Oxidative and Hormonal Disruptions Underlie Bisphenol A - Induced Testicular Toxicity in Male Rabbits
The presence of endocrine-disrupting compounds,
such as bisphenol A (BPA), in the environment can cause serious
health problems. However, there are controversial opinions. This
study investigated the reproductive, metabolic, oxidative and
immunologic-disrupting effects of bisphenol A in male rabbits.
Rabbits were divided into five groups. The first four rabbit groups
were administered oral BPA (1, 10, 50, or 100 mg/kg/day) for ten
weeks. The fifth group was administered corn oil as the vehicle. BPA
significantly decreased serum testosterone, estradiol and the free
androgen index (FAI) and significantly increased sex hormone
binding globulin (SHBG) compared with the placebo group. The
higher doses of BPA showed a significant decrease in follicular
stimulating hormone (FSH) and luteinizing hormone (LH). A
significant increase in blood glucose levels was identified in the BPA
groups. The non-significant difference in insulin levels is a novel
finding. The cumulative testicular toxicity of BPA was clearly
demonstrated by the dose-dependent decrease in absolute testes
weight, primary measures of semen quality and a significant increase
in testicular malonaldehyde (MDA). Moreover, BPA significantly
decreased total antioxidant capacity (TAC) and significantly
increased immunoglobulin G (IgG) at the highest concentration. Our
results suggest that BPA, especially at higher doses, is associated
with many adverse effects on metabolism, oxidative stress, immunity,
sperm quality and markers of androgenic action.
 L.N. Vandeberg, M.V. Maffini, C. Sonnenschein, B.S. Rubin, A.M.
Soto, Bisphenol-A and the great divide: a review of controversies in the
filed of endocrine disruption. Endocrine Review, vol. 30(1), pp. 75-95,
 US Environmental Protection Agency, Memorandum to EDSTAC
Members RE: Definition of “Endocrine Disruptor”. Washington D.C.,
 A.K. Hotchkiss, C.V. Rider, C.R. Blystone, V.S. Wilson, P.C. Hartig,
G.T. Ankley, P.M. Foster, C.L. Gray, Fifteen years after “wingspread”
environmental endocrine disrupters and human and wildlife health:
where we are today and where we need to go. Toxicology Sciences, vol.
105, pp. 235-259, 2008.
 I.R. Falconer, H.F. Chapman, M.R. Moore, G. Ranmuthugala,
Endocrine-disrupting compounds: a review of their challenge to
sustainable and safe water supply and water reuse. Environmental
Toxicology, vol. 21, pp. 181-191, 2006.
 L.N. Vandenberg, Human exposure to bisphenol A. Reproductive
Toxicology, vol. 24(2), pp. 139-177, 2007.
 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 Perspectives, vol. 116(1), pp. 39-44, 2008.
 C.S. Mazur, J.F. Kenneke, J.K. Hess-Wilson, J.C. Lipscomb,
Differences between human and rat intestinal and hepatic bisphenol A
glucuronidation and the influence of alamethicin on in vitro kinetic
measurements. Drug Metabolism, vol. 38 (12), pp. 2232-2238, 2010.
 F.S. Vom Saal, “Chapel hill bisphenol A expert panel consensus
statement: integration of mechanisms, effects in animals and potential to
impact human health at current levels of exposure,” Reproductive
Toxicology, vol. 8, pp. 131-138, 2008.
 L.N. Vandenberg, T. Colborn, T.B. Hayes, “Hormones and endocrinedisrupting
chemicals: low-dose effects and nonmonotonic dose
responses.” Endocrine Review, vol. 6, pp. 254-261, 2012.
 S.H. Lam, M.M. Hlaing, X. Zhang, “Toxicogenomic and phenotypic
analyses of bisphenol-A early-life exposure toxicity in zebrafish,” Plos
One. Vol. 6 (12), pp. 282-289, 2011.
 L.C. Saalu, A.O. Adesanya, A.O. Oyewopo, Y. Raji, An evaluation of
the deleterious effect of unilateral cryptorchidism on the contralateral
normally descended testis. Scientific Research Essays, vol. 2(3), pp. 74-
 WHO. World health organization laboratory manual for the examination
of human semen and semen-cervical mucus interactions. 4th ed.
