Mouse Genome Informatics
hm1
    Cyp19a1tm1Esi/Cyp19a1tm1Esi
involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Cyp19a1tm1Esi/Cyp19a1tm1Esi livers are larger, pale and accumulate lipid droplets

growth/size
• progressively accumulate more intraabdominal adipose tissue than wild-type
• increased adiposity is not due to hyperphagia or reduced resting energy expenditure
• the increase in fat mass is accompanied by a decrease in lean mass
• females are heavier starting at 3 months of age, while males show an increase in weight beginning at 1 year of age

adipose tissue
• progressively accumulate more intraabdominal adipose tissue than wild-type
• increased adiposity is not due to hyperphagia or reduced resting energy expenditure
• increase in adipocyte volume and size in gonadal fat pads over time
• both males and females have significantly larger gonadal fat pads from 3-4 months of age onward
• both males and females have significantly larger infrarenal fat pads from 3-4 months of age onward
• administration of exogenous 17beta-estradiol to females for 21 days restores the fat deposits to masses comparable to wild-type

homeostasis/metabolism
• seen in mutants at 3-4 months and 1 year of age
• seen in mutants at 1 year of age, but not at 3-4 moths of age
• seen in mutants at 1 year of age, but not at 3-4 moths of age
• circulating triglyceride levels are elevated in 1 year old males but not in females
• glucose oxidation rates are 59% lower than in wild-type, however resting energy expenditure and fat oxidation rates are normal
• seen in male mutants at 1 year of age, but not at 3-4 moths of age

liver/biliary system
• at 1 year of age
• accumulation of lipid droplets in the livers at 3 months and 1 year of age
• at 1 year of age

behavior/neurological
• older females exhibit reduced spontaneous physical activity
• reduced mounting behavior exhibited by males at 12 to 14 weeks of age and at 1 year of age
• males at 12 to 14 weeks of age and at 1 year of age demonstrated impaired mounting behavior (J:83254)

reproductive system
• increase in incidence of hemorrhagic cysts when fed a soy-free diet (J:78634)
• the ovaries of mice on a soy free diet exhibit seminiferous tubule-like structures throughout 80% of ovaries, hemorrhagic cysts, and age dependent increase in collagen deposition (J:78634)
• in constrast, animals fed a soy diet do not display Sertoli-like cells in follicles (J:78634)
• ovaries lack corpora lutea when mice are fed a soy-free diet (J:78634)
• absence of healthy antral follicles when fed a soy-free diet with ag (J:78634)
• on a soy-free diet, mature follicles appear atretic; uneven granulose cell layers and cellular debris within antral compartments (J:78634)
• ovaries of 16-18 week old mice on a soy-free diet show a near-complete block in folliculogenesis at the primordial or primary stage (J:78634)
• normal follicular morphology is partly restored by estradiol treatment (J:78634)
• increase in incidence of hemorrhagic cysts when fed a soy-free diet (J:78634)
• decreased number of round spermatids and/or spermatocytes at 3.5 months of age (J:83254)
• reduced sperm concentration at 1 year of age (J:83254)
• normal sperm concentration at 15 weeks of age (J:83254)
• on a soy free diet, the ovaries develop cells that possess structural and functional characteristics of testicular interstitial (Leydig) cells and of seminiferous tubule-like structures lined with Sertoli cells
• the development of testicular tissue is postponed and reduced with estrogen replacement
• at 3.5 months of age, males sired fewer litters than wild-type, with 50% siring no litters at all (J:83254)
• decreased sperm motility evident at 15 weeks of age and more severe at 1 year of age (J:83254)
• fertilization was possible in vitro at 15 weeks of age, but not at 1 year of age (J:83254)

hearing/vestibular/ear
• following accoustic trauma, mice exhibit a greater shift in brainstem auditory evoked potential compared with similarly treated wild-type mice

cardiovascular system
• increase in incidence of hemorrhagic cysts when fed a soy-free diet (J:78634)

