@article{cao_rebuli_rogers_todd_leyrer_ferguson_patisaul_2013, title={Prenatal Bisphenol A Exposure Alters Sex-Specific Estrogen Receptor Expression in the Neonatal Rat Hypothalamus and Amygdala}, volume={133}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kft035}, abstractNote={Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERβ) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6-21 with vehicle, 2.5 or 25 μg/kg bw/day BPA, or 5 or 10 μg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Cao, Jinyan and Rebuli, Meghan E. and Rogers, James and Todd, Karina L. and Leyrer, Stephanie M. and Ferguson, Sherry A. and Patisaul, Heather B.}, year={2013}, month={May}, pages={157–173} }
 @article{losa-ward_todd_mccaffrey_tsutsui_patisaul_2012, title={Disrupted Organization of RFamide Pathways in the Hypothalamus Is Associated with Advanced Puberty in Female Rats Neonatally Exposed to Bisphenol A}, volume={87}, ISSN={["1529-7268"]}, DOI={10.1095/biolreprod.112.100826}, abstractNote={ABSTRACT Hypothalamic neurons, which produce the kisspeptin family of peptide hormones (Kp), are critical for initiating puberty and maintaining estrous cyclicity by stimulating gonadotropin-releasing hormone (GnRH) release. Conversely, RFamide-related peptide-3 (RFRP3) neurons inhibit GnRH activity. It has previously been shown that neonatal exposure to bisphenol A (BPA) can alter the timing of female pubertal onset and induce irregular estrous cycles or premature anestrus. Here we tested the hypothesis that disrupted ontogeny of RFamide signaling pathways may be a mechanism underlying advanced puberty. To test this, we used a transgenic strain of Wistar rats whose GnRH neurons express enhanced green fluorescent protein. Pups were exposed by daily subcutaneous injection to vehicle, 17beta-estradiol (E2), 50 μg/kg BPA, or 50 mg/kg BPA, from Postnatal Day (PND) 0 through PND 3, and then cohorts were euthanized on PNDs 17, 21, 24, 28, and 33 (5–8 animals per age per exposure; males were collected on PNDs 21 and 33). Vaginal opening was advanced by E2 and 50 μg/kg BPA. On PND 28, females exposed to E2 and 50 μg/kg BPA had decreased RFRP-3 fiber density and contacts on GnRH neurons. RFRP3 perikarya were also decreased in females exposed to 50 μg/kg BPA. Data suggest that BPA-induced premature puberty results from decreased inhibition of GnRH neurons.}, number={2}, journal={BIOLOGY OF REPRODUCTION}, author={Losa-Ward, Sandra M. and Todd, Karina L. and McCaffrey, Katherine A. and Tsutsui, Kazuyoshi and Patisaul, Heather B.}, year={2012}, month={Aug} }
 @article{losa_todd_sullivan_cao_mickens_patisaul_2011, title={Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat}, volume={31}, ISSN={["0890-6238"]}, DOI={10.1016/j.reprotox.2010.10.002}, abstractNote={Neonatal exposure to estrogenic endocrine disrupting compounds (EDCs) can advance pubertal onset and induce premature anestrous in female rats. It was recently discovered that hypothalamic kisspeptin (KISS) signaling pathways are sexually dimorphic and regulate both the timing of pubertal onset and estrous cyclicity. Thus we hypothesized that disrupted sex specific ontogeny of KISS signaling pathways might be a mechanism underlying these EDC effects. We first established the sex specific development of KISS gene expression, cell number and neural fiber density across peripuberty in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), hypothesizing that the sexually dimorphic aspects of KISS signaling would be most vulnerable to EDCs. We next exposed female rats to the phytoestrogen genistein (GEN, 1 or 10 mg/kg bw), estradiol benzoate (EB, 10 μg), or vehicle from post natal day (P) 0-3 via subcutaneous (sc) injection. Animals were sacrificed on either P21, 24, 28, or 33 (n=5-14 per group at each age). Vaginal opening was significantly advanced by EB and the higher dose of GEN compared to control animals and was accompanied by lower numbers of KISS immunoreactive fibers in the AVPV and ARC. Ovarian morphology was also assessed in all age groups for the presence of multiple oocyte follicles (MOFs). The number of MOFs decreased over time in each group, and none were observed in control animals by P24. MOFs were still present, however, in the EB and 10 mg/kg GEN groups beyond P24 indicating a disruption in the timing of ovarian development.}, number={3}, journal={REPRODUCTIVE TOXICOLOGY}, author={Losa, Sandra M. and Todd, Karina L. and Sullivan, Alana W. and Cao, Jinyan and Mickens, Jillian A. and Patisaul, Heather B.}, year={2011}, month={Apr}, pages={280–289} }
