16^th Global Summit on Toxicology and Applied Pharmacology October 15-16, 2018 Las Vegas, Nevada, USA

Javier Del Pino received his PharmD degree at the University Complutense University of Madrid in 2004. He has two Masters in Sciences 2009 and 2010. He specialized in neurotoxicology and neurodevelopmental toxicology and received his PhD in Toxicology in 2009. In 2010 he worked in Institute of Health Carlos III in the National Center of Environmental Health. From 2010 to 2012 he was Associated Researcher at University of Massachusetts (UMASS) working in Sandra Petersen´s Lab in a National Institute of Health (NIH) project on developmental effects of TCDD endocrine disruptor on sexual differentiation. In 2016, he got a position as Associate Professor of Toxicology at the Complutense University of Madrid.

Chlordimeform, as a member of the formamidine pesticides family, has been described to induce permanent sex- and region-dependent effects on the development of monoaminergic neurotransmitter systems. Although these effects could be related to monoamine oxidase (MAO) inhibition, chlordimeform is a very weak MAO inhibitor, thus that other mechanism should be involved. In this regard, chlordimeform, in particular, as formamidines, in general, alters the serum levels of steroid hormones that regulate the expression of enzymes whose action is to mediate the synthesis and metabolism of monoaminergic neurotransmitters. Therefore, an alteration of these hormones could mediate the observed effects on monoaminergic neurotransmitter system observed in different brain regions. We hypothesized that chlordimeform produces disruption of sex hormones in some of the brain regions in which alteration of monoaminergic neurotransmitter system has been observed. With the intention to confirm our hypothesis, we evaluated the effect on the levels of testosterone and estradiol in the striatum of male and female rats at 11 days of age, after maternal exposure to chlordimeform (5mg/kg body weight). Treatment-induced a significant decrease in testosterone and estradiol levels in the striatum of rats at 11 days of age, observing sex interaction with treatment in the content of T and E2. The present findings indicate that after maternal exposure to chlordimeform, a sex hormones disruption, in the striatum, is induced. These results could explain the alteration observed in monoaminergic systems in the striatum, in particular, and in the rest of brain regions affected after chlordimeform exposure, in general. Further studies are necessary to confirm the implication of our result in monoaminergic system alterations observed.

Paula Moyano received her JD degree at the University Complutense University of Madrid in 2013. She has a Masters in Pedagogical Sciences 2017. She specialized in neurotoxicology and legal sciences and received his PhD in Toxicology and legal medicine in 2016.

Manganese (Mn) is an essential metal with industrial applications that have been shown to produce memory and learning deficits after acute and repeated exposure similar to those induced in Alzheimer’s disease (AD). However, the complete mechanisms through which it induces these effects are unknown. In this regard, basal forebrain is one of the main regions involved in regulation of learning and memory processes and a degeneration of cholinergic neurons or cholinergic transmission disruption in this region has been related with cognitive disorders. Besides, it has been reported that manganese can affect cholinergic transmission, which may explain its effects on learning and memory processes. According to these data, we hypothesized that Mn could induce basal forebrain cholinergic transmission alteration. To prove this hypothesis, we evaluated in SN56 cell culture from basal forebrain, the Mn toxic effects after 24 h and 14 consecutive days of exposure on cholinergic transmission. This study shows that Mn decreased acetylcholine levels after 24 h and 14 days of exposure. Mn did not have any effect on vesicular acetylcholine transporter (VAChT) expression, although it induced acetylcholinesterase (AChE) activity and decreased choline acetyltransferase (ChAT) activity and high-affinity choline transporter (CHT) gene expression after 24 h and 14 days exposure, which suggests that these alteration mediated acetylcholine levels disruption. Our present results provide a new view of the mechanisms contributing to Mn neurotoxicity and may explain cognitive dysfunctions observed after Mn exposure.

Javier Del Pino received his PharmD degree at the University Complutense University of Madrid in 2004. He has two Masters in Sciences 2009 and 2010. He specialized in neurotoxicology and neurodevelopmental toxicology and received his PhD in Toxicology in 2009. In 2010 he worked in Institute of Health Carlos III in the National Center of Environmental Health. From 2010 to 2012 he was Associated Researcher at University of Massachusetts (UMASS) working in Sandra Petersen´s Lab in a National Institute of Health (NIH) project on developmental effects of TCDD endocrine disruptor on sexual differentiation. In 2016 he got a position as Associate Professor of Toxicology at the Complutense University of Madrid.

Chlordimeform is a pesticide from the formamidine family. Such family of pesticides has been shown to permanently alter monoaminergic neurotransmitter systems in a sex- and region-dependent way. Those effects may be related to monoamine oxidase (MAO) inhibition, although chlordimeform has been shown to be a very weak MAO inhibitor, suggesting that other mechanism should be involved. Thus, chlordimeform may alter the expression of enzymes that control synthesis and metabolism of monoaminergic neurotransmitters systems, which could mediate the observed effects. In order to confirm that chlordimeform produces an alteration on the enzymes that synthesize and/or metabolize monoaminergic neurotransmitters systems, thus inducing permanent alterations of the monoamine neurotransmitter systems, we evaluated, in hippocampus of male and female rats, the effect on the expression of MAO, COMT, BDH, TH, TRH, and AD enzymes at 60 days of age after maternal exposure to chlordimeform (5mg/kg body weight). Our results show that MAO and BDH enzymes expression was not altered by chlordimeform treatment, but TH enzyme expression was decreased and COMT, BDH, and TRH enzymes expression were increased in both males and females after treatment with chlordimeform. Besides, females showed a bigger increase in the expression of COMT [58.83% (P<0.001)], AD [46.74% (P<0.001)], TH [43.65% (P<0.001)] and TRH [37.85% (P<0.001)] enzymes. Our findings show that maternal exposure to formamidines in general, and chlordimeform in particular, induces a permanent alteration of monoaminergic neurotransmitters, through alteration of the enzymes that synthesize these neurotransmitters, in the hippocampus.