Cambridge, UK/New York: Cambridge University Press, 1999.
 R.E. Chapin, J. Adams, K. Boekelheide, “NTP-CERHR expert panel
report on the reproductive and developmental toxicity of bisphenol A,”
Birth Defects Research, vol. 83 (3), pp. 157–395, 2008.
 M. Razzoli, P. Valsecchi, P. Palanza, “Chronic exposure to low doses
bisphenol A interferes with pair-bonding and exploration in female
Mongolian gerbils,” Brain Reseach Bulletin, vol. 65 (3), pp. 249–254 ,
 K. Yamasaki, M. Sawaki, S. Noda, N. Imatanaka, M. Takatsuki,
“Subacute oral toxicity study of ethynylestradiol and bisphenol A, based
on the draft protocol for the ‘enhanced OECD test guideline no. 407’.
Archive Toxicology, vol. 76 (2), pp. 65–74, 2002.
 F. Lahnsteiner, B. Berger, M. Kletz, T. Weismann, Effect of Bisphenol
A on maturation and quality of semen and eggs in the brown trout,
Salmo trutta f. fario. Aquatic Toxicology, vol. 75, pp. 213-224, 2005.
 P. Labadie, H. Budzinski, Alteration of steroid hormone balance in
juvenile turbot (Psetta maxima) exposed to nonylphenol, bisphenol A,
tetrabromodiphenyl ether 47, diallylphthalate, oil, and oil spiked with
alkylphenols. Archive Environmental Contamination Toxicology, vol.
50, pp. 552-561, 2006.
 E. Haubruge, F. Petit, M.J. Gage, Reduced sperm counts in guppies
(Poecilia reticulata) following exposure to low levels of tributylin and
bisphenol A. Biologial Sciences, vol. 1459, pp. 2333-2337, 2000.
 C.A. Richter, L.S. Birnbaum, F. Farabollini, R.R. Newbold, B.S. Rubin,
C.E. Talsness, In vivo effects of bisphenol A in laboratory rodent
studies. Reproductive Toxicology, vol. 24, pp. 199–224, 2007.
 C.B. Herath, W. Jin, G. Watanabe, K. Arai, A.K. Suzuki, K. Taya,
Adverse effects of environmental toxicants, octylphenol and bisphenol
A, on male reproductive functions in pubertal rats. Endocrine. Vol. 25,
pp. 163–172, 2004.
 A. Tohei, S. Suda, K. Taya, T. Hashimoto, H. Kogo, Bisphenol A
inhibits testicular functions and increases luteinizing hormone secretion
in adult male rats. Experimental Biological Medicine, vol. 226, pp. 216–
 A. Norazit, J. Mohamad, S. Abdul Razak, M.A. Abdulla, A. Azmil,
M.A. Mohd, Effects of soya bean extract, bisphenol A and 17β-estradiol
on the testis and circulating levels of testosterone and estradiol among
peripubertal juvenile male sprague-dawley rats. Sains Malaysiana, vol.
41(1), pp. 63–69, 2012.
 O. Takahashi, S. Oishi, Testicular toxicity of dietary or parenterally
administered bisphenol A in rats and mice. Food and Chemical
Toxicology, vol. 41, pp. 1035-1044, 2003.
 Y. Toyama, S. Yuasa, Effects of neonatal administration of 17β-
estradiol, β-estradiol 3-benzoate, or bisphenol A on mouse and rat
spermatogenesis. Reproductive Toxicology, vol. 19, pp. 181-188, 2004.
 A. Hossaini, M. Dalgaard, A.M. Vinggaard, P. Pararinen, J.J. Larsen,
Male reproductive effects of octylphenol and estradiol in Fischer and
Wistar rats. Reproductive Toxicology, vol. 17, pp. 607-615, 2003.
 M. Furuya, F. Sasaki, A.M.A. Hassanin, S. Kuwahara, Y. Tsukamoto,
Effects of bisphenol-A on the growth of comb and testes of male
chicken. Candian Journal of Veterinary Research, vol. 67, pp. 68-71,
 T. Hanaoka, N. Kawamura, K. Hara, S. Tsugane, Urinary bisphenol A
and plasma hormone concentrations in male workers exposed to
bisphenol A diglycidyl ether and mixed organic solvents. Occupational
Environmental Medicine, vol. 59, pp. 625–628, 2002.
