Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting

This manuscript provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward

The Neurotoxicity of DOPAL: Behavioral and Stereological Evidence for Its Role in Parkinson Disease Pathogenesis

BACKGROUND: The etiology of Parkinson disease (PD) has yet to be fully elucidated. We examined the consequences of injections of 3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite of dopamine, into the substantia nigra of rats on motor behavior and neuronal survival. METHODS/PRINCIPAL FINDINGS: A total of 800 nl/rat of DOPAL (1 µg/200 nl) was injected stereotaxically into the substantia nigra over three sites while control animals received similar injections of phosphate buffered saline. Rotational behavior of these rats was analyzed, optical density of striatal tyrosine hydroxylase was calculated, and unbiased stereological counts of the substantia nigra were made. The rats showed significant rotational asymmetry ipsilateral to the lesion, supporting disruption of dopaminergic nigrostriatal projections. Such disruption was verified since the density of striatal tyrosine hydroxylase decreased significantly (p<0.001) on the side ipsilateral to the DOPAL injections when compared to the non-injected side. Stereological counts of neurons stained for Nissl in pars compacta of the substantia nigra significantly decreased (p<0.001) from control values, while counts of those in pars reticulata were unchanged after DOPAL injections. Counts of neurons immunostained for tyrosine hydroxylase also showed a significant (p=0.032) loss of dopaminergic neurons. In spite of significant loss of dopaminergic neurons, DOPAL injections did not induce significant glial reaction in the substantia nigra. CONCLUSIONS: The present study provides the first in vivo quantification of substantia nigra pars compacta neuronal loss after injection of the endogenous toxin DOPAL. The results demonstrate that injections of DOPAL selectively kills SN DA neurons, suggests loss of striatal DA terminals, spares non-dopaminergic neurons of the pars reticulata, and triggers a behavioral phenotype (rotational asymmetry) consistent with other PD animal models. This study supports the "catecholaldehyde hypothesis" as an important link for the etiology of sporadic PD

Alteration to Dopaminergic Synapses Following Exposure to Perfluorooctane Sulfonate (PFOS), in Vitro and in Vivo

Our understanding of the contribution exposure to environmental toxicants has on neurological disease continues to evolve. Of these, Parkinson’s disease (PD) has been shown to have a strong environmental component to its etiopathogenesis. However, work is still needed to identify and characterize environmental chemicals that could alter the expression and function of the nigrostriatal dopamine system. Of particular interest is the neurotoxicological effect of perfluorinated compounds, such as perfluorooctane sulfonate (PFOS), which has been demonstrated to alter aspects of dopamine signaling. Using in vitro approaches, we have elaborated these initial findings to demonstrate the neurotoxicity of PFOS to the SH-SY5Y neuroblastoma cell line and dopaminergic primary cultured neurons. Using an in vivo model, we did not observe a deficit to dopaminergic terminals in the striatum of mice exposed to 10 mg/kg PFOS for 14 days. However, subsequent exposure to the selective dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) significantly reduced the expression of dopamine transporter (DAT) and tyrosine hydroxylase (TH), and resulted in an even greater reduction in DAT expression in animals previously exposed to PFOS. These findings suggest that PFOS is neurotoxic to the nigrostriatal dopamine circuit and this neurotoxicity could prime the dopamine terminal to more extensive damage following additional toxicological insults

Research Capacity Training on Environmental Health and Noncommunicable Diseases in the Country of Georgia: Challenges and Lessons Learned during the COVID-19 Pandemic

COVID-19 presented challenges for global health research training programs. The Clean Air Research and Education (CARE) program, which aims to enhance research capacity related to noncommunicable diseases and environmental health in the country of Georgia, was launched in 2020-as the COVID-19 pandemic began. At its foundation is mentorship and mentored research, alongside formal didactic training, informal training/meetings, and other supports. Current analyses examined CARE\u27s initial 1.5 years (e.g., program benefits, mentorship relationships) using data from an evaluation survey among trainees and faculty in January 2022. Trainees (100% response rate: = 12/12; 4 MPH, 8 PhD) and faculty (86.7% response rate: = 13/15; 7 Georgia-based, 6 United States-based) rated factors related to mentor-mentee relationships highly, particularly mutual consideration of each other\u27s thoughts, opinions, and perspectives; one major challenge was completing goals planned. Trainees and faculty identified several growth experiences and program benefits (e.g., skills development, expanding professional network) but also identified challenges (e.g., meeting program demands, communication gaps, unclear expectations)-exacerbated by the pandemic. Findings underscore the importance of strong mentorship relationships and that the pandemic negatively impacted communication and clarity of expectations. Given the likely ongoing impact of the pandemic on such programs, program leaders must identify ways to address these challenges

The association between organophosphate insecticides, blood pressure dysregulation, and metabolic syndrome among U.S. Adults: NHANES 2015-2016

Organophosphate (OP) insecticides represent some of the most common environmental contaminants in the United States. Organophosphate insecticide use has been associated with numerous adverse health outcomes, including hypertension (HTN) and metabolic syndrome (MetS), but results from current studies are conflicting and inconclusive. In a study of 916 U.S. adults from the 2015–2016 NHANES cycle, we investigated the association between five dialkyl phosphate (DAP) metabolites of OP insecticides and blood pressure parameters (systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, HTN), as well the association between total body burden of DAPs with HTN and MetS. Weighted, multivariable linear regression revealed significant, inverse associations between diethylphosphate and systolic blood pressure (β= -0.16 p = 0.02), diethylthiophosphate and systolic blood pressure (β= -0.91 p = 0.01), total DAP exposure and systolic blood pressure (β= -0.13, p = 0.04), and between dimethylphosphate and diastolic blood pressure (β= -0.15, p = 0.0075). No significant associations were observed between total DAP exposure and odds of HTN. We additionally modeled the odds of abnormally high pulse pressure given specific quartile of total DAP exposure. Results showed a significant association between diethylphosphate and odds of abnormal pulse pressure (OR=1.29, 95% CI[1.01,1.65]), and between total DAP exposure and odds of abnormal pulse pressure (OR=1.05, 95% CI[1.03,1.10]). Lastly, we found that adults in the 3rd quartile of OP metabolite exposure had a 3.61 increased odds of having MetS when compared to individuals in the 1st quartile (OR=3.61, 95% CI[1.32,9.85]).Our preliminary findings support data from previous studies suggesting a role for OP insecticides in the pathogenesis of blood pressure dysregulation and MetS. Future studies are warranted to corroborate these findings, determine population-level clinical significance, and to elucidate potential mechanisms explaining these associations