BACKGROUND
iodine is essential for the synthesis of thyroid hormone, including during pregnancy.
maternal thyroid hormones have essential roles in foetal brain development, regulating both morphological and biochemical changes before the onset of foetal thyroid function
<cit> .
moderate and severe iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring
<cit> .
in china the universal salt iodization  policy was implemented in  <dig> and since then the average resident’s iodine status was in excess for three years and more than adequate for six years.
previously, we conducted a five-year follow-up study from  <dig> to  <dig> to evaluate the effect of different iodine intake on thyroid diseases.
we found that more than adequate  and iodine excess  could increase the prevalence of subclinical hypothyroidism
<cit> .
however whether more than adequate and excessive iodine intake can affect the neurodevelopment of the offspring has not been investigated.
the genes c-fos and c-jun are essential for spatial learning and memory consolidation in rats, and hypothyroidism due to iodine deficiency is associated with reduced expressions of c-fos and c-jun in the rat hippocampal ca <dig> region
<cit> .
maternal hypothyroidism affects the expression of foetal and neonatal brain-derived neurotrophic factor
<cit>  and neuroendocrine-specific protein -a
<cit> , both of which are important mediators of thyroid hormone and have essential roles in brain development.
in our present study, female wistar rats were maintained on low-iodine grain and randomly assigned to three groups based on the iodated water concentration: low iodine , normal iodine , and 3-fold high iodine  groups.
furthermore we explored whether maternal iodine excess in rats could lead to changes in neurological function in offspring.
RESULTS
urinary and thyroidal iodine content
urine iodine concentrations of the adult female rats paralleled their iodine intake; urine and tissue iodine concentrations increased gradually with increasing iodine intake.
in the low iodine  group, urinary iodine was only  <dig> % that of the normal iodine  group, and the thyroidal iodine was  <dig> % that of the ni group.
at the same time, the 3-fold iodine  group had significantly elevated concentrations of iodine in urine and thyroid tissue, which was  <dig> % and  <dig> %, respectively, that of the ni group .
values are expressed as the mean ± sem .
*p   <  <dig>  compared with normal iodine control group.
maternal and pup thyroid hormone
maternal thyroid hormone: after 12 weeks of treatment , total thyroxine  and free thyroxine  concentrations in the sera of the adult females were significantly lower in the li group compared with those in the ni .
tt <dig> and ft <dig> levels in the maternal serum were significantly higher in the 3hi group than those in ni control group .
on gestational  day  <dig>  tt <dig> and ft <dig> concentrations in sera of the adult females remained significantly lower in the li group compared with those in the ni , while the 3hi group still exhibited significantly higher circulating tt <dig> level compared with the control group .
however, on g <dig> the level of ft <dig> was a increasing trend, however no significant difference in ft <dig> concentration between the ni and 3hi groups.
after 12 weeks of treatment  and on g <dig>  thyroid stimulating hormone  concentrations were significantly higher in the li group compared with the ni , while there were descending trends, although no significant changes were found in the tsh levels after 12 weeks of treatment  and on g <dig> in the 3hi rats compared with these levels in the ni .
values are expressed as mean ± sem; n =  <dig> for each group.
*p <  <dig>  compared with the ni control on the same day; athe sensitivity of the chemiluminescence immunoassay for tt <dig> was  <dig>  μg/dl.
pup thyroid hormone: on postnatal  day  <dig>  and day  <dig> , the sera of pups in the li group had significantly higher tsh levels, and lower tt <dig> and ft <dig> levels, than those in the ni group .
on pn <dig>  pups from the 3hi group had a significantly higher serum tsh level compared with ni pups .
however, there was no significant difference between the 3hi and ni groups in tt <dig> and ft <dig> levels.
on pn <dig> there was no significant difference in any of the serum thyroid hormone levels between pups of the 3hi and ni groups .
this indicated that the thyroid dysfunction of the pups from the 3hi group could be rectified by pn <dig>
values are expressed as mean ± sem; n =  <dig> for each group.