 J.D. Meeker, A.M. Calafat, R. Hauser, Urinary bisphenol A
concentrations in relation to serum thyroid and reproductive hormone
levels in men from an infertility clinic. Environmental Science
Technology, vol. 44, pp. 1458–1463, 2010.
 R.M. Sharpe, N.E. Skakkebaek, Testicular dysgenesis syndrome:
mechanistic insights and potential new downstream effects. Fertility and
Sterility, vol. 89(2), pp. 33–38, 2008.
 RJ. Witorsch, Endocrine disruptors: can biological effects and
environmental risks be predicted? Regulatory Toxicology and
Pharmacology vol. 36, pp. 118-130, 2002.
 R.W. Stahlhut, W.V. Welshons, S.H. Swan, Bisphenol-A data in
NHANES suggest longer than expected half-life, substantial nonfood
exposure, or both. Environmental Health Perspective, vol. 117, pp. 784-
 R. Urbatzka, A. van Cauwenberge, S. Maggioni, L. Viganò, A.
Mandich, E. Benfenati, I. Lutz, W. Kloas, Androgenic and
antiandrogenic activities in water and sediment samples from the river
Lambro, Italy, detected by yeast androgen screen and chemical analyses.
Chemosphere, vol. 67, pp. 1080-1087, 2007.
 G. Pelletier, Localization of androgen and estrogen receptors in rat and
primate tissues. Histology and Histopathology, vol. 15, pp. 1261–1270,
 J.S. Finkelstein, O’Dea, L.S. R.W. Whitcomb, W.F. Crowley, Sex
steroid control of gonadotropin secretion in the human male. II. Effects
of estradiol administration in normal and gonadotropin-releasing
hormone-deficient men. Journal Clinical Endocrinology Metabolism,
vol. 73, pp. 621–628, 1991.
 B.T. Akingbemi, C.M. Sottas, A.I. Koulova, G.R. Klinefelter, M.P.
Hardy, Inhibition of testicular steroidogenesis by the xenoestrogen
bisphenol A is associated with reduced pituitary luteinizing hormone
secretion and decreased steroidogenic enzyme gene expression in rat
Leydig cells. Endocrinology, vol. 145, pp, 592–603, 2004.
 Y.B. Wetherill, B.T. Akingbemi, J. Kanno, J.A. McLachlan, A. Nadal,
C. Sonnenschein, In vitro molecular mechanisms of bisphenol A action.
Reproductive Toxicology, vol. 24, pp. 178–198, 2007.
 D. Li, Z. Zhou, D. Qing, Y. He, T. Wu, M. Miao, Occupational exposure
to bisphenol-A (BPA) and the risk of self-reported male sexual
dysfunction. Human. Reproduction, vol. 25(2), pp. 519–527, 2010.
 K.C. Chitra, C. Latchoumycandane, P.P. Mathur, Induction of oxidative
stress by bisphenol A in the epididymal sperm of rats. Toxicology, vol.
185, pp. 119-127, 2003.
 M. Aydoğan, A. Korkmaz, N. Barlas, D. Kolankaya, Pro-oxidant effect
of vitamin C coadministration with bisphenol A, nonylphenol, and
octylphenol on the reproductive tract of male rats. Drug Chemical
Toxicology, vol. 33(2), pp. 193-203, 2010.
 P. Kovacic, How safe is bisphenol A? Fundamentals of toxicity:
metabolism, electron transfer and oxidative stress. Medical Hypotheses,
vol. 75(1), pp. 1-4, 2010.
 T. Takeuchi, O. Tsutsumi, Serum bisphenol A concentrations showed
gender differences, possibly linked to androgen levels. Biochemistry
Biophysics. Research Communication, vol. 291, pp. 76–78, 2002.
 K. Halldin, C. Berg, A. Bergman, I. Brandt, B. Brunström, Distribution
of bisphenol A and tetrabromobisphenol A in quail eggs, embryos and
laying birds and studies on reproduction variables in adults following in
ovo exposure. Archive Toxicology, vol. 75, pp. 597-603, 2001.
