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Physiologically Oriented Interactions of Nutrients and Toxicants (POINT) Model of Mercury-Selenium Interactions During Fetal Development (FS08-08-19).

Objectives
This study used POINT models to assess the effects of differing levels of MeHg exposures on selenium (Se) distributions in adolescent rat brain tissues and the effects of maternal rat MeHg exposures on Se distribution and functions in their brains and those of their offspring as a means of predicting interactive effects of MeHg and Se in human epidemiological studies. The effects of dietary MeHg and Se intakes on activities of thioredoxin reductase (TXNRD) and glutathione peroxidase (GPX1) in brain tissues in adult and fetal rats are known to be indicative of Hg-dependent disruptions of Se homeostasis and physiology.


Methods
Using the previously developed Physiologically Oriented Interactions of Nutrients and Toxicants (POINT) model, the toxicokinetic and toxicodynamics of MeHg that had previously been observed in laboratory rat feeding studies were reanalyzed to create a predictive model of how dietary MeHg exposures accumulate and distribute into adult as well as maternal/fetal tissues and use inhibition of selenoenzyme activities to indirectly assess Se availability.


Results
Applying retention coefficients to predict tissue Hg and Se concentrations provided toxicokinetic and toxicodymanic influences of MeHg on Se distributions and functions as well as Se effects on MeHg distributions. In adolescent rats, brain Se was significantly related to dietary Se (F = 42.0; P < 0.0001) and but not to MeHg in the diet. Brain Hg was strongly related to dietary MeHg (F = 248.9; P < 0.0001), but not dietary Se. Brain Se availability was strongly related to dietary MeHg (F = 111.6; P < 0.0001), but not to diet Se. Brain GPx activity was significantly associated with brain Se availability (F = 13.8; P < 0.001) and brain Se contents (F = 7.4; P = 0.01), but not to brain Hg. Brain TRx activity was significantly associated with brain Se availability (F = 48.2; P < 0.00001) and brain Hg contents (F = 25.8; P < 0.0001). Fetal brain was particularly sensitive to maternal MeHg and Se intakes, providing a highly consistent relationship between calculated [HgSe] and [Hg][Se] (F = 652; P < 0.000001).


Conclusions
POINT Models provide reliable predictions of tissue Hg and Se relationships that reflect associated risks vs. benefits.


Funding Sources
This work was funded by the United States Environmental Protection Agency (U.S. E.P.A.) and the National Oceanic and Atmospheric Administration (NOAA).