*p <  <dig>  compared with ni control on the same day.
effect of 3hi on the protein expressions of c–fos and c-jun in the ca <dig> area of hippocampus
photomicrographs of the immunohistochemistry-stained hippocampal tissues from pn <dig> pups showed positive expression of c-fos and c-jun in area ca <dig> in all treatment groups .
the iod values of c-fos and c-jun in ca <dig> area were significantly decreased in the pups of the li group compared with control pups .
however, there was no significant difference in c-fos and c-jun expressions between the 3hi and ni groups .
on pn <dig>  the expression of c-fos and c-jun in the li group was also the lowest among the three groups .
there was no significant difference in the expressions of c-fos and c-jun in ca <dig> region of hippocampus between the 3hi pups and dams of the ni group .
effect of 3hi on bdnf and nsp-a expression in the hippocampus
on pn <dig> and pn <dig>  bdnf protein expression levels were significantly lower in both the li and 3hi pups compared with the ni controls.
specifically, on pn <dig> the bdnf levels in the pups of the li group were  <dig> % that of the ni  , and the bdnf levels of the pups in the 3hi group were  <dig> % that of the ni .
on pn <dig>  the bdnf levels in the pups of the li group were  <dig> % that of the ni , and the bdnf levels of the pups in the 3hi group were  <dig> % that of the ni .
on the other hand, on pn <dig> the expression of nsp-a was higher in the li and 3hi pups when compared with the ni controls: the levels of nsp-a of the li and 3hi pups were  <dig> % and  <dig> %, respectively, that of the ni pups .
nsp-a protein expression levels were significantly higher in the li pups compared with the ni controls on pn <dig>  the levels of nsp-a of the li pups were  <dig> % that of the ni pups .
however, no significant differences in the nsp-a levels were observed between the 3hi dams and ni dams on pn <dig> .
morris water maze  test
to evaluate whether various levels of iodine intake during gestation could cause cognitive and behavioral alterations in offspring, the pups underwent the mwm test on pn40- <dig>  the time to reach the hidden platform  of all treatment groups became shorter as the number of training trials increased.
however, the escape latencies were significantly longer for pups in the li group compared with the ni group.
interestingly, our data showed that the 3hi pups took more time than the controls to learn the spatial cues required to find the hidden platform for all 5 days of testing, and there was a statistical difference when compared with the ni control group on the third day .
discussion
much recent attention has focused on elucidating the effects of iodine deficiency on neurodevelopmental impairment
<cit> .
however, the effects of iodine excess should not be overlooked.
we investigated whether and how a 3-fold increase in the physiological dose of iodine in rat would affect brain development of their offspring.
the rat brain at pn <dig> is considered developmentally equivalent to the human brain at birth
<cit> .
rat brain development at pn <dig> approximates the late toddler stage of humans, and pn <dig> equates to the teenager stage
<cit> .
we selected pn <dig> and pn <dig> as two crucial time points in the brain development of the rat to explore the effect of maternal excessive iodine intake on the neurodevelopment and cognitive function in their offspring.
our results show for the first time that there were changes in bdnf and nsp-a expression and neurodevelopmental impairment in rat pups whose mothers had a 3-fold higher-than-normal intake of iodine prior to pregnancy and throughout gestation and breastfeeding.
iodine intake levels that are either lower or higher than the recommended range are associated with an increase in the incidence of thyroid disease in china
<cit> .
both thyroid hormone deficiency and excess have detrimental effects on the expression of neuronal proteins during neurodevelopmental stages
<cit> .
iodine deficiency is the most common cause of hypothyroidism.
the results of some studies regarding excess iodine suggested that high iodine intake was associated with increased incidence of hypothyroidism
<cit> , while others found that it led to hyperthyroidism
<cit> .
these different results may be related to the duration of high iodine exposure.
the incidence of hyperthyroidism after the initiation of the universal salt iodization  program began to rise at about 6 months, peaked at 1–3 years and returned to the baseline within 3–10 years
<cit> .
iodine-induced thyrotoxicosis lasting the first few years after the implementation of iodine supplementation was reported in lesotho
<cit>  and poland
<cit> .
however our epidemiological study demonstrated that there was no difference in either the prevalence or the incidence of hyperthyroidism among mildly deficient, more than adequate, and excessive iodine intake areas .