 @article{adewale_todd_mickens_patisaul_2011, title={The impact of neonatal bisphenol-A exposure on sexually dimorphic hypothalamic nuclei in the female rat}, volume={32}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2010.07.008}, abstractNote={Now under intense scrutiny, due to its endocrine disrupting properties, the potential threat the plastics component bisphenol-A (BPA) poses to human health remains unclear. Found in a multitude of polycarbonate plastics, food and beverage containers, and medical equipment, BPA is thought to bind to estrogen receptors (ERs), thereby interfering with estrogen-dependent processes. Our lab has previously shown that exposure to BPA (50mg/kg bw or 50μg/kg bw) during the neonatal critical period is associated with advancement of puberty, early reproductive senescence and ovarian malformations in female Long Evans rats. Here, using neural tissue obtained from the same animals, we explored the impact of neonatal BPA exposure on the development of sexually dimorphic hypothalamic regions critical for female reproductive physiology and behavior. Endpoints included quantification of oxytocin-immunoreactive neurons (OT-ir) in the paraventricular nucleus (PVN), serotonin (5-HT-ir) fiber density in the ventrolateral subdivision of the ventromedial nucleus (VMNvl) as well as ERα-ir neuron number in the medial preoptic area (MPOA), the VMNvl, and the arcuate nucleus (ARC). Both doses of BPA increased the number of OT-ir neurons within the PVN, but no significant effects were seen on 5-HT-ir fiber density or ERα-ir neuron number in any of the areas analyzed. In addition to hypothalamic development, we also assessed female sex behavior and body weight. No effect of BPA on sexual receptivity or proceptive behavior in females was observed. Females treated with BPA, however, weighed significantly more than control females by postnatal day 99. This effect of BPA on weight is critical because alterations in metabolism, are frequently associated with reproductive dysfunction. Collectively, the results of this and our prior study indicate that the impact of neonatal BPA exposure within the female rat hypothalamus is region specific and support the hypothesis that developmental BPA exposure may adversely affect reproductive development in females.}, number={1}, journal={NEUROTOXICOLOGY}, author={Adewale, Heather B. and Todd, Karina L. and Mickens, Jillian A. and Patisaul, Heather B.}, year={2011}, month={Jan}, pages={38–49} }
 @article{patisaul_todd_mickens_adewale_2009, title={Impact of neonatal exposure to the ERα agonist PPT, bisphenol-A or phytoestrogens on hypothalamic kisspeptin fiber density in male and female rats}, volume={30}, ISSN={0161-813X}, url={http://dx.doi.org/10.1016/j.neuro.2009.02.010}, DOI={10.1016/j.neuro.2009.02.010}, abstractNote={Neonatal exposure to endocrine disrupting compounds (EDCs) can impair reproductive physiology, but the specific mechanisms by which this occurs remain largely unknown. Growing evidence suggests that kisspeptin (KISS) neurons play a significant role in the regulation of pubertal onset and ovulation, therefore disruption of KISS signaling could be a mechanism by which EDCs impair reproductive maturation and function. We have previously demonstrated that neonatal exposure to phytoestrogens decreases KISS fiber density in the anterior hypothalamus of female rats, an effect which was associated with early persistent estrus and the impaired activation gonadotropin releasing hormone (GnRH) neurons. The goals of the present study were to (1) determine if an ERalpha selective agonist (PPT) or bisphenol-A (BPA) could produce similar effects on hypothalamic KISS content in female rats and (2) to determine if male KISS fiber density was also vulnerable to disruption by EDCs. We first examined the effects of neonatal exposure to PPT, a low (50 microg/kg bw) BPA dose, and a high (50 mg/kg bw) BPA dose on KISS immunoreactivity (-ir) in the anterior ventral periventricular (AVPV) and arcuate (ARC) nuclei of adult female rats, using estradiol benzoate (EB) and a sesame oil vehicle as controls. AVPV KISS-ir, following ovariectomy (OVX) and hormone priming, was significantly lower in the EB and PPT groups but not the BPA groups. ARC KISS-ir levels were significantly diminished in the EB and high dose BPA groups, and there was a nonsignificant trend for lower KISS-ir in the PPT group. We next examined effects of neonatal exposure to a low (50 microg/kg bw) dose of BPA and the phytoestrogens genistein (GEN) and equol (EQ) on KISS-ir in the AVPV and ARC of adult male rats, using OVX females as an additional control group. None of the compounds affected KISS-ir in the male hypothalamus. Our results suggest that the organization of hypothalamic KISS fibers may be vulnerable to disruption by EDC exposure and that females might be more sensitive than males.}, number={3}, journal={NeuroToxicology}, publisher={Elsevier BV}, author={Patisaul, Heather B. and Todd, Karina L. and Mickens, Jillian A. and Adewale, Heather B.}, year={2009}, month={May}, pages={350–357} }