@article{patisaul_mabrey_adewale_sullivan_2014, title={Soy but not bisphenol A (BPA) induces hallmarks of polycystic ovary syndrome (PCOS) and related metabolic co-morbidities in rats}, volume={49}, ISSN={["0890-6238"]}, DOI={10.1016/j.reprotox.2014.09.003}, abstractNote={Polycystic ovarian syndrome (PCOS) is the most common female endocrine disorder with a prevalence as high as 8-15% depending on ethnicity and the diagnostic criteria employed. The basic pathophysiology and mode of inheritance remain unclear, but environmental factors such as diet, stress and chemical exposures are thought to be contributory. Developmental exposure to endocrine disrupting compounds (EDCs) have been hypothesized to exacerbate risk, in part because PCOS hallmarks and associated metabolic co-morbidities can be reliably induced in animal models by perinatal androgen exposure. Here we show that lifetime exposure to a soy diet, containing endocrine active phytoestrogens, but not developmental exposure (gestational day 6-lactational day 40) to the endocrine disrupting monomer bisphenol A (BPA), can induce key features of PCOS in the rat; results which support the hypothesis that hormonally active diets may contribute to risk when consumed throughout gestation and post-natal life.}, journal={REPRODUCTIVE TOXICOLOGY}, author={Patisaul, Heather B. and Mabrey, Natalie and Adewale, Heather B. and Sullivan, Alana W.}, year={2014}, month={Nov}, pages={209–218} }
 @article{patisaul_sullivan_radford_walker_adewale_winnik_coughlin_buckley_gore_2012, title={Anxiogenic Effects of Developmental Bisphenol A Exposure Are Associated with Gene Expression Changes in the Juvenile Rat Amygdala and Mitigated by Soy}, volume={7}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0043890}, abstractNote={Early life exposure to Bisphenol A (BPA), a component of polycarbonate plastics and epoxy resins, alters sociosexual behavior in numerous species including humans. The present study focused on the ontogeny of these behavioral effects beginning in adolescence and assessed the underlying molecular changes in the amygdala. We also explored the mitigating potential of a soy-rich diet on these endpoints. Wistar rats were exposed to BPA via drinking water (1 mg/L) from gestation through puberty, and reared on a soy-based or soy-free diet. A group exposed to ethinyl estradiol (50 µg/L) and a soy-free diet was used as a positive estrogenic control. Animals were tested as juveniles or adults for anxiety-like and exploratory behavior. Assessment of serum BPA and genistein (GEN), a soy phytoestrogen, confirmed that internal dose was within a human-relevant range. BPA induced anxiogenic behavior in juveniles and loss of sexual dimorphisms in adult exploratory behavior, but only in the animals reared on the soy-free diet. Expression analysis revealed a suite of genes, including a subset known to mediate sociosexual behavior, associated with BPA-induced juvenile anxiety. Notably, expression of estrogen receptor beta (Esr2) and two melanocortin receptors (Mc3r, Mc4r) were downregulated. Collectively, these results show that behavioral impacts of BPA can manifest during adolescence, but wane in adulthood, and may be mitigated by diet. These data also reveal that, because ERβ and melanocortin receptors are crucial to their function, oxytocin/vasopressin signaling pathways, which have previously been linked to human affective disorders, may underlie these behavioral outcomes.}, number={9}, journal={PLOS ONE}, author={Patisaul, Heather B. and Sullivan, Alana W. and Radford, Meghan E. and Walker, Deena M. and Adewale, Heather B. and Winnik, Bozena and Coughlin, Janis L. and Buckley, Brian and Gore, Andrea C.}, year={2012}, month={Sep} }
 @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} }