we found that more than adequate and excessive iodine intake could increase the prevalence of subclinical hypothyroidism
<cit> .
the usi policy had been implemented for  <dig> to 8 years in china, since  <dig>  when we conducted the epidemiological study from  <dig> to  <dig>  therefore we did not obtain epidemiological data for the early stage of iodine supplementation.
in the present animal study, after 12 weeks of treatment , the serum tt <dig> and ft <dig> levels were significantly higher in the adult female rats of the 3hi group compared with those of the ni group.
on g <dig>  the tt <dig> concentration of the adult females remained the higher level in the 3hi group compared with that of the ni.
although no significant changes were found in the tsh levels on pre-pregnancy and g <dig> in the 3hi rats compared with those of the ni, there were descending trends in the 3hi group.
before the onset of foetal thyroid function in both humans  and rats , early foetal brain development is completely dependent on maternal thyroxine  supply
<cit> .
even after the foetal thyroid has begun to secrete hormone, as much as  <dig> % of foetal t <dig> derives from transplacental transfer
<cit> .
recent studies have reported that excess thyroid hormone could impair foetal brain development and affect the neurological outcome of rat offspring
<cit> .
excessive iodine intake has been shown to inhibit foetal thyroid function and lead to iodine-induced neonatal hypothyroidism in asian populations
<cit> .
our previous study
<cit>  found that excessive iodine intake increased the risk of subclinical hypothyroidism in offspring.
furthermore, excessive iodine content from breast milk caused subclinical hypothyroidism in preterm infants
<cit> .
these studies were consistent with our finding in the present study that maternal iodine excess caused subclinical hypothyroidism of rat pups on pn <dig>  although the thyroid hormone levels of pups in the 3hi group were within the normal range on pn <dig>  our results indicated that maternal thyroid hormone disruption during sensitive periods of brain development caused by mildly maternal iodine excess could lead to thyroid dysfunction of pups and cause neurodevelopmental defects in offspring.
the proteins c-fos and c-jun in the nuclei of neurons are involved in neuroplastic mechanisms and neuronal differentiation, and also have important roles in memory formation and consolidation
<cit> .
in our study, c-fos and c-jun expression in the hippocampal ca <dig> area of rat pups was not significantly affected by the 3-fold high iodine intake of their mothers during gestation.
it is possible that compensatory mechanisms restored c-fos and c-jun to normal levels in spite of maternal thyroid dysfunction.
another possibility is that c-fos and c-jun were not involved in the neurodevelopmental impairment of pups from the 3hi group.
bdnf, a neurotrophin protein, has significant influence on crucial processes of brain development, including neurogenesis, neuronal differentiation, synaptogenesis, memory formation, and consolidation
<cit> .
previous reports have documented that maternal thyroid dysfunction could affect the expression of bdnf and cause neurological defects in neonates
<cit>  and adult rats
<cit> .
our previous studies
<cit>  reported that maternal subclinical hypothyroidism decreased bdnf expression in rat pup hippocampi and impaired spatial learning; pups required more time during the morris water maze test to find the hidden platform, compared with pups from ni mothers.
the present study found that bdnf protein levels were decreased in the hippocampi of the pups from both the 3hi and li mothers.
on pn <dig>  the bdnf expression in the 3hi pups remained lower than control pups, although circulating levels of thyroid hormone had fully recovered.
our study indicated that a persistently lower bdnf level may contribute to the adverse effect of 3hi on the developing brain.
however, the impairment was mild compared with hypothyroidism induced by iodine deficiency.
nsp-a is known to be an important mediator of thyroid hormone effects during brain development and is involved in neuronal differentiation and axonal guidance
<cit> .
dowling et al.
