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Published on: November 20, 2015
Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus
Sarah M Dickerson1, Stephanie L Cunningham, Andrea C Gore
1Center for Molecular and Cellular Toxicology, Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX 78712, USA.
Insights
Prenatal exposure to endocrine disrupting chemicals (EDCs) like polychlorinated biphenyls (PCBs) alters hypothalamic gene expression and apoptosis in neonatal rats, impacting brain sexual differentiation and future reproductive health.
Area of Science:
- Neuroendocrinology
- Developmental Toxicology
- Environmental Health
Background:
- Neonatal exposure to endocrine disrupting chemicals (EDCs) can disrupt hormone-sensitive developmental processes, including brain sexual differentiation.
- Polychlorinated biphenyls (PCBs) are common EDCs with potential to interfere with neurodevelopment.
Purpose of the Study:
- To investigate whether gestational EDC exposure alters hypothalamic gene and protein expression as early as postnatal day 1.
- To assess the impact of PCBs and estradiol benzoate (EB) on apoptosis and estrogen receptor alpha (ERα) expression in sexually dimorphic hypothalamic regions.
Main Methods:
- Pregnant Sprague-Dawley rats were exposed to Aroclor 1221 (A1221), a PCB mixture, or estradiol benzoate (EB) on gestational days 16 and 18.
- On postnatal day 1, pups were assessed for anogenital distance (AGD) and body weight.
- Hypothalamic tissue (preoptic area, AVPV, MPN) was analyzed for apoptosis (TUNEL), ERα expression (immunohistochemistry), and gene expression (qPCR).
Main Results:
- Gestational EB or A1221 exposure caused sex-specific increases in apoptosis in the anteroventral periventricular nucleus (AVPV) of females.
- EB treatment increased ERα expression in the medial preoptic nucleus (MPN) in both sexes; A1221 and PCB mixtures had no effect.
- Prenatal EDC exposure altered the expression of nine genes in the preoptic area (POA) in a sex- and treatment-dependent manner.
Conclusions:
- Disrupted sexual differentiation of the hypothalamus by prenatal EDC exposure is detectable as early as postnatal day 1.
- These early alterations may impact postnatal development and compromise adult reproductive function.
- Neonatal exposure to EDCs like PCBs can have lasting effects on neuroendocrine development.
Abstract:
Neonatal exposure to endocrine disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) can interfere with hormone-sensitive developmental processes, including brain sexual differentiation. We hypothesized that disruption of these processes by gestational PCB exposure would be detectable as early as the day after birth (postnatal day (P) 1) through alterations in hypothalamic gene and protein expression. Pregnant Sprague-Dawley rats were injected twice, once each on gestational days 16 and 18, with one of the following: DMSO vehicle; the industrial PCB mixture Aroclor 1221 (A1221); a reconstituted mixture of the three most prevalent congeners found in humans, PCB138, PCB153, and PCB180; or estradiol benzoate (EB). On P1, litter composition, anogenital distance (AGD), and body weight were assessed. Pups were euthanized for immunohistochemistry of estrogen receptor α (ERα) or TUNEL labeling of apoptotic cells or quantitative PCR of 48 selected genes in the preoptic area (POA). We found that treatment with EB or A1221 had a sex-specific effect on developmental apoptosis in the neonatal anteroventral periventricular nucleus (AVPV), a sexually dimorphic hypothalamic region involved in the regulation of reproductive neuroendocrine function. In this region, exposed females had increased numbers of apoptotic nuclei, whereas there was no effect of treatment in males. For ERα, EB treatment increased immunoreactive cell numbers and density in the medial preoptic nucleus (MPN) of both males and females, while A1221 and the PCB mixture had no effect. PCR analysis of gene expression in the POA identified nine genes that were significantly altered by prenatal EDC exposure, in a manner that varied by sex and treatment. These genes included brain-derived neurotrophic factor, GABA(B) receptors-1 and -2, IGF-1, kisspeptin receptor, NMDA receptor subunits NR2b and NR2c, prodynorphin, and TGFα. Collectively, these results suggest that the disrupted sexual differentiation of the POA by prenatal EDC exposures is already evident as early as the day after birth, effects that may change the trajectory of postnatal development and compromise adult reproductive function.
