Sex Differences in Neurotoxicogenetics

Torres-Rojas, Carolina; Jones, Byron C.

doi:10.3389/fgene.2018.00196

Cited by 46 publications

(25 citation statements)

References 100 publications

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“…Collectively, our data give support to the influence of Rhes in regulating the survival of DA neurons [7]. The present results are also in line with previous findings showing that MDMA may induce neuroinflammatory and toxic effects in a gender-dependent manner and that males are more susceptible to these effects [50,51,52]. Although the results obtained in the present study confirm that Rhes signaling pathways are implicated in glial activation and neuronal survival [6,10,51,52,53,54], the mechanism that forms the basis of glial activation and DA neuron degeneration in Rhes KO mice must be elucidated by further studies.…”

Section: Discussionsupporting

confidence: 91%

Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age

Costa

Porceddu

Serra

et al. 2019

IJMS

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Ras homolog enriched in striatum (Rhes) is a protein that exerts important physiological functions and modulates psychostimulant drug effects. On this basis, the object of this study was to assess 3,4-methylenedioxymethamphetamine (MDMA) effects on microglial (CD11b) and astroglial (GFAP) activation and on dopamine neuron degeneration (TH) in wild-type (WT) and Rhes knockout (KO) male and female mice of different ages. Motor activity was also evaluated. Adult (3 months) MDMA-treated mice displayed an increase in GFAP-positive cells in striatum (STR), whereas the substantia nigra pars compacta (SNc) was affected only in male mice. In these mice, the increase of CD11b was more extensive including STR, SNc, motor cortex (CTX), ventral tegmental area (VTA), and nucleus accumbens (NAc). MDMA administration also affected TH immunoreactivity in both STR and SNc of male but not female WT and Rhes KO mice. In middle-aged mice (12 months), MDMA administration further increased GFAP and CD11b and decreased TH immunoreactivity in STR and SNc of all mice. Finally, MDMA induced a higher increase of motor activity in adult Rhes KO male, but not female mice. The results show that Rhes protein plays an important role on MDMA-mediated neuroinflammation and neurodegeneration dependent on gender and age, and confirm the important role of Rhes protein in neuroinflammatory and neurodegenerative processes.

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Section: Discussionsupporting

confidence: 91%

Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age

Costa

Porceddu

Serra

et al. 2019

IJMS

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“…Although often unanticipated, sex is an important variable in neuroscience. Sex‐dependent differences attributable to sexually dimorphic neurodevelopment can affect neurodevelopmental disorders and neurotoxic events including early anesthetic exposures (Torres‐Rojas & Jones 2018; Werling et al 2016; Cabrera et al 2020). While our present results show sex‐dependent changes in inhibitory synaptic transmission, similar female‐dependent changes have also been reported in neonatal mice (PND7) (Woodward et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Increasing the interval between repeated anesthetic exposures reduces long‐lasting synaptic changes in late post‐natal mice

Cui

Lee

et al. 2020

Journal of Neurochemistry

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While recent studies strongly suggest that a single, short anesthetic exposure does not affect neurodevelopment, the effects of multiple exposures remain unclear. Unfortunately, studying “multiple exposures” is challenging as it is an extremely heterogeneous descriptor comprising diverse factors. One potentially important, but unrecognized factor is the interval between anesthetic exposures. In order to evaluate the significance of interval, we exposed post‐natal day 16, 17 mice to three sevoflurane exposures (2.5%, 1 hr) with short (2 hr) or long (24 hr) intervals. Changes in synaptic transmission, plasticity, protein expression, and behavior were assessed in male and female mice. We discovered that short‐interval exposures induced a female‐dependent decrease in miniature inhibitory post‐synaptic current (mIPSC) frequency 5 days after the last exposure (control: 18.44 ± 2.86 Hz, sevoflurane:14.65 ± 4.54 Hz). Short‐interval sevoflurane exposed mice also displayed long‐term behavioral deficits at adult age (hypoactivity, anxiety). These behavioral changes were consistent with the sex‐dependent changes in inhibitory transmission, as they were more robust in female mice. Although there was no change in learning and memory, short‐interval sevoflurane exposures also impaired LTP in a non‐sex‐dependent manner (control: 171.10 ± 26.90%, sevoflurane: 149.80 ± 26.48 %). Most importantly, we were unable to find long‐lasting consequences in mice that received long‐interval sevoflurane exposures. Our study provides novel insights regarding the significance of the interval between multiple exposures, and also suggests that the neurotoxic effects of multiple anesthetic exposures may be reduced by simply increasing the interval between each exposure.

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“…Evidence of sex and gender differences has been reported in chronic diseases such as diabetes, cardiovascular disorders, neurological diseases 3 , mental health disorders 4 , cancer 5 , autoimmunity 6 , as well as physiological processes such as brain aging 7 and sensitivity to pain 8 . Moreover, differences in lifestyle factors that are associated with sex and gender, such as diet, physical activity, tobacco use and alcohol consumption, also correlate with the epidemiology of diseases [9][10][11] . Nonetheless, there are still open questions regarding health differences across the gender spectrum, reflected by the scarcity of studies dedicated to intersex, transgender and nonbinary individuals 12,13 .…”

Section: Introductionmentioning

confidence: 99%

Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare

et al. 2020

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Precision Medicine implies a deep understanding of inter-individual differences in health and disease that are due to genetic and environmental factors. To acquire such understanding there is a need for the implementation of different types of technologies based on artificial intelligence (AI) that enable the identification of biomedically relevant patterns, facilitating progress towards individually tailored preventative and therapeutic interventions. Despite the significant scientific advances achieved so far, most of the currently used biomedical AI technologies do not account for bias detection. Furthermore, the design of the majority of algorithms ignore the sex and gender dimension and its contribution to health and disease differences among individuals. Failure in accounting for these differences will generate sub-optimal results and produce mistakes as well as discriminatory outcomes. In this review we examine the current sex and gender gaps in a subset of biomedical technologies used in relation to Precision Medicine. In addition, we provide recommendations to optimize their utilization to improve the global health and disease landscape and decrease inequalities.

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Sex Differences in Neurotoxicogenetics

Cited by 46 publications

References 100 publications

Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age

Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age

Increasing the interval between repeated anesthetic exposures reduces long‐lasting synaptic changes in late post‐natal mice

Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare

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