<cit>  showed that the expression of nsp-a was regulated by thyroid hormone, and the expression of nsp-a was selectively affected by maternal hypothyroidism in the proliferative zone of the fetal rat brain cortex.
our data also found that the expression of nsp-a in the hippocampus on pn <dig> was affected by mildly maternal excessive iodine intake.
the abnormal expression of nsp-a in the neonatal brain appears to be related to the neurodevelopmental impairment in the pups of the 3hi group, but the impairment was less severe than pups in the li group.
in this study, spatial learning ability and memory of the rat pups were assessed using the mwm test on pn40- <dig>  pups in the li group required more time to find the hidden platform, compared with pups from ni mothers.
the severe impairment of spatial and learning ability was associated with the thyroid dysfunction and abnormal levels of proteins related to neurodevelopment, which were not reversed by pn <dig> in li group, and the neurodevelopmental impairment thus appeared to be permanent.
the mean escape latency of 3hi pups was longer than for the ni control pups, and the difference was significant on the third day .
our results suggested that the offspring in the 3hi group may have had a mildly impaired learning capacity, which could be associated with a decrease in bdnf and an increase in nsp-a levels.
the mild spatial learning and memory impairment was temporary, which was consistent with the recovery of nsp-a expression on pn <dig>  and the long-term effects of mildly maternal excessive iodine intake on neurodevelopment and cognitive function need to be investigated in our future study.
CONCLUSIONS
in summary, this study found that both low and high levels of iodine intake by rats could affect the neurological development of offspring.
reduced the expression of bdnf and enhanced that of nsp-a during hippocampal development of the offspring might be related with the impaired cognitive functions.
however the impairment induced by maternal 3-fold high iodine intake was mild and temporary, which suggested that careful control of maternal iodine intake level is important to prevent neurodevelopmental defects in offspring.

 iodine is essential for the synthesis of thyroid hormone, including during pregnancy. maternal thyroid hormones have essential roles in foetal brain development, regulating both morphological and biochemical changes before the onset of foetal thyroid function. moderate and severe iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring. in china the universal salt iodization policy was implemented in and since then the average resident’s iodine status was in excess for three years and more than adequate for six years. previously, we conducted a five-year follow-up study from to to evaluate the effect of different iodine intake on thyroid diseases. we found that more than adequate and iodine excess could increase the prevalence of subclinical hypothyroidism. however whether more than adequate and excessive iodine intake can affect the neurodevelopment of the offspring has not been investigated. the genes c-fos and c-jun are essential for spatial learning and memory consolidation in rats, and hypothyroidism due to iodine deficiency is associated with reduced expressions of c-fos and c-jun in the rat hippocampal ca region. maternal hypothyroidism affects the expression of foetal and neonatal brain-derived neurotrophic factor and neuroendocrine-specific protein -a, both of which are important mediators of thyroid hormone and have essential roles in brain development. in our present study, female wistar rats were maintained on low-iodine grain and randomly assigned to three groups based on the iodated water concentration: low iodine, normal iodine, and 3-fold high iodine groups. furthermore we explored whether maternal iodine excess in rats could lead to changes in neurological function in offspring.  urinary and thyroidal iodine content urine iodine concentrations of the adult female rats paralleled their iodine intake; urine and tissue iodine concentrations increased gradually with increasing iodine intake. in the low iodine group, urinary iodine was only % that of the normal iodine group, and the thyroidal iodine was % that of the ni group. at the same time, the 3-fold iodine group had significantly elevated concentrations of iodine in urine and thyroid tissue, which was % and %, respectively, that of the ni group. values are expressed as the mean ± sem. *p  <  compared with normal iodine control group. maternal and pup thyroid hormone maternal thyroid hormone: after 12 weeks of treatment, total thyroxine and free thyroxine concentrations in the sera of the adult females were significantly lower in the li group compared with those in the ni. tt and ft levels in the maternal serum were significantly higher in the 3hi group than those in ni control group. on gestational day tt and ft concentrations in sera of the adult females remained significantly lower in the li group compared with those in the ni, while the 3hi group still exhibited significantly higher circulating tt level compared with the control group. however, on g the level of ft was a increasing trend, however no significant difference in ft concentration between the ni and 3hi groups. after 12 weeks of treatment and on g thyroid stimulating hormone concentrations were significantly higher in the li group compared with the ni, while there were descending trends, although no significant changes were found in the tsh levels after 12 weeks of treatment and on g in the 3hi rats compared with these levels in the ni. values are expressed as mean ± sem; n =  for each group. *p <  compared with the ni control on the same day; athe sensitivity of the