endocrine/exocrine glands
• increase in incidence of hemorrhagic cysts when fed a soy-free diet (J:78634)
• the ovaries of mice on a soy free diet exhibit seminiferous tubule-like structures throughout 80% of ovaries, hemorrhagic cysts, and age dependent increase in collagen deposition (J:78634)
• in constrast, animals fed a soy diet do not display Sertoli-like cells in follicles (J:78634)
• ovaries lack corpora lutea when mice are fed a soy-free diet (J:78634)
• absence of healthy antral follicles when fed a soy-free diet with ag (J:78634)
• on a soy-free diet, mature follicles appear atretic; uneven granulose cell layers and cellular debris within antral compartments (J:78634)
• ovaries of 16-18 week old mice on a soy-free diet show a near-complete block in folliculogenesis at the primordial or primary stage (J:78634)
• normal follicular morphology is partly restored by estradiol treatment (J:78634)
• increase in incidence of hemorrhagic cysts when fed a soy-free diet (J:78634)


Mouse Genome Informatics
hm2
    Cyp19a1tm1Esi/Cyp19a1tm1Esi
involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Absence of corpora lutea in Cyp19a1tm1Esi/Cyp19a1tm1Esi ovaries

pigmentation
• at 3 weeks of age, both male and female homozygotes exhibit a dull coat

adipose tissue
• males and females exhibited a 50% and 50% to 80% increase in gonadal fat pad weight, respectively
• females exhibited a 50% to 80% increase in mammary fat pad weight

endocrine/exocrine glands
• by 21-23 weeks of age (J:63458)
(J:48086)
• at 10-12 weeks of age, the mutant ovary displays follicles of all types (primordial, primary secondary, and antral), but no corpora lutea (J:63458)
• at 10-12 weeks, aberrant and non-uniform layers of granulosa cells and numerous pyknotic nuclei are detected, with marked apoptosis in granulosa cells of larger, antral size follicles (J:63458)
• at 21-23 weeks of age, follicles at all stages are still observed but many follicles are atretic; preantral follicles are randomly scattered and many antral follicles appear cystic and hemorrhagic (J:63458)
• by 1 yr of age, no secondary or antral follicles are identified; remnants of large follicles, many of which are cystic and hemorrhagic, are present while primary follicles consist of oddly shaped and mostly pyknotic granulosa cells (J:63458)
(J:48086)
• at 10-12 and 21-23 weeks and 1 yr of age (J:63458)
• marked apoptosis in granulosa cells of larger, antral size follicles at 10-12 weeks of age (J:63458)
• widespread granulosa cell apoptosis by 1 yr of age (J:63458)
• though ovaries contained numerous follicles with abundant granulosa cells, antrum formation was arrested before ovulation (J:48086)
• no corpora leutea (J:48086)
(J:63458)
• hemorrhagic cystic follicles are observed by 21-23 weeks of age (J:63458)
• at 16-26 weeks of age, male mutants display significant enlargement of the ventral, anterior and dorsolateral prostatic lobes (J:70204)
• increase in absolute volume of individual tissue compartments is attributed to increased volume of the entire prostate organ (J:70204)
• no increase in the diameter of individual ducts or localized dysplastic growth are observed in one individual cell type or tissue compartment (J:70204)
• increase in combined prostate/urinary bladder weight (J:48086)
• wet weights of ventral prostates are increased by 60%, 46%, and 57% at 8-14, 16-26, and 48-56 weeks of age, respectively, relative to wild-type controls (J:70204)
• anterior prostate weights are increased by 40%, 21%, and 25% at 8-14, 16-26, and 48-56 weeks, respectively, relative to wild-type controls (J:70204)
• dorsolateral prostate weights are also increased by 54%, 55%, and 46%, respectively (J:70204)
• diet (regular vs soy-free) had no significant effect on the weight or volume of prostate from animals of the same genotype (J:70204)
• no significant differences in body weights are noted between age-matched mutant and wild-type males at all ages examined (J:70204)
• male mutants exhibit a hyperplasia of the entire prostate gland, which is induced at 8-14 weeks and maintained up to 56 weeks of age (J:70204)
• in the ventral prostatic lobe, hyperplasia characterized by increased infolding of the prostatic epithelium is first noted at 8-14 weeks and becomes prominent at 48-56 weeks, in the absence of epithelial dysplasia (J:70204)
• in the anterior and dorsolateral lobes, hyperplasia is observed at 16-26 weeks in the absence of increased infolding of the glandular epithelium (J:70204)
• observed changes are unaffected by maintaining mice on regular or soy-free diets (J:70204)
• no signs of aberrant growth or enhanced malignancy are observed even at 56 weeks of age (J:70204)
• short-term exposure to DES resulted in comparable regression of the prostate lobes and induction of squamous metaplasia in the anterior prostate of both wild-type and mutant males (J:70204)
• increased weight of seminal vescicles, putatively due to an increased volume of secretions rather than due to structural changes (J:48086)
• at 4.5 months of age, 4 of 5 male homozygotes showed normal testicular morphology, but one animal displayed grossly dysmorphic seminiferous tubules and disrupted spermatogenesis (J:56358)
• at 1 yr of age, all male homozygotes show evidence of Leydig cell hyperplasia/hypertrophy, as evidenced by an increase in the absolute volume of Leydig cells per testis (J:56358)
• at 1 yr of age, male homozygotes show a significant decrease in the volume of seminiferous epithelium (J:56358)
• however, no dilated lumens or other changes in the seminiferous tubule luminal volume are observed (J:56358)
• by 1 yr of age, all male homozygotes show a reduction in testis weight (J:56358)
• at 16 weeks of age, tissue levels of 5alpha-dihydrotestosterone are significantly increased in the anterior prostate of mutant males relative to wild-type males (J:70204)
• in contrast, tissue testosterone levels in the anterior prostate remain unchanged (J:70204)

