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Cited by 102Effects and risks of endocrine disrupting chemicalsHypothalamic control of reproductive hormonesSexual Differentiation and Disorders

Neonatal bisphenol A exposure alters sexually dimorphic gene expression in the postnatal rat hypothalamus

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Cao, Jinyan, Mickens, Jillian A., McCaffrey, Katherine A., Leyrer, Stephanie M., Patisaul, Heather B.·2012·NeuroToxicology
DOI 10.1016/j.neuro.2011.11.002PMC PMC3273679
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Abstract

Developmental exposure to Bisphenol A (BPA), a component of polycarbonate and epoxy resins, has been purported to adversely impact reproductive function in female rodents. Because neonatal life is a critical window for the sexual dimorphic organization of the hypothalamic-pituitary-gonadal (HPG) axis, interference with this process could underlie compromised adult reproductive physiology. The goal of the present study was to determine if neonatal BPA exposure interferes with sex specific gene expression of estrogen receptor alpha (ERα), ER beta (ERβ) and kisspeptin (Kiss1) in the anterior and mediobasal hypothalamus. Long Evans (LE) neonatal rats were exposed to vehicle, 10μg estradiol benzoate (EB), 50mg/kg BPA or 50μg/kg BPA by subcutaneous injection daily from postnatal day 0 (PND 0) to PND 2. Gene expression was assessed by in situ hybridization on PNDs 4 and 10. Within the anterior hypothalamus ERα expression was augmented by BPA in PND 4 females, then fell to male-typical levels by PND 10. ERβ expression was not altered by BPA on PND 4, but significantly decreased or eliminated in both sexes by PND 10. Kiss1 expression was diminished by BPA in the anterior hypothalamus, especially in females. There were no significant impacts of BPA in the mediobasal hypothalamus. Collectively, BPA effects did not mirror those of EB. The results show that neonatal hypothalamic ER and Kiss1 expression is sensitive to BPA exposure. This disruption may alter sexually dimorphic hypothalamic organization and underlie adult reproductive deficiencies. Additionally, the discordant effects of EB and BPA indicate that BPA likely disrupts hypothalamic organization by a mechanism other than simply acting as an estrogen mimic.

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  • Developmental exposure to doses as low as 2.5 μg/kg bw sex specifically alters the mRNA expression of ERα and ERβ in sexually dimorphic hypothalamic and limbic subnuclei in the neonatal and older rat brain.

    “For example, we have repeatedly shown that developmental exposure to doses as low as 2.5 µg/kg bw sex specifically alters the mRNA expression of ERα and ERβ in sexually dimorphic hypothalamic and limbic subnuclei in the neonatal and older rat brain (86–90).”

    From Endocrine Disruption of Vasopressin Systems and Related Behaviors (2017) · cites this paper as [90]

    The Results (§§3.2–3.4; page unavailable) report sex-, age-, and region-dependent changes in hypothalamic ERα and ERβ mRNA after neonatal BPA exposure. But Materials and Methods (§2.1; page unavailable) specifies a lowest dose of 50 µg/kg body weight, not 2.5 µg/kg, and animals were examined only on postnatal days 4 and 10. This paper does not establish effects in limbic subnuclei or older rats. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Developmental BPA exposure can perturb ERα and ERβ gene expression throughout the rat hypothalamus and components of the mesolimbic dopamine system, including the PVN and BnST, across the lifespan.

    “We have repeatedly shown that developmental BPA exposure can perturb ERα and ERβ gene expression throughout the rat hypothalamus and components of the mesolimbic dopamine system, including the PVN and BnST (86–90), across the lifespan.”

    From Endocrine Disruption of Vasopressin Systems and Related Behaviors (2017) · cites this paper as [90]

    The Discussion (page unavailable) reports that neonatal BPA exposure altered ERα and ERβ expression in the postnatal rat hypothalamus in a region- and time-specific manner. The Methods identify the regions measured as the AVPV, MPOA, VMNvl, and ARC—not the PVN, BnST, or mesolimbic dopamine system. The study measured expression on postnatal days 4 and 10; it suggests possible lifelong consequences but does not demonstrate expression changes across the lifespan. (LLM, conf=0.90)

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Authors
Cao, J., Mickens, J. A., McCaffrey, K. A., Leyrer, S. M., & Patisaul, H. B.
Affiliations
North Carolina State University (US)
Corresponding author
Patisaul, Heather B.
ORCID
Venue
NeuroToxicology
Publisher
Elsevier BV
Published
2012-01
Volume
33
Issue
1
Pages
23-36
ISSN
0161-813X (ISSN-L)
DOI
10.1016/j.neuro.2011.11.002
PMC
PMC3273679
OpenAlex
W2052517186
Cited by
102
References
6
Citations by year
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FWCI
5.63
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • NeuroToxicology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Environmental Health Sciences (R01ES016001)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
bisphenol A, sexually dimorphic gene expression, hypothalamus, estrogen receptor alpha, estrogen receptor beta, kisspeptin, anterior hypothalamus, mediobasal hypothalamus, hypothalamic-pituitary-gonadal axis, estradiol benzoate, reproductive disorders
MeSH terms
Bisphenol A Compounds, Age Factors, Analysis of Variance, Animals, Animals, Newborn, Benzhydryl Compounds, Estrogens, Non-Steroidal, Female, Hypothalamus, Male, Phenols, RNA, Messenger, Sex Characteristics, Gene Expression Regulation, Developmental, Rats, Long-Evans, Estrogen Receptor alpha, Estrogen Receptor beta, Rats, Kisspeptins

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