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OCR for page 169
TO
Biologic Markers
of Reproductive Development and Aging
Toxicants and other environmental fac-
tors can influence female reproductive
function during development, as well as
during later age-related changes. This
chapter discusses biologic markers of
female reproduction across the life span,
including markers of neuroendocrine func-
tion that are potentially pertinent to
reproduction. Some of these markers might
be used to assess effects of toxicants.
Little information is available on cri-
tical periods or ages of particular vul-
nerability for effects of toxicants on
postnatal development and aging. Some
effects of toxicants could be equivalent
to accelerated senescence.
Cryptic damage-damage not immediately
manifested—might interact with other
insults. All-or-none effects might not
be associated immediately with a particu-
lar exposure. Daughters exposed to DES
in utero manifested an increased incidence
of genital tract cancer as adults (Herbst
et al., 1974~. Exposure of neonatal rats
to DDT causes major impairments of female
reproductive functions that emerge after
, . .
puberty (He~nr~chs et al., 1971~. Chronic
exposure of mice to endogenous ovarian
steroids secreted during young adult life
is a cause of age-related estrous cycle
lengthening (Felicio et al., 1986) or pre-
mature loss of estrous cycles after the
169
estrogen treatment ends (Mobbs et al.
1984; Kohama et al., 1986~.
These rodent phenomena have no human
analogues. However, the likelihood of
hot flushes at menopause when estrogen
concentrations decrease appears to
depend on exposure to ovarian steroids
during puberty. Women with Turnerts syn-
drome, whose estrogen concentrations are
the same as postmenopausal concentra-
tions, do not have hot flushes; however,
withdrawal from estrogen treatment will
cause hot flushes in these women (Yen,
1977~. That important result indicates
that the adult human nervous system has
memory mechanisms for exposure to steroids
such that the effects can be manifested
decades after the exposure (Finch et al.,
1984~. In analyzing interactions of estro-
genic toxicants with the nervous system,
we should anticipate potential cryptic
effects on the numerous neurons throughout
the brain that contain receptors with high
affinity for estrogens and other steroids.
Many examples demonstrate cryptic
brain damage during early adulthood.
The relation between viral encephalitis
(don Economo's disease) and parkinsonism
is a classic case (Poskanzer and Schwab,
1961; Finch, 1976; Caine et al., 1986~.
Parkinsonism induced by ingesting the
neurotoxicant methyl~phenyl~tetrahydro-
OCR for page 170
170
pyridine (MPTP), which often contaminates
synthetic heroin, might not occur immedi-
ately; some persons without necrologic
symptoms have depressed metabolisms in
their dopaminergic systems, as determined
by positron emission tomography analysis
(Calneetal., 1985~.
Those examples constitute ample pre-
cedent for considering possible long-
term adverse effects of toxicants on neuro-
endocrine loci that might be incurred oc-
cupationally (e.g., by metal workers).
Most biologic markers of toxicant-re-
lated effects on female reproductive func-
tions are physiologic or morphologic.
Among the best-characterized markers used
in epidemiologic surveys and individual
case studies are infertility and length
of menstrual cycles, which appear to be
sensitive to many of the same environmental
influences in humans and rodent models.
However, human neuroendocrine repro-
ductive functions appear to differ in im-
portant ways from those of rodents; the
hypothalamus might be less crucial in regu-
lating the preovulatory surge in humans
than of rodents (Knobil, 1980~. Nonethe-
less, human female reproductive functions
clearly are susceptible to neurogenic
influences from stress (Peyser et al.,
1973) and perhaps from pheromones (Russell
etal., 1980~.
Transgenerational toxic effects can
arise in several ways. The oocyte comple-
ment of an adult female is attained in utero
before the midpoint of gestation. Toxi-
cants might reduce the number of oocytes
and, if mutagenic, affect later genera-
tions. Furthermore, toxicants in the ma-
ternal environment that affect fetal brain
development could influence the maternal
physiology and behavior of female off-
spring, which then affects the next genera-
tion. For example, environmental influ-
ences that extend to the F2 generation have
been demonstrated in rats (Zamenhof et
al., 1972~. Malnutrition during pregnancy
reduces the number of brain cells in rats
for at least two generations, despite
crossfostering of pups with normal sur-
rogate nurses (Zamenhof et al., 1972~.
The concept of transgenerational envi-
ronmental effects is well known to develop-
FEMALE REPRODUCTIVE TOXICOLOGY
mental biologists, but has not been dis-
cussed widely as an aspect of toxicology.
MARKERS OF MATURATION
Adrenarche
Increases in plasma DHEA-S (a metabolite
of DHEA) precede increases in estrogens
by several years in humans and indicate
maturation of adrenal cortical function.
The stimuli for increased secretions of
DHEA and other adrenal steroids before
puberty are poorly understood and do not
seem to involve direct action of ACTH or
gonadotropins. Although readily meas-
ured by radioimmunoassays, the increase
in the plasma metabolite DHEA-S is linked
only circumstantially to functional
changes in maturation.
Ovary and Uterus
Size changes in the uterus and ovary
can be followed by ultrasonography
_ . . .