homeostasis/metabolism
• at 16 weeks of age, serum 5alpha-dihydrotestosterone levels in mutant males are 2-fold higher than those in wild-type males
• female testosterone level was increased to ~10 times the level in wild-type females (J:48086)
• male testosterone levels varied though they were in general increased relative to those of control males (J:48086)
• at 4.5 months and 1 yr of age, male serum testosterone levels are variable, with no significant increase or decrease, although levels are initially elevated at 12-14 weeks of age (J:56358)
• at 16 weeks of age, serum testosterone levels in mutant males are ~10-fold higher than those in wild-type males (J:70204)
• female FSH levels were elevated 3- to 4-fold relative to wild-type females (J:48086)
• at 4.5 months and 1 yr of age, male serum FSH levels are unchanged relative to age-matched wild-type males (J:56358)
• female serum FSH levels are significantly higher than wild-type and heterozygous levels at 10-12 and 21-23 weeks and 1 yr of age (J:63458)
• at 1 yr of age, female serum FSH levels are 3-fold higher than wild-type levels (J:63458)
• female LH levels were elevated 2- to 10-fold relative to wild-type females (J:48086)
• LH levels were also increased in male mice (J:48086)
• at 4.5 months and 1 yr of age, male homozygotes show elevated serum LH levels, similar to those initially reported at 12-14 weeks of age (J:56358)
• by 1 yr of age, serum LH levels of homozygous mutant mice are ~3-fold higher than wild-type and heterozygous levels (J:63458)
• at 16 weeks of age, serum prolactin levels in mutant males are 3-fold higher than those in wild-type males
• at 10-14 weeks of age, 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme levels remain unchanged in most tissues of female homozygotes, except in the kidney, where they are reduced to only 10% of wild-type levels
• estradiol administered to mutant females restores renal 11betaHSD2 to wild-type levels, but does not further increase levels in wild-type mice