 P. Nieminen, P. Lindstrom-Seppa, A. Mustonen, H. Mussalo-Rauhamaa,
J.V.K. Kukkonen, Bisphenol A affects endocrine physiology and
biotransformation enzyme activities of the field vole (Microtus agrestis).
Gen. Comparative Endocrinology, vol. 126, pp. 183-189, 2002a.
 H. Kato, T. Furuhashi, M. Tanaka, Y. Katsu, H. Watanabe, Y. Ohta, T.
Iguchi, Effects of bisphenol A given neonatally on reproductive
functions of male rats. Reproductive Toxicology, vol. 22, pp. 20-29,
 E.P. Murono, R.C. Derk, J.H. de Leon, Differential effects of
octylphenol, 17β-estradiol, endosulfan, or bisphenol A on the
steroidogenic competence of cultured adult Leydig cells. Reproductive
Toxicology, vol. 15, pp. 551-560, 2001.
 T.M. Batista, P. Onso-Magdalena, E. Vieira, M.E. Amaral, C.R.
Cederroth, S. Nef, I. Quesada, E.M. Carneiro, A. Nadal, Short-term
treatment with bisphenol-A leads to metabolic abnormalities in adult
male mice. Plos One, vol. 7(3), pp. 338-344, 2012.
 S. Soriano, P. Alonso-Magdalena, M. García-Arévalo, A. Novials, S.J.
Muhammed, Rapid insulinotropic action of low doses of bisphenol-a on
mouse and human islets of langerhans: role of estrogen receptor β. PLos
One. vol. 7(2), pp. 311-318, 2012.
 F.S. Vom Saal, S.C. Nagel, B.L. Coe, B.M. Angle, J.A. Taylor, The
estrogenic endocrine disrupting chemical bisphenol A (BPA) and
obesity. Moleculae Cell Endocrinology, vol. 354(1-2), pp. 74-84, 2012.
 I.A. Lang, T.S. A. Galloway, Scarlett, “Association of urinary bisphenol
a concentration with medical disorders and laboratory abnormalities in
adults.” Journal of American Medicine Association, vol. 11, pp. 1303-
 D. Melzer, "Urinary bisphenol: A concentration and risk of future
coronary artery disease in apparently healthy men and women."
Circulation, vol. 125(12), pp. 1482-90, 2012.
 E.R. Hugo, T.D. Brandebourg, J.G. Woo, “Bisphenol A at
environmentally relevant doses inhibits adiponectin release from human
adipose tissue explants and adipocytes,” Environmental Health
Perspective, vol. 116 (12), pp. 1642-1647, 2008.
 S.C. D´ Cruz, R. Jubendradass, M. Jaykanthan, S.J.A. Rani, P.P. Mathur,
Bisphenol A impairs insulin signalling and glucose homeostasis and
decreases steroidogenesis in rat testis: An in vivo and in silico study.
Food and Chemical Toxicology, vol. 1(1), pp. 41-49, 2011.
 S.A. Ahmed, The immune system as a potential target for environmental
estrogens (endocrine disrupters): a new emerging field. Toxicology, vol.
150(1–3), pp. 191–206, 2000.
 H. Ishibashi, N. Matsumura, M. Hirano, M. Matsuoka, H. Shiratsuchi,
Y. Ishibashi, Effects of triclosan on the early life stages and reproduction
of medaka Oryzias latipes and induction of hepatic vitellogenin. Aquatic
Toxicology, vol. 67(2), pp. 167–179, 2004.
 J.J. Segura, A. Jiménez-Rubio, R. Pulgar, N. Olea, Guerrero, J.M.;
Calvo, J.R. In vitro effect of the resin component bisphenol A on
substrate adherence capacity of macrophages. Journal Endocrinology,
vol. 25(5), pp. 341–344, 1999.
 R.R. Dietert, J.C. Dewitt, D.R. Germolec, J.T. Zelikoff, Breaking
patterns of environmentally influenced disease for health risk reduction:
immune perspectives. Environmental Health Perspective, vol. 118, pp.