chemiluminescence immunoassay for tt was  μg/dl. pup thyroid hormone: on postnatal day and day, the sera of pups in the li group had significantly higher tsh levels, and lower tt and ft levels, than those in the ni group. on pn pups from the 3hi group had a significantly higher serum tsh level compared with ni pups. however, there was no significant difference between the 3hi and ni groups in tt and ft levels. on pn there was no significant difference in any of the serum thyroid hormone levels between pups of the 3hi and ni groups. this indicated that the thyroid dysfunction of the pups from the 3hi group could be rectified by pn values are expressed as mean ± sem; n =  for each group. *p <  compared with ni control on the same day. effect of 3hi on the protein expressions of c–fos and c-jun in the ca area of hippocampus photomicrographs of the immunohistochemistry-stained hippocampal tissues from pn pups showed positive expression of c-fos and c-jun in area ca in all treatment groups. the iod values of c-fos and c-jun in ca area were significantly decreased in the pups of the li group compared with control pups. however, there was no significant difference in c-fos and c-jun expressions between the 3hi and ni groups. on pn the expression of c-fos and c-jun in the li group was also the lowest among the three groups. there was no significant difference in the expressions of c-fos and c-jun in ca region of hippocampus between the 3hi pups and dams of the ni group. effect of 3hi on bdnf and nsp-a expression in the hippocampus on pn and pn bdnf protein expression levels were significantly lower in both the li and 3hi pups compared with the ni controls. specifically, on pn the bdnf levels in the pups of the li group were % that of the ni, and the bdnf levels of the pups in the 3hi group were % that of the ni. on pn the bdnf levels in the pups of the li group were % that of the ni, and the bdnf levels of the pups in the 3hi group were % that of the ni. on the other hand, on pn the expression of nsp-a was higher in the li and 3hi pups when compared with the ni controls: the levels of nsp-a of the li and 3hi pups were % and %, respectively, that of the ni pups. nsp-a protein expression levels were significantly higher in the li pups compared with the ni controls on pn the levels of nsp-a of the li pups were % that of the ni pups. however, no significant differences in the nsp-a levels were observed between the 3hi dams and ni dams on pn. morris water maze test to evaluate whether various levels of iodine intake during gestation could cause cognitive and behavioral alterations in offspring, the pups underwent the mwm test on pn40- the time to reach the hidden platform of all treatment groups became shorter as the number of training trials increased. however, the escape latencies were significantly longer for pups in the li group compared with the ni group. interestingly, our data showed that the 3hi pups took more time than the controls to learn the spatial cues required to find the hidden platform for all 5 days of testing, and there was a statistical difference when compared with the ni control group on the third day. discussion much recent attention has focused on elucidating the effects of iodine deficiency on neurodevelopmental impairment. however, the effects of iodine excess should not be overlooked. we investigated whether and how a 3-fold increase in the physiological dose of iodine in rat would affect brain development of their offspring. the rat brain at pn is considered developmentally equivalent to the human brain at birth. rat brain development at pn approximates the late toddler stage of humans, and pn equates to the teenager stage. we selected pn and pn as two crucial time points in the brain development of the rat to explore the effect of maternal excessive iodine intake on the neurodevelopment and cognitive function in their offspring. our results show for the first time that there were changes in bdnf and nsp-a expression and neurodevelopmental impairment in rat pups whose mothers had a 3-fold higher-than-normal intake of iodine prior to pregnancy and throughout gestation and breastfeeding. iodine intake levels that are either lower or higher than the recommended range are associated with an increase in the incidence of thyroid disease in china. both thyroid hormone deficiency and excess have detrimental effects on the expression of neuronal proteins during neurodevelopmental stages. iodine deficiency is the most common cause of hypothyroidism. the results of some studies regarding excess iodine suggested that high iodine intake was associated with increased incidence of hypothyroidism, while others found that it led to hyperthyroidism. these different results may be related to the duration of high iodine exposure. the incidence of hyperthyroidism after the initiation of the universal salt iodization program began to rise at about 6 months, peaked at 1–3 years and returned to the baseline within 3–10 years. iodine-induced thyrotoxicosis lasting the first few years after the implementation of iodine supplementation was reported in lesotho and poland. however our epidemiological study demonstrated that there was no difference in either the prevalence or the incidence of hyperthyroidism among mildly deficient, more than adequate, and excessive iodine intake areas. we found that more than adequate and excessive iodine intake could increase the prevalence of subclinical hypothyroidism. the usi policy had been implemented for to 8 years in china, since when we conducted the epidemiological study from to therefore we did not obtain epidemiological data for the early stage of iodine supplementation. in the present animal study, after 12 weeks of treatment, the serum tt and ft levels