reproductive system
(J:48086)
• at 10-12 weeks of age, the mutant ovary displays follicles of all types (primordial, primary secondary, and antral), but no corpora lutea (J:63458)
• at 10-12 weeks, aberrant and non-uniform layers of granulosa cells and numerous pyknotic nuclei are detected, with marked apoptosis in granulosa cells of larger, antral size follicles (J:63458)
• at 21-23 weeks of age, follicles at all stages are still observed but many follicles are atretic; preantral follicles are randomly scattered and many antral follicles appear cystic and hemorrhagic (J:63458)
• by 1 yr of age, no secondary or antral follicles are identified; remnants of large follicles, many of which are cystic and hemorrhagic, are present while primary follicles consist of oddly shaped and mostly pyknotic granulosa cells (J:63458)
(J:48086)
• at 10-12 and 21-23 weeks and 1 yr of age (J:63458)
• marked apoptosis in granulosa cells of larger, antral size follicles at 10-12 weeks of age (J:63458)
• widespread granulosa cell apoptosis by 1 yr of age (J:63458)
• though ovaries contained numerous follicles with abundant granulosa cells, antrum formation was arrested before ovulation (J:48086)
• no corpora leutea (J:48086)
(J:63458)
• hemorrhagic cystic follicles are observed by 21-23 weeks of age (J:63458)
• 3-fold enlargement of the clitoral gland relative to that of wild-type (J:48086)
• labial folds do not develop (J:48086)
• unlike in wild-type mice, mean uterine weights fail to increase significantly with age in mutant mice (J:63458)
• by 1 yr of age, uterine weights of homozygous mutants are only 30% of wild-type and heterozygous weights (J:63458)
• underdeveloped uterus observed at 12 to 14 weeks of age (J:48086)
• at 1 yr of age, no significant decreases are observed in Sertoli cell numbers or in spermatogonia and spermatocyte populations; however, significantly less round and elongated spermatids are present in the mutant epithelium relative to wild-type controls (J:56358)
• at 4.5 months of age, the numbers of Sertoli cells, spermatogonia, spermatocytes, round spermatids, and elongated spermatids are comparable to those of wild-type males (J:56358)
• male homozygotes develop spermatogenic disruptions between 4.5 months and 1 yr of age, despite no significant reductions in gonadotrophins or androgens (J:56358)
• at 1 yr of age, tubules with early spermiogenic arrest exhibit defects in early acrosomal development (J:56358)
• multiple acrosomal vesicles are observed and, in some cases, acrosomes fail to uniformly spread over the spermatid nuclei (J:56358)
• at 1 yr of age, male homozygotes show a significant reduction in round and elongated spermatids, but no changes in Sertoli cells and earlier germ cells relative to wild-type males (J:56358)
• male homozygotes show a specific defect in the development of spermatids during spermiogenesis (J:56358)
• at 1 yr of age, the site of spermatogenic disruption appears to be early spermiogenesis with symplasts and degenerating round spermatids frequently observed (J:56358)
• most mutants also display some tubules with normal morphology adjacent to tubules with spermiogenic arrest, suggesting a heterogeneous disruption (J:56358)
• at 16-26 weeks of age, male mutants display significant enlargement of the ventral, anterior and dorsolateral prostatic lobes (J:70204)
• increase in absolute volume of individual tissue compartments is attributed to increased volume of the entire prostate organ (J:70204)
• no increase in the diameter of individual ducts or localized dysplastic growth are observed in one individual cell type or tissue compartment (J:70204)
• increase in combined prostate/urinary bladder weight (J:48086)
• wet weights of ventral prostates are increased by 60%, 46%, and 57% at 8-14, 16-26, and 48-56 weeks of age, respectively, relative to wild-type controls (J:70204)
• anterior prostate weights are increased by 40%, 21%, and 25% at 8-14, 16-26, and 48-56 weeks, respectively, relative to wild-type controls (J:70204)
• dorsolateral prostate weights are also increased by 54%, 55%, and 46%, respectively (J:70204)
• diet (regular vs soy-free) had no significant effect on the weight or volume of prostate from animals of the same genotype (J:70204)
• no significant differences in body weights are noted between age-matched mutant and wild-type males at all ages examined (J:70204)
• male mutants exhibit a hyperplasia of the entire prostate gland, which is induced at 8-14 weeks and maintained up to 56 weeks of age (J:70204)
• in the ventral prostatic lobe, hyperplasia characterized by increased infolding of the prostatic epithelium is first noted at 8-14 weeks and becomes prominent at 48-56 weeks, in the absence of epithelial dysplasia (J:70204)
• in the anterior and dorsolateral lobes, hyperplasia is observed at 16-26 weeks in the absence of increased infolding of the glandular epithelium (J:70204)
• observed changes are unaffected by maintaining mice on regular or soy-free diets (J:70204)
• no signs of aberrant growth or enhanced malignancy are observed even at 56 weeks of age (J:70204)
• short-term exposure to DES resulted in comparable regression of the prostate lobes and induction of squamous metaplasia in the anterior prostate of both wild-type and mutant males (J:70204)
• increased weight of seminal vescicles, putatively due to an increased volume of secretions rather than due to structural changes (J:48086)
• at 4.5 months of age, 4 of 5 male homozygotes showed normal testicular morphology, but one animal displayed grossly dysmorphic seminiferous tubules and disrupted spermatogenesis (J:56358)
• at 1 yr of age, all male homozygotes show evidence of Leydig cell hyperplasia/hypertrophy, as evidenced by an increase in the absolute volume of Leydig cells per testis (J:56358)
• at 1 yr of age, male homozygotes show a significant decrease in the volume of seminiferous epithelium (J:56358)
• however, no dilated lumens or other changes in the seminiferous tubule luminal volume are observed (J:56358)
• by 1 yr of age, all male homozygotes show a reduction in testis weight (J:56358)
• at 1 yr of age, mutant epididymes show reduced or complete absence of sperm (J:56358)
• by 21-23 weeks of age (J:63458)
• at 1 yr of age, decline in round spermatid number is due to increased cell death in the adluminal compartment of the seminiferous epithelium (J:56358)
• in contrast, tissue testosterone levels in the anterior prostate remain unchanged (J:70204)
• at 16 weeks of age, tissue levels of 5alpha-dihydrotestosterone are significantly increased in the anterior prostate of mutant males relative to wild-type males (J:70204)
• female homozygotes fail to ovulate (J:63458)
(J:48086)
(J:63458)
• male homozygotes are initially fertile with normal testis morphology at 12-14 weeks, but develop progressive infertility between 4.5 months and 1 yr of age (J:56358)
• mutant males mated at 7 months of age for an average of 6 months fail to sire litters (J:56358)