The data base is
modest t~or ultrasound measurements of
these morphologic changes, but such
measurements can be obtained in conjunc-
tion with other common clinical markers
of puberty.
~rs~n~ et a ., 15~84 .
Menarche
Onset of menstrual bleeding is the
most obvious sign of active ovarian
steroid secretion. The onset is triggered
by increases in E2 and progesterone, fol-
lowed by decreases in progesterone within
a few days. Ovulatory cycles usually are
established months after menarche and
vary considerably in timing and hormonal
characteristics.
Thelarche and Pubic Hair
The ages of thelarche and the appearance
of pubic hair are used widely to judge
whether puberty is precocious or delayed,
and an extensive data base is available.
Five morphologic stages of breast develop-
ment generally are accepted (Marshall and
Tanner, 1969~. The five stages can vary
extensively in duration and can revert
OCR for page 171
REPRODUCTIVE DEVELOPMENT AND AGING
to earlier stages. Four pubic hair stages
also show extensive individual var-
iations. Breast and pubic hair stages
often are asynchronous and by themselves
do not precisely indicate the rate of
development.
MENSTRUATION
Menstrual cycles constitute the most
accessible and noninvasive biologic mark-
er of female reproductive function in hu-
mans. The cycle lengths can vary (average,
28 days); determination of amenorrhea or
other acyclic conditions requires a
daily menstrual record for at least some
3 months in humans and higher primates.
Because the menstrual cycle can fluctuate
as a result of nutrition, stress, use of
oral contraceptives, and other influ-
ences, detailed personal and medical
histories must be collected from study
subjects.
Laboratory rodents do not have menstrual
cycles, but have estrous cycles, and their
cycle status usually can be established
from cell changes in daily vaginal smears.
Acyclicity is defined as 14-30 days without
evidence of ovulation in a proestrus
smear. The onset of acyclicity can be stud-
ied as part of the aging processes or as
a response to experimental intervention.
Strings of cornified smears for 14 days
or more indicate a polyfollicular anovula-
tory condition (persistent vaginal cor-
nification), which is the most common ini-
tial acyclic state during aging (Finch
et al., 1984~. Similar vaginal smear pat-
terns after acute or chronic exposure of
young rodents to suspected environmental
toxicants indicate severe disruption of
the reproductive neuroendocrine system.
Whether acyclicity is reversible depends
on the agent, age at exposure, and duration
of exposure. Permanent acyclicity has
been induced in rats by DDT (Heinrichs et
al., 1971~.
Menstrual or estrous cycles can be
analyzed for cycle length distributions
and for lengths of consecutive cycles.
The most detailed analyses have been done
on rodents during aging. The frequency
distribution of estrous-cycle lengths
(e.g., 4-day, 5-day, or 6-day cycles)
..`
171
and the frequency of length transitions
(e.g., 4-day to 4-day or 4-day to 5-day
transitions) are sensitive indicators
of maturation and aging as well as for ef-
fects of estrogen toxicity in mice (Fig.
13-1 ) (Nelson et al., 1982~.
Available longitudinal menstrual rec-
ords should be analyzed in more detail (see
Treloar et al., 1970~. Many powerful sta-
tistical time-series analyses might de-
tect random and structured effects of toxi-
cants on cycle length. For example, a
digital filtering technique that removed
atypical frequency variations (Orr and
Hoffman, 1974) detected cyclic increases
in gonadotropins in premenarchal girls
(Hanson et al., 1975~. Several groups have
analyzed pulsatile LH in rats (Ellis and
Desjardins, 1984) with the iterative ap-
proach of the Cycle Detector Program
(Clifton and Steiner, 1983~. Phase rela-
tionships and couplings among cycle length
distributions should be investigated in
depth.
LOSS OF FERTILITY AND
FECUNDITY
Using infertility to assess the effects
of toxicants is difficult, because of the
common use of oral contraceptives and the
importance of male-specific factors
(e.g., oligospermia). Proper diagnosis
of infertility usually requires endocrine
and gynecologic data.
Resorption of most abnormal rodent fe-
tuses is reflected in reduced litter
size; the age-related decrease in litter
size does not result from the shedding of
fewer ova at ovulation (Holinka et al.,
1979~. Age-related increases in number
of stillborn pups contribute to reductions
in litter size and are associated with an
increase in length of gestation (Holinka
et al., 1979~. In humans, there is also
an age-related decrease in number of
offspring long before the approach to meno-
pause, in which behavioral factors also
are important (see Fig. 11-7~. The age-
related frequency of increasing fetal
malformations causes increased rates
of spontaneous abortion.
OCR for page 172
172 FERTILE REPRODUCTIVE TOXICOLOGY
Cohort A Cohort B Cohort C
a
0—
-
CJ)
llJ
_
co
lo
O
co ~
~ ~ 10
oh
o
z
8
o
z
LL
C'
LL
G
LL
50
, 50
us
10
50
I
~ 10
. . . . . . .
. . . . . . · · . . . .
L 1
l 2 X'
Nfl
\..W,... \
`~_]
.'. ..~....-..., 1
L: I...
· . . .
