F. Allred, R. Menon, R. Riordan, B. R. Weeks, A. Jayaraman, et al., Bisphenol-A alters microbiota metabolites derived from aromatic amino acids and worsens disease activity during colitis, Exp Biol Med (Maywood), 2018, vol. 243, no. 10, pp. 864-75.