cardiovascular system
• by 21-23 weeks of age (J:63458)
• at 6 months of age, the maximum rate of change in blood pressure (dP/dT) occuring during systole is 40% higher in conscious female homozygotes relative to wild-type controls (1427 9 vs 1019 14 mm Hg/sec, respectively)
• at 6 months of age, HR variability is lower in conscious female homozygotes relative to wild-type controls over all frequency ranges
• total HR variability is only 43% of the value in wild-type female mice
• at 6 months of age, conscious female homozygotes exhibit a ~7% increase in heart rate relative to wild-type females (514 5 vs 481 5 beats/min, respectively)
• however, no significant differences in respiratory rate are observed
• at 6 months of age, conscious female homozygotes show a significnat increase in BP variability within specific frequency ranges, namely the mid and high frequency bands
• specifically, the mid frequency power (0.3-0.5 Hz) corresponding to the autonomic range is 1.7 times greater while the high frequency region (0.5-1 Hz) is 2.4 times greater in female homozygotes relative to wild-type controls
• however, the overall BP variability (0-1 Hz) is not statistically different between mutant and wild-type females
• at 6 months of age, conscious female homozygotes show a 4.5 2.0 mm Hg reduction in MAP relative to wild-type females
• at 6 months of age, conscious female homozygotes show a lower diastolic arterial pressure than wild-type females (86.5 0.4 vs 92.6 0.5 mm Hg, respectively)
• however, no significant differences in the systolic blood pressure are observed

cellular
• at 1 yr of age, decline in round spermatid number is due to increased cell death in the adluminal compartment of the seminiferous epithelium (J:56358)
• by 1 yr of age, granulosa cell apoptosis is widespread throughout the ovary, as indicated by TUNEL analysis

nervous system
• at 6 months of age, the baroreflex sensitivity (BRS) in female conscious homozygotes is 46% of the value observed in wild-type females

muscle
• at 6 months of age, the maximum rate of change in blood pressure (dP/dT) occuring during systole is 40% higher in conscious female homozygotes relative to wild-type controls (1427 9 vs 1019 14 mm Hg/sec, respectively)

integument
• at 3 weeks of age, both male and female homozygotes exhibit a dull coat


