"Neuroendocrine disruption caused by the indoor organohalogen - PowerPoint PPT Presentation

Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz” México D.F. TOXIC EARTH:TOXIC BODIES Binational Perspectives in Environmental Health "Neuroendocrine disruption caused by the indoor organohalogen pollutants PBDEs” Martha León Olea Ph. D. Depto. Neuromorfología Funcional Dirección de Investigaciones en Neurociencias

If you've been in contact with You can be contaminated

PBDEs Blood concentrations in Mexican children Chemosphere Maldonado et al., 2009

PCBs Blood concentration in Mexican children San Nicolas, Tequisquiapan, Qro . Trejo-Acevedo A. Chemosphere. 2009

During physiological challenges: PACAP: somatodendritic AVP release PACAP and PAC-1 receptor This suggests that PACAP may function as a physiological brake for excessive release of VP during intense or prolonged physiological demand. Without this physiological brake, pituitary VP stores are depleted and plasma osmolality is dysregulated. Gillard et al., 2006.

NO - Nitric oxide is critical for AVP hormone release regulation. During hyperosmotic stimulation: AVP release (somatodendritic) and plasmatic AVP PCBs and PBDEs X Nitric Oxide Synthase This suggest that exposure to PCB-like compounds may lead to dysregulation of body water. Kadekaro, 2004; Kadowaki, et al., 1994; Villar et al., 1994; Ueta et al., 1998; Sharma and Kodavanti, 2002; Coburn et al., 2006, 2007; Gillard et al, 2007.

Aim: To examine the effect of PCB (Aroclor-1254) and PBDE (DE-71) perinatal exposure on the immunoreactivity to VP, PACAP and NOS, in SON and PVN magnocellular neurons of adult rats, both hydrated and dehydrated.

Perinatal exposure to Aroclor 1254 or DE-71 Oral doses Aroclor 1254: GD 10-19: 30 mg/kg/d DE-71: GD 6- PND 21: 3 months Pn day 10 Experimental Groups Hydrated Dehydrated Plasma Control NaCl osmolality Treated : Treated: Sacrifice A-1254 NaCl + A-1254 DE-71 NaCl + DE-71 - Histological processing of the brain - NADPH-d histochemistry to NOS, Drinking 2% NaCl sol. Drinking water - Immunohistochemistry to VP, PACAP and nNOS, 5 days

10 Pn days Control Aroclor-1254

Nitric Oxide Synthase Activity (NADPH-d), 10 Pn day PVN SON Integrated Optical Density PeF

NADPH-d: 3 Months Control Aroclor-1254 NaCl NaCl + Aroclor-1254

AVP/nNOS Immunoreactivity FITC/TRITC ( green/red) PVN Aroclor 1254 Control Aroclor-1254 IOD NaCl NaCl + Aroclor-1254

nNOS Immunoreactivity, DE-71 Control DE-71 Control DE-71 nNOS en PVN + DE-71 nNOS en SON + DE-71 Densidad Optica Integrada Densidad Optica Integrada Integrated optical density NaCl + DE-71 NaCl NaCl NaCl + DE_71 TRITC

AVP Immunoreactivity, DE-71 Control DE-71 Control DE-71 Vasopressin in SON / DE-71 Male Vasopressin in PVN / DE-71 Male 4000 4000 *** * * * *** ** *** Integrated Optical Density Integrated Optical Density 3000 3000 NaCl NaCl + DE_71 NaCl NaCl + DE_71 2000 2000 1000 1000 0 0 Control DE-71 NaCl NaCl+DE-71 Control DE-71 NaCl NaCl+DE-71 n = 5 n = 4 n = 4 n = 4 n = 4 n = 5 n = 4 n = 4 n s = 12 n s = 15 n s = 11 n s = 13 n s = 13 n s = 14 n s = 14 n s = 13

PACAP Immunoreactivity DE-71 PVN SON Control DE-71 Control DE-71 Integrated Optical Density NaCl NaCl+DE-71 NaCl NaCl+DE-71

Conclusions: • Perinatal exposure to PCBs and PBDEs produces long term alterations in the immunoreactivity to AVP, PACAP and nNOS in the adult SON and PVN. • The neurotoxic effects of PCBs are similar to those observed for PBDEs. • In 10 Pn day PCB-exposed pups there is a decrease in the number of nitrergic neurons and signs of morphological damage and neuronal death. • The dehydration-induced increase of VP, PACAP and nNOS immunoreactivity is absent in treated rats. • Pups exposed to PCBs and PBDEs are prone to subtle but measurable developmental problems.

