In the past three decades, selenium has been found to be essential to various aspects of health . It has been found to play a role in prevention of cancer and cardiovascular disease as well as in regulating mood . Exposure to environmental factors, such as selenium, can also play a role in depression and anxiety states. Past research has shown that low selenium concentrations were related to depression status and other negative affective states [18, 20]. In addition, studies have indicated that selenium may be useful in preventing postpartum depression .
In the current study, higher groundwater selenium levels were associated with lower scores on the Geriatric Depression Scale. This finding is consistent with past research indicating that low selenium status is related to increased incidence of depression and other negative affective states [18, 20]. In addition to the decrease in total depression scores, higher selenium levels were specifically related to a decrease in symptoms of Dysphoria, Meaninglessness, and Apathy, indicating that selenium may have an impact on particular types of depressive manifestations. It is interesting to note that selenium concentrations were only minimally related to the cognitive impairment subscale, as we have previously shown selenium to be selectively protective of memory functioning . This suggests that, despite the potential role of selenium concentrations in preserving cognitive function, depressive symptoms related to thoughts of cognitive dysfunction appear to be unrelated and may be related to the concept of insight.
This is the first study to examine residential groundwater selenium levels and depression. A myriad of factors determine the chemical make-up of groundwater in a given area, and it is important to be cognizant of the potential health impacts from such substances. Research on groundwater and its implications on human health can have profound implications in the realms of public health and policy. Additionally, results obtained by groundwater research could prove to be the impetus for the formation or reformation of population-based prevention strategies concerning groundwater safety and exposure. This study was conducted in a rural agricultural area where higher concentrations of groundwater selenium are typically found. Aligning with this, the mean selenium level in this study was 17.70 μg/L, whereas the national average is 10 μg/L .
The protective impact of selenium on mental health fits with its biological activity and is supported by both animal model and human research. Selenium, a main constituent of neuronal selenoproteins, may be particularly important for sustaining healthy cerebral function  through its key role in protection against oxidative damage [15, 20, 49]. Oxidative damage is a key biological mechanism in depression pathophysiology, and many anti-depressants, like fluoxetine  and venlafaxine , reduce oxidative damage. Another possible mechanism of action is through selenium’s impact on brain-derived neurotrophic factor (BDNF), which has been linked to depression and found to be decreased in selenium deficient rats . Additionally, depression is also associated with lower antioxidant levels. Research has suggested that antioxidant deficiency found in depression may predispose individuals to greater inflammatory and oxidative and nitrosative responses , which may contribute to the protective effects of selenium against depression.
Ours is the first study to directly examine the link between the GPX1 Pro198Leu polymorphism and depressive risk as well as its impact on the selenium-depression link. Our findings point to gene-environment interaction, which is supported by the gene-dose impact. Specifically, the C allele of the GPX1 polymorphism was associated with significantly increased risk of depression in a dose-dependent manner (i.e. CC > CT > TT). Additionally, the impact of environmental selenium concentrations on depression scores was stronger for the CC than CT group. The TT group showed a substantial impact in the expected direction, but due to the small sample number of TT homozygotes, these results must be replicated. It is also important to note the differences in effect sizes for selenium on depression observed in each genotypic group. Among CC homozygotes, the majority of variance accounted for in GDS scores was from selenium concentrations with age, gender, education, and language of test administration contributing less to GDS scores. Among the TT group, the amount of variance accounted for by selenium concentrations alone was substantial; however, covariates in the model also accounted for a larger portion of the variance. Future work is needed to delve more thoroughly into this gene-environment interaction as well as the dose-response impact of the C allele of the GPX1 polymorphism on risk for depression. Additional work is also required to examine other potential genes of interest. For example, Galecki and colleagues  identified polymorphisms of the NOS2A gene, which are important in the nitric oxide pathways, as related to recurrent depression. Given that selenium (i.e. selenoproteins) is involved in the nitric oxide pathway as well, NOS2A and other genes relevant to pathways linked to selenium should be examined. It is likely that more sophisticated bioinformatic analyses will be necessary to disentangle these multi-level gene-(biological mechanism) – environmental exposure – depression interactions.
These results point towards possible pharmacogenetic implications of the Pro198Leu GPX1 polymorphism. Specifically, in our sample, CC homozygotes had significantly increased risk for depression; however, selenium was also most powerfully protective against depression and depressive symptoms among those particular carriers. Therefore, future research looking at the therapeutic impact of selenium on depression should examine this genotype. Additionally, previously conducted clinical trials of anti-depressant medications with stored DNA (or previously conducted genetic analyses) can determine if Pro198Leu GPX1 genotype predicts optimal treatment response. Lastly, the Pro198Leu GPX1 polymorphism may be useful for identifying those individuals most likely to benefit from anti-depressant medications in new clinical trials.
There are limitations to the current study. One is the GIS-based estimate of selenium concentration rather than direct measurement. However, our prior work, as well as that of others, has shown that GIS-based methods are valid ways for estimating environmental exposures. The current findings should be replicated using direct selenium measurement. The cross-sectional nature of the study is another limitation; however, our prior work has shown selenium to be preventative of cognitive decline prospectively in a subset of this cohort . Future studies will examine the protective impact of selenium concentrations on both depression and cognitive decline as future waves become available. The current study also has several strengths. Specifically, this is the first study to examine this link in such detail (i.e. depressive symptoms rather than only global scores) as well as look at this topic among rural-dwelling adults and elders. This is also the first study to examine the impact of genetic variation within GPX1 on depression risk as well as the selenium-depression link. Taken together, these results point to the need for continued work in the area, as selenium may provide a therapeutic target for preventative strategies aimed at reducing depressive incidence rates in vulnerable populations. Additional work is also needed to determine the pharmacogenetic implications of the Pro198Leu GPX1 polymorphism in depression therapies.