Mouse Genome Informatics
hm3
    Cyp19a1tm1Esi/Cyp19a1tm1Esi
involves: 129S6/SvEvTac * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• at 6 months of age, male (but not female) homozygotes develop compulsive behaviors including excessive barbering, grooming and wheel running
• male-specific excessive wheel running and grooming activities are accompanied by a significant decrease in catechol-O-methyltransferase (COMT1) protein expression in the hypothalamus and can be reversed by 3 weeks of 17beta-estradiol treatment
• at 6 months of age, male homozygotes display extreme barbering with a significant increase in facial hair loss relative to wild-type controls
• no significant differences are observed in barbering activity between female homozygotes and wild-type control females
• at 6 months of age, male homozygotes show a significant increase in grooming activity, both in terms of frequency of initiation and duration of grooming, as analyzed during a 20-min period immediately after a water-mist spray
• male-specific excessive grooming activities are accompanied by a significant decrease in COMT1 protein expression in the hypothalamus and can be reversed by 3 weeks of 17beta-estradiol treatment
• no significant differences in grooming activity are observed between female homozygotes and wild-type control females
• at ~3 months of age, both male and female homozygotes show a significant reduction in the total time spent in the novel arm of the Y-maze recognition task relative to wild-type controls
• both male and female mutants spent an equal time exploring all three arms of the Y-maze, suggesting a failure to recognize the novel arm
• gonadectomy reduces Y-maze responses in male and female wild-type controls, but has no effect in mutant mice
• after gonadectomy, there is no significant difference in the percentage time spent in the novel arm between mutant mice and wild-type controls
• notably, male and female mutants are NOT found to display increased anxiety-induced freezing or reduced explorative behavior in the elevated plus maze task
• at 6 months of age, male homozygotes display a significant increase in wheel running activity relative to wild-type controls; excessive wheel running is male-specific and can be suppressed upon 17beta-stradiol replacement
• in contrast, male homozygotes display a significantly reduced general ambulatory activity, indicating a specific increase in wheel running as opposed to a general hyperactivity
• no significant differences are observed in either wheel running or ambulatory activity between female homozygotes and wild-type control females
• no stereotypic behaviors such as barmouthing, jumping, somersaulting or route-tracing are observed in male homozygotes housed in an "enriched environment"

Mouse Models of Human Disease
OMIM IDRef(s)
Obsessive-Compulsive Disorder; OCD 164230 J:129528


Mouse Genome Informatics
cx4
    Apoetm1Unc/Apoetm1Unc
Cyp19a1tm1Esi/Cyp19a1tm1Esi

involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• increased body weight at 3, 6, and 12 months of age

cardiovascular system
• 3 month old mutants exhibit small aortic root lesions that are extensive at 6 months of age
• double mutants tend to have slightly larger lesion sizes than single Apoe mutants
• mutants develop large atherosclerotic lesions in the aortic root by 12 months of age; lesions are advanced in development and show a clear fibrous component
• however there is little evidence of atherosclerotic plaque formation within the thoracic aorta with only small lesion development seen in the thoracic aorta at 12 months of age
• mutants have moderately increased mean arterial blood pressure at 3 months of age
• mutants develop hypertension by 6 months of age which is sustained in older animals

adipose tissue
• mutants exhibit an increase in adipocyte size with a larger mean diameter compared to wild-type adipocytes, however no difference in the number of individual adipocytes
• increase in gonadal adipose

homeostasis/metabolism
• 3 month old mutants show a small elevation in baseline blood glucose concentration after an overnight fast
• mutants of all ages show reduced plasma insulin levels
• random-fed non-fasting mutants show an increase in serum cholesterol levels
• plasma levels of C-reactive protrein (CRP), IL-6, and TNF-alpha are increased in 12 month old mutants
• mutants administered a bolus of glucose show elevated plasma glucose
• 3 month old mutants show a blunted plasma glucose response in response to exogenous insulin administration; this blunted response becomes more pronounced with age

immune system
• plasma levels of C-reactive protrein (CRP), IL-6, and TNF-alpha are increased in 12 month old mutants

liver/biliary system
• from 6 months of age, livers begin to show yellow coloration
• increase in liver weight at 3 and 6 months of age
• 3 month old mutants start to show small lipid droplets forming within livers which become more pronounced at 6 and 12 months of age