 @article{adewale_jefferson_newbold_patisaul_2009, title={Neonatal Bisphenol-A Exposure Alters Rat Reproductive Development and Ovarian Morphology Without Impairing Activation of Gonadotropin-Releasing Hormone Neurons}, volume={81}, ISSN={["1529-7268"]}, DOI={10.1095/biolreprod.109.078261}, abstractNote={Developmental exposure to endocrine-disrupting compounds is hypothesized to adversely affect female reproductive physiology by interfering with the organization of the hypothalamic-pituitary-gonadal axis. Here, we compared the effects of neonatal exposure to two environmentally relevant doses of the plastics component bisphenol-A (BPA; 50 μg/kg and 50 mg/kg) with the ESR1 (formerly known as ERalpha)-selective agonist 4,4′,4″-(4-propyl-[1H]pyrazole-1,3,5-triyl)trisphenol (PPT; 1 mg/kg) on the development of the female rat hypothalamus and ovary. An oil vehicle and estradiol benzoate (EB; 25 μg) were used as negative and positive controls. Exposure to EB, PPT, or the low dose of BPA advanced pubertal onset. A total of 67% of females exposed to the high BPA dose were acyclic by 15 wk after vaginal opening compared with 14% of those exposed to the low BPA dose, all of the EB- and PPT-treated females, and none of the control animals. Ovaries from the EB-treated females were undersized and showed no evidence of folliculogenesis, whereas ovaries from the PPT-treated females were characterized by large antral-like follicles, which did not appear to support ovulation. Severity of deficits within the BPA-treated groups increased with dose and included large antral-like follicles and lower numbers of corpora lutea. Sexual receptivity, examined after ovariectomy and hormone replacement, was normal in all groups except those neonatally exposed to EB. FOS induction in hypothalamic gonadotropic (GnRH) neurons after hormone priming was impaired in the EB- and PPT-treated groups but neither of the BPA-treated groups. Our data suggest that BPA disrupts ovarian development but not the ability of GnRH neurons to respond to steroid-positive feedback.}, number={4}, journal={BIOLOGY OF REPRODUCTION}, author={Adewale, Heather B. and Jefferson, Wendy N. and Newbold, Retha R. and Patisaul, Heather B.}, year={2009}, month={Oct}, pages={690–699} }
 @article{patisaul_burke_hinkle_adewale_shea_2009, title={Systemic administration of diarylpropionitrile (DPN) or phytoestrogens does not affect anxiety-related behaviors in gonadally intact male rats}, volume={55}, ISSN={["1095-6867"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-58849100773&partnerID=MN8TOARS}, DOI={10.1016/j.yhbeh.2008.11.004}, abstractNote={The development of highly selective agonists for the two major subforms of the estrogen receptor (ERalpha and ERbeta) has produced new experimental methodologies for delineating the distinct functional role each plays in neurobehavioral biology. It has also been suggested that these compounds might have the potential to treat estrogen influenced behavioral disorders, such as anxiety and depression. Prior work has established that the ERbeta agonist, diarylpropionitrile (DPN) is anxiolytic in gonadectomized animals of both sexes, but whether or not this effect persists in gonadally intact individuals is unknown. Isoflavone phytoestrogens, also potent but less selective ERbeta agonists, have also been shown to influence anxiety in multiple species and are becoming more readily available to humans as health supplements. Here we determined the effects of 0.5, 1 or 2 mg/kg DPN, 1 mg/kg of the ERalpha agonist propyl-pyrazole-triol (PPT), 3 or 20 mg/kg of the isoflavone equol (EQ) and 3 or 20 mg/kg of the isoflavone polyphenol resveratrol (RES) on anxiety behavior in the gonadally intact male rat using the light/dark box and the elevated plus maze. We first determined that DPN can be successfully administered either orally or by subcutaneous injection, although plasma DPN levels are significantly lower if given orally. Once injected, plasma levels peak rapidly and then decline to baseline levels within 3 h of administration. For the behavioral studies, all compounds were injected and the animals were tested within 3 h of treatment. None of the compounds, at any of the doses, significantly altered anxiety-related behavior. Plasma testosterone levels were also not significantly altered suggesting that these compounds do not interfere with endogenous androgen levels. The results suggest that the efficacy of ERbeta agonists may depend on gonadal status. Therefore the therapeutic potential of ERbeta selective agonists to treat mood disorders may be limited.}, number={2}, journal={HORMONES AND BEHAVIOR}, author={Patisaul, Heather B. and Burke, Katherine T. and Hinkle, Ruth E. and Adewale, Heather B. and Shea, Damian}, year={2009}, month={Feb}, pages={319–328} }