PCBs and PBDEs alter AVP content and the regulatory factors PACAP and NO, leading to dysregulated hydroelectrolitic balance which is essential for normal physiology.

Departamento de Neuromorfología Funcional Carolina Miller Pérez Ph. D. Eduardo Sánchez Islas Ph. D. Samuel Mucio Ramírez. Biol. José Mendoza Sotelo EMEACM. René Garduño Gutiérrez. Postgraduate candidate Feliciano Camacho García Technician This work was supported by grants: UC-MEXUS-CONACYT; Fondo para la investigación Miguel Alemán; Fondo para la investigación Instituto Nacional de Psiquiatria R.F.M. The experiments was conducted in accordance with national and institutional guidelines for the protection of animal subjects.

"What if BEFORE we start doing What we have to do, we BEGIN by doing what we should HAVE DONE ?"

PACAP Immunoreactivity SON PVN Control Aroclor-1254 Control Aroclor-1254 A PACAP in PVN / Aroclor-1254 2000 Integrated Optical Density 1500 NaCl NaCl+Aroclor-1254 NaCl NaCl+Aroclor-1254 *** *** *** 1000 500 0 Control A1254 NaCl NaCl+A1254 Aroclor 1254

PACAP Immunoreactivity DE-71 PVN SON Control DE-71 Control DE-71 Integrated Optical Density NaCl NaCl+DE-71 NaCl NaCl+DE-71

We also performed polymerase chain reaction (PCR) preliminary studies in PVN and SON micropunches to understand the disrupting effects of the PACAP gene expression in response to the exposition of PCBs.

The flame retardant industry argues that the benefit accrued through saving lives by fire prevention outweighs the cost incurred by any medical consequences. Over time however, this cost/benefit radio is likely to shift. In the meantime, it is imperative that a more aggressive approach be taken to circumvent or regulate their use.

Some reported PCBs and PBDEs effects • They cross the placental barrier. • They are found in blood and breast milk. • Neurotoxicity (dopamine, nitric oxide, PKC, NOS, Ca +). Endocrine system: Thyroid , estrogenicity, vasopressin. • • Immune system depression. • Carcinogenic in animals and humans. • Children are the most affected: - impaired growth and development - motor behavior - learning and memory Safe S., 1993; Jacobson and Jacobson, 1996; Tilson and Kodavanti, 1997; Sharma and Kodavanti, 2002; Kodavanti and Curras-Collazo, 2010.

DE-71 Diphenyl ether mixture used in the manufacture of textiles and polyurethane foams. DE-71 is composed of the congeners 2,2´,4,4´,5-pentabromodiphenyl ether (PBDE 99; pentaBDE) and 2,2´,4,4´-tetrabromodiphenyl ether (PBDE 47; tetraBDE) as the major constituents (Hale et al., 2001; LaA Guardia et al., 2006). A number of studies suggest that DE-71 has the potential to disrupt endocrine homeostasis and reproductive development (Stoker et al., 2004, 2005) and this mixture has been shown to significantly decrease circulating total serum thyroxin (T4) in perinatally exposed rats (Ellis-Hutchings et al., 2006). Generalized structure of PCBs Generalized structure of PBDEs

Hay 187 químicos considerados como tóxicos para los organismos vivos. (Comité Intergubernamental de Negociación sobre “Contaminantes Orgánicos Persistentes”, (COP). Dentro de los 12 más tóxicos, están los plaguicidas como el DDT y Los Bifenilos policlorinados (PCB).

Kunisue et al., 2003 Trejo-Acevedo et al., 2009

Prueba de condicionamiento de evitación inhibitoria

AVP/nNOS SON Immunoreactivity FITC/TRITC Aroclor 1254 Aroclor-1254 Control IOD NaCl NaCl + Aroclor-1254