Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals

Abstract

Humans are increasingly and consistently exposed to a variety of endocrine disrupting chemicals (EDCs), chemicals that have been linked to neurobehavioral disorders such as ADHD and autism. Many of such EDCs have been shown to adversely influence brain mesocorticolimbic systems raising the potential for cumulative toxicity. As such, understanding the effects of developmental exposure to mixtures of EDCs is critical to public health protection. Consequently, this study compared the effects of a mixture of four EDCs to their effects alone to examine potential for enhanced toxicity, using behavioral domains and paradigms known to be mediated by mesocorticolimbic circuits (Fixed Interval (FI) schedule controlled behavior, novel object recognition memory and locomotor activity) in offspring of pregnant mice that had been exposed to vehicle or relatively low doses of four EDCs, Atrazine (ATR – 10mg/kg), Perfluorooctanoic acid (PFOA – 0.1 mg/kg), Bisphenol-A (BPA - 50μg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD – 0.25μg/kg) alone or combined in a mixture (MIX), from gestational day 7 until weaning. EDC-treated males maintained significantly higher horizontal activity levels across 3 testing sessions, indicative of delayed habituation, whereas no effects were found in females. Statistically significant effects of MIX were seen in males, but not females, in the form of increased FI response rates, in contrast to reductions in response rate with ATR, BPA and TCDD, and reduced short term memory in the novel object recognition paradigm. MIX also reversed the typically lower neophobia levels of males compared to females. With respect to individual EDCs, TCDD produced notable increases in FI response rates in females, and PFOA significantly increased ambulatory locomotor activity in males. Collectively, these findings show the potential for enhanced behavioral effects of EDC mixtures in males and underscore the need for animal studies to more fully investigate mixtures, including chemicals that converge on common physiological substrates to examine potential mechanisms of toxicity with full dose effect curves to assist in interpretations of relevant mechanisms.

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…[24] Dioxin and polychlorinated biphenyl maternal blood levels also related to autistic traits in a German study [25]. polychlorinated dibenzo-p-dioxin exposure during the brain growth spurtextending from the third trimester of pregnancy to age 2 related to autism: Reviewed in [3] relatively low doses of four endocrine disruptors , atrazine (10mg/kg), perfluorooctanoic acid (0.1mg/kg), bisphenol-A (50 µg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.25 µg/kg) alone or combined in a mixture, from gestational day 7 until weaning produce behavioural toxicity , which for mixture effects was predominantly seen in male mice offspring [26].…”

Liberação de Bisfenol A de sistemas adesivos resinosos ortodônticos por meio de cromatografia gasosa - Estudo <i>in vitro</i> e <i>in vivo</i>

“…Mais de 2 milhões de toneladas dessa substância são produzidas por ano. (Fleisch 2010;Chen e Suh, 2013;Kotyk e Wiltshire, 2013) Devido ao aumento no número de produtos à base de resinas epóxicas e plásticos policarbonatados, a exposição humana ao Bisfenol A tem aumentado rapidamente (Sobolewski et al 2014;Kang et al, 2006;Lang et al, 2008).…”

“…A ação estrogênica dos polímeros acontece devido a uma ligação competitiva das moléculas poliméricas semelhantes ao estrógeno, tal como o Bisfenol A, aos receptores hormonais naturais (Sobolewski et al, 2014). A exposição do organismo a essa substância química sintética pode resultar em alguns efeitos adversos, principalmente por sua ação estrogênica e pelo seu potencial tóxico agudo para os organismos aquáticos.…”

“…Apesar de inúmeros trabalhos da área médica enfatizarem os efeitos adversos do uso de materiais que liberam BPA no organismo (Sobolewski et al 2014;Hines EP et al 2014, De Coster andvan Larebeke, 2012;Rubin et al, 2001;Takai et al, 2001;Al-Hiyasat e Darmani, 2006;Della Seta et al, 2006;Lang et al, 2008), poucos estudos têm sido realizados, na Odontologia, a esse respeito. Em detrimento da grande aceitação e difusão do uso de materiais resinosos na atualidade, alguns autores avaliaram a presença de Bisfenol A na saliva, na urina e no sangue de pacientes, após a aplicação desses materiais na cavidade bucal (Kloukos et al, 2013;Han et al, 2012;Kingman et al, 2012;Eramo et al, 2010;Völkel et al, 2005;Joskow ET al., 2006;Michelsen et al, 2012;Tarumi et al, 2000;Fung et al, 2000).…”

“…Outro fator preocupante, é que as pesquisas têm mostrado efeitos prejudiciais em animais, com quantidades muito pequenas de exposição a essa substância química. (Sobolewski et al 2014;Goldberg et al 2014;Chen e Suh, 2013;Gioiosa et al, 2013 ) Entretanto, as discussões quanto à necessidade de proibir o uso de BPA na produção de materiais ainda são contraditórias. Quitmeyer e Roberts (2007) expõem e discutem o impacto que as grandes empresas e todos aqueles com interesse na produção e uso de BPA exercem sobre os órgãos fiscalizadores.…”