were significantly higher in the adult female rats of the 3hi group compared with those of the ni group. on g the tt concentration of the adult females remained the higher level in the 3hi group compared with that of the ni. although no significant changes were found in the tsh levels on pre-pregnancy and g in the 3hi rats compared with those of the ni, there were descending trends in the 3hi group. before the onset of foetal thyroid function in both humans and rats, early foetal brain development is completely dependent on maternal thyroxine supply. even after the foetal thyroid has begun to secrete hormone, as much as % of foetal t derives from transplacental transfer. recent studies have reported that excess thyroid hormone could impair foetal brain development and affect the neurological outcome of rat offspring. excessive iodine intake has been shown to inhibit foetal thyroid function and lead to iodine-induced neonatal hypothyroidism in asian populations. our previous study found that excessive iodine intake increased the risk of subclinical hypothyroidism in offspring. furthermore, excessive iodine content from breast milk caused subclinical hypothyroidism in preterm infants. these studies were consistent with our finding in the present study that maternal iodine excess caused subclinical hypothyroidism of rat pups on pn although the thyroid hormone levels of pups in the 3hi group were within the normal range on pn our results indicated that maternal thyroid hormone disruption during sensitive periods of brain development caused by mildly maternal iodine excess could lead to thyroid dysfunction of pups and cause neurodevelopmental defects in offspring. the proteins c-fos and c-jun in the nuclei of neurons are involved in neuroplastic mechanisms and neuronal differentiation, and also have important roles in memory formation and consolidation. in our study, c-fos and c-jun expression in the hippocampal ca area of rat pups was not significantly affected by the 3-fold high iodine intake of their mothers during gestation. it is possible that compensatory mechanisms restored c-fos and c-jun to normal levels in spite of maternal thyroid dysfunction. another possibility is that c-fos and c-jun were not involved in the neurodevelopmental impairment of pups from the 3hi group. bdnf, a neurotrophin protein, has significant influence on crucial processes of brain development, including neurogenesis, neuronal differentiation, synaptogenesis, memory formation, and consolidation. previous reports have documented that maternal thyroid dysfunction could affect the expression of bdnf and cause neurological defects in neonates and adult rats. our previous studies reported that maternal subclinical hypothyroidism decreased bdnf expression in rat pup hippocampi and impaired spatial learning; pups required more time during the morris water maze test to find the hidden platform, compared with pups from ni mothers. the present study found that bdnf protein levels were decreased in the hippocampi of the pups from both the 3hi and li mothers. on pn the bdnf expression in the 3hi pups remained lower than control pups, although circulating levels of thyroid hormone had fully recovered. our study indicated that a persistently lower bdnf level may contribute to the adverse effect of 3hi on the developing brain. however, the impairment was mild compared with hypothyroidism induced by iodine deficiency. nsp-a is known to be an important mediator of thyroid hormone effects during brain development and is involved in neuronal differentiation and axonal guidance. dowling et al. showed that the expression of nsp-a was regulated by thyroid hormone, and the expression of nsp-a was selectively affected by maternal hypothyroidism in the proliferative zone of the fetal rat brain cortex. our data also found that the expression of nsp-a in the hippocampus on pn was affected by mildly maternal excessive iodine intake. the abnormal expression of nsp-a in the neonatal brain appears to be related to the neurodevelopmental impairment in the pups of the 3hi group, but the impairment was less severe than pups in the li group. in this study, spatial learning ability and memory of the rat pups were assessed using the mwm test on pn40- pups in the li group required more time to find the hidden platform, compared with pups from ni mothers. the severe impairment of spatial and learning ability was associated with the thyroid dysfunction and abnormal levels of proteins related to neurodevelopment, which were not reversed by pn in li group, and the neurodevelopmental impairment thus appeared to be permanent. the mean escape latency of 3hi pups was longer than for the ni control pups, and the difference was significant on the third day. our results suggested that the offspring in the 3hi group may have had a mildly impaired learning capacity, which could be associated with a decrease in bdnf and an increase in nsp-a levels. the mild spatial learning and memory impairment was temporary, which was consistent with the recovery of nsp-a expression on pn and the long-term effects of mildly maternal excessive iodine intake on neurodevelopment and cognitive function need to be investigated in our future study.  in summary, this study found that both low and high levels of iodine intake by rats could affect the neurological development of offspring. reduced the expression of bdnf and enhanced that of nsp-a during hippocampal development of the offspring might be related with the impaired cognitive functions. however the impairment induced by maternal 3-fold high iodine intake was mild and temporary, which suggested that careful control of maternal iodine intake level is important to prevent neurodevelopmental defects in offspring. 
