Dynamic Postnatal Developmental and Sex-Specific Neuroendocrine Effects of Prenatal Polychlorinated Biphenyls in rats
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Gestational exposures to estrogenic compounds, both endogenous hormones and exogenous endocrine-disrupting chemicals (EDCs), have long-term effects on reproductive physiology and behavior. We tested the hypothesis that prenatal treatment of rats with low doses of Aroclor 1221 (A1221), a weakly estrogenic polychlorinated biphenyl mix previously used in industry, or estradiol benzoate (EB), alters development of the hypothalamus in a sexually dimorphic manner and subsequently perturbs reproductive function. Pregnant Sprague-Dawley rats were injected on embryonic days 16 and 18 with vehicle (dimethylsulfoxide), A1221 (1 mg/kg), or EB (50 μg/kg). Developmental milestones were monitored, and on postnatal days 15, 30, 45, and 90, 1 male and 1 female per litter were euthanized. Because of their key roles in the mediation of steroid actions on reproductive function, the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) were punched for a low-density quantitative PCR array of 48 neuroendocrine genes and analysis of DNA methylation of a subset of genes. Gestational exposure to A1221 or EB delayed the timing of puberty in males and disrupted estrous cyclicity in females. In the AVPV, 28 genes were affected by treatment in a developmental stage–specific manner, mostly in females, which exhibited a masculinized expression profile. This included 2 clock genes, Per2 and Arntl, implicating circadian circuits as being vulnerable to endocrine disruption. DNA methylation analysis of 2 genes, Per2 and Ar, showed no effect of EDCs and suggested alternative mechanisms for the altered mRNA levels. In the ARC, 12 genes were affected by treatment, mostly in males, again with dynamic developmental changes. Bionetwork analysis of relationships among genes, hormones, and physiological markers showed sexually dimorphic effects of estrogenic EDC exposures, with the female AVPV and the male ARC being most vulnerable, and provided novel relationships among hypothalamic genes and postnatal reproductive maturation.
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In female rats, PCB exposure increases gene expression profiles from P15-90 such that they are more similar to vehicle-treated male rats.
“In female rats, PCB exposure increases gene expression profiles from P15-90 such that they are more similar to vehicle-treated male rats [ 35 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [35]
Exposure of Sprague-Dawley rats to Aroclor 1221 at 1 mg/kg on GD16 and GD18 alters gene expression in a sex-specific manner, perturbing reproductive function by delaying time to puberty in males and altering cyclicity of estrous in females.
“Exposure of Sprague-Dawley rats to Aroclor 1221, a technical mixture of PCBs, at 1 mg/kg on GD16 and GD18 alters gene expression in a sex-specific manner, perturbing reproductive function by delaying time to puberty in males and altering cyclicity of estrous in females [ 35 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [35]
These results are confounded by the fact that DNA methylation levels for genes expressed in the AVPV at P15 are already low, which could limit levels of detection.
“These results are confounded by the fact that DNA methylation levels for genes expressed in the AVPV at P15 are already low, which could limit levels of detection [ 35 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [35]
DNA methylation at 4 CpG sites of Ar was positively correlated with Ar mRNA expression uniquely in the AVPV of females exposed to PCBs versus control females.
“Although PCB-induced changes in promoter DNA methylation were not detected in two genes upregulated by PCBs, including the androgen receptor ( Ar ), DNA methylation at 4 CpG sites of Ar was positively correlated with Ar mRNA expression uniquely in the AVPV of females exposed to PCBs versus control females [ 35 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [35]
PCB treatment increases expression of Dnmt1 from P15-90 in the female rat AVPV to levels that are more typical of male expression.
“This masculinization pattern is seen in Dnmt1 expression as well, with PCB treatment increasing expression of Dnmt1 from P15-90 in the female rat AVPV to levels that are more typical of male expression [ 35 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [35]
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Neuroendocrine disruption of reproduction
Moralia, M.-A., Fudvoye, J., & Parent, A. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-13825-6.00276-4
Ernstsen, C., Nielsen, B. S., Mjoseng, H. K., Nielsen, J. E., Christensen, S. L., Jensen, T. K., Lindahl‐Jacobsen, R., Johannsen, M. L., Styrishave, B., Hay‐Schmidt, A., et al. (2026) · Reproduction · doi:10.1093/reprod/xaag007
- Authors
- Walker, D. M., Goetz, B. M., & Gore, A. C.
- Affiliations
- The University of Texas at Austin (US)
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2014-01-01
- Volume
- 28
- Issue
- 1
- Pages
- 99-115
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC3874456
- OpenAlex
- W1983378305
- Cited by
- 73
- References
- 80
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 3 · 2018: 11 · 2017: 7 · 2016: 4 · 2015: 8 · 2014: 5
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01es020662-05)
- National Institute on Aging (F31AG034813)
- National Institute of Environmental Health Sciences (R01-ES020662, 1R01 ES020662, RC1ES018139)
- 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
- polychlorinated biphenyls, Aroclor 1221, estradiol benzoate, endocrine disruptors, prenatal estrogen exposure, hypothalamic development, anteroventral periventricular nucleus, arcuate nucleus, puberty onset, estrous cyclicity, DNA methylation, clock genes, Per2, Bmal1, reproductive maturation
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, Aroclors, Estradiol, Female, Growth Disorders, Male, Pregnancy, Prenatal Exposure Delayed Effects, Promoter Regions, Genetic, Puberty, Delayed, Receptors, Androgen, Sex Characteristics, Gonadal Steroid Hormones, Cluster Analysis, Rats, Sprague-Dawley, Gene Expression Regulation, Developmental, Maternal Exposure, DNA Methylation, Midline Thalamic Nuclei, Estrous Cycle, Rats, Endocrine Disruptors, Gene Regulatory Networks, Period Circadian Proteins, Transcriptome
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