In Utero and Lactational Exposure to Bisphenol A, In Contrast to Ethinyl Estradiol, Does Not Alter Sexually Dimorphic Behavior, Puberty, Fertility, and Anatomy of Female LE Rats

Abstract

Many chemicals released into the environment display estrogenic activity including the oral contraceptive ethinyl estradiol (EE2) and the plastic monomer bisphenol A (BPA). EE2 is present in some aquatic systems at concentrations sufficient to alter reproductive function of fishes. Many concerns have been raised about the potential effects of BPA. The National Toxicology Program rated the potential effects of low doses of BPA on behavior and central nervous system (CNS) as an area of "some concern," whereas most effects were rated as of "negligible" or "minimal" concern. However, the number of robust studies in this area was limited. The current study was designed to determine if maternal exposure to relatively low oral doses of EE2 or BPA in utero and during lactation would alter the expression of well-characterized sexually dimorphic behaviors or alter the age of puberty or reproductive function in the female Long-Evans rat offspring. Pregnant rats were gavaged with vehicle, EE2 (0.05-50 microg/kg/day), or BPA (2, 20, and 200 microg/kg/day) from day 7 of gestation to postnatal day (PND) 18, and the female offspring were studied. EE2 (50 microg/kg/day) increased anogenital distance and reduced pup body weight at PND2, accelerated the age at vaginal opening, reduced F1 fertility and F2 litter sizes, and induced malformations of the external genitalia (5 microg/kg). F1 females exposed to EE2 also displayed a reduced (male-like) saccharin preference (5 microg/kg) and absence of lordosis behavior (15 microg/kg), indications of defeminization of the CNS. BPA had no effect on any of the aforementioned measures. These results demonstrate that developmental exposure to pharmacologically relevant dosage levels of EE2 can permanently disrupt the reproductive morphology and function of the female rat.

Scientific Opinion on Bisphenol A: evaluation of a study investigating its neurodevelopmental toxicity, review of recent scientific literature on its toxicity and advice on the Danish risk assessment of Bisphenol A

“…This study shows no effects on male offspring regarding anogenital distance, age at puberty, morphology of external genitalia, areolae/nipple retention, reproductive organ weights and sperm numbers (Howdeshell et al, 2008). Also in female offspring, no effects on anogenital distance, age at puberty, morphology of external genitalia or fecundity were reported (Ryan et al, 2010a). The latter study also addressed specifically the impact of BPA on the sexually dimorphic behaviour of female rats, i.e.…”

“…In this section only in vivo studies fully compliant with the selection criteria set in section 3 "Introduction" (PART II) are addressed. To meet the request of the Danish Minister for Food, Agriculture and Fisheries, in this section also the studies by Ryan et al (2010a) and Howdeshell et al (2008) in female and male rats, respectively, of the same reproductive toxicity study are addressed (see section 5.2.1.1). EFSA Journal 2010; 8(9):1829 5.2.1.1.…”

“…In addition, previous evaluations of these studies revealed no consistent treatment-related effects in the behavioural endpoints and did not impact on the overall risk assessment (EFSA, 2006;EC, 2008). Also the review of more recently published studies, which do cover part of the shortcoming as indicated in this paragraph (in particular sexually dimorphic behaviour in females; see Ryan et al, 2010; discussed in Part II of this opinion) does not give rise to change the current position of the Panel. Other more recent studies on developmental neurotoxicity studies as reviewed in Part II were considered invalid or inadequate for risk assessment purposes.…”

“…However, in the absence of a correlation with a functional adverse effect, the relevance of these observations for human health cannot be assessed. The impact of BPA on development of sexually dimorphic behaviour was addressed in the study by Ryan et al (2010a), who observed a male-like reduced saccharin preference and inhibition of lordosis behaviour in female rat offspring from oestrogen-treated but not from BPA-treated dams. In the study reported by Stump et al (2009) The study by is the first oral study on a possible BPA-induced enhancement of sensitivity of the mammary gland to carcinogen-induced breast tumour formation in rat offspring following lactational BPA exposure of pups.…”

Endocrine disruptors and falling sperm counts: lessons learned or not!

“…It is noteworthy that two preeminent reproductive biologists who have made highly significant contributions to this field have developed scepticism on the claimed effects for BPA. Ryan and co-workers 60 showed that BPA did not alter sexually dimorphic behaviour, puberty, fertility or anatomy of female LongEvans rats, which contradicted prior results or conclusions drawn by other groups. In a commentary, Sharpe, 61 a coauthor of the initial endocrine disruptor hypothesis, clearly answered in the affirmative the title of his highlight 'Is it time to end concerns over the estrogenic effects of BPA?'.…”