no significant difference was observed in the expressions of c-fos or c-jun in the hippocampal ca region of the 3hi group compared to the controls. the results of our previous epidemiological study suggested that mild iodine excess might increase the prevalence of subclinical hypothyroidism. results from the morris water maze test revealed that pups of the 3hi group had mild learning and spatial memory deficits. iodine deficiency and iodine excess are both associated with adverse health consequences. iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring. in the present study, female wistar rats maintained on low-iodine grain were randomly assigned to three groups based on iodated water concentration: low iodine, normal iodine, and 3-fold high iodine. the present study investigated whether higher-than-normal iodine intake by rats from before pregnancy until breastfeeding affects the postnatal neurodevelopment of their offspring during particularly sensitive periods in brain development. after 12 weeks of treatment, iodine concentrations in urine and thyroid tissue and circulating thyroxine of adult females correlated with iodine intake. brain-derived neurotrophic factor expression in the hippocampi of pups on pn and pn was decreased in 3hi group compared to the ni controls on pn and pn the bdnf levels of the 3hi pups were % and %, respectively, that of the ni pups. nsp-a levels of the 3hi pups were % that of the ni pups. in addition, the 3hi group had a higher neuroendocrine-specific protein a level than the ni controls on pn. the neurodevelopmental and cognitive deficits of the 3hi pups were mild and temporary, likely related to the changes in hippocampal protein expressions of bdnf and nsp-a.
 iodine deficiency and iodine excess are both associated with adverse health consequences. iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring. the results of our previous epidemiological study suggested that mild iodine excess might increase the prevalence of subclinical hypothyroidism. in the present study, female wistar rats maintained on low-iodine grain were randomly assigned to three groups based on iodated water concentration: low iodine, normal iodine, and 3-fold high iodine. the present study investigated whether higher-than-normal iodine intake by rats from before pregnancy until breastfeeding affects the postnatal neurodevelopment of their offspring during particularly sensitive periods in brain development.  after 12 weeks of treatment, iodine concentrations in urine and thyroid tissue and circulating thyroxine of adult females correlated with iodine intake. brain-derived neurotrophic factor expression in the hippocampi of pups on pn and pn was decreased in 3hi group compared to the ni controls on pn and pn the bdnf levels of the 3hi pups were % and %, respectively, that of the ni pups. in addition, the 3hi group had a higher neuroendocrine-specific protein a level than the ni controls on pn. nsp-a levels of the 3hi pups were % that of the ni pups. no significant difference was observed in the expressions of c-fos or c-jun in the hippocampal ca region of the 3hi group compared to the controls. results from the morris water maze test revealed that pups of the 3hi group had mild learning and spatial memory deficits.  the neurodevelopmental and cognitive deficits of the 3hi pups were mild and temporary, likely related to the changes in hippocampal protein expressions of bdnf and nsp-a. iodine deficiencyiodine excessthyroid hormonehippocampusneurodevelopment 