5 10 15 5 10 15 5 10 15
AGE (months)
FIGURE 13-1 Frequency profiles of estrous-pycle length transitions (4 4, ~5, and ~5 + 54 days) in three
cohorts of aging virgin mice. Phase designations are described in Figure 11-5. Reprinted with permission from
Nelson et al., 1982.
PRECOCIOUS MENOPAUSE
Early menopause can have various
causes, including hereditary influences
associated with either parent, autoimmune
destruction of ovarian tissue, mumps oo-
phoritis, and exposure to ionizing radia-
tion (Mattison et al., 1983; Gosden, 1985;
Finch and Gosden, 1986~. Premature onset
of infertility and menopause usually is
attributed to premature depletion of the
ovarian follicular stock (Golden, 1985~.
Rodents are susceptible to premature
infertility syndromes in association with
neuroendocrine damage, as when steroids
are administered to neonates in submas-
culinizing doses (Mobbs et al., 1984~.
Natural variation of rodent infertility
occurs due to in utero factors; female
fetuses flanked by males eventually become
infertile several months before fetuses
flanked by females; such effects probably
are limited to a critical period during
development (Vom Saal and Moyer, 1985~.
OVARIAN OOCYI E DEPLETION
Oocytes become depleted throughout
the lifetime of an individual female.
Assays of the oocyte stock require labor-
ious histologic analyses of excised ova-
ries. Very few human ovaries have been
sectioned serially to determine oocyte
numbers. Biopsies or ultrasound examina-
tions can show whether the ovaries are
cystic or atrophied (Orsini et al.,
1984), and continued improvements in image
analysis systems could make large-scale
histological analyses of human oocyte
stock plausible in the near future.
More information about ovarian oocyte
stock might come from administering ex-
ogenous gonadotropins for controlled
hyperstimulation in new reproductive
technologies. Mouse ovaries produce
ova with endogenous or exogenous gonado-
tropic stimuli until almost immediately
before the stock is exhausted (Gosden et
al., 1983), as do human ovaries (Sherman
et al., 1976~.
OCR for page 173
REPRODUCTIVE DEVELOPMENT AND AGING
HORMONES
Gonadotropins and steroids can be as-
sayed accurately in small blood samples-
0.01-5 ml. Most assays can be scaled down
for mice and rats with appropriate immuno-
reagents. In addition, human urine and
saliva are sources for measurements of
major changes.
Gonadotropins
Pregnancy-related increases in chorion-
ic gonadotropins in urine can be detected
by a highly sensitive assay as early as 8
days after fertilization. The assay can
help to identify groups with inapparent
spontaneous abortion in early pregnancy
(Wilcox et al., 1985) that might be due to
effects of toxicants. Daily urine samples
are needed, in addition to records of in-
tercourse frequency and menstrual cycles.
A large epidemiologic study is described
in Chapter 15.
Measurement of LH and FSH to monitor
the complex changes during puberty and
menopause is problematic because of in-
dividual variations. However, postmeno-
pausal LH and FSH increases are detected
easily, and their absence after menopause
might be an indirect biologic marker of
hyper - prolac tine mia , since prolac tin
suppresses LH secretion at the pituitary
(Cheung, 1983~. Stable, increased LH and
FSH constitute a biologic marker of prema-
ture ovarian exhaustion or atrophy. More
refined analyses of daily fluctuations
in women of reproductive age require multi-
ple daily blood sampling over several
months, which is difficult to do on a large
scale. Resolution of toxic effects on
high-frequency LH surges is even more dif-
ficult, and requires sampling every 5 to
1 5 minutes.
Prolactin also might be important for
monitoring toxicants and drugs that pro-
mote growth of lactotropes (pituitary
acidophilic cells that secrete prolac-
tin). Rodents are susceptible to prolac-
tinemia and the spontaneous lactotrope-
containing pituitary tumors that commonly
arise during acyclicity; these can be in-
duced by chronic exposure to estrogens
in some genotypes (Finch et al., 1984~.
173
Although lactotrope adenomas in humans
have not been linked to estrogen exposure
(E1 Etreby, 1980), the possibility is still
being considered. Some widely prescribed
drugs, such as haloperidol and reserpine,
increase prolactin. Monitoring prolactin
may not require serial daily blood sam-
pling. Fluctuations in prolactin across
menstrual cycles (Guyda and Friesen,
1973) are much smaller than increases
often seen in hypersecreting pituitary
tumors.
Steroids
E2, progesterone, and DHEA-S are major
age-related biologic markers from men-
arche through menopause. All are best
measured from blood, but all have small
daily fluctuations and can be assayed in
small blood samples (5-10 ml). Urine also
can be used to assay estrogens (Thijssen
et al., 1975), progesterone metabolites
(Teitz et al., 1971; Speroff et al., 1983;
Rebar, 1986; Shackleton, 1986), and etio-
cholanolone, an androgen related to DHEA-
S (Bulbrook et al., 1971~. DHEA-S changes
little across the menstrual cycle (Guer-
rero et al., 1976) or diurnally (Rosenfeld
et al., 1975~. Daily sampling for proges-
terone is needed to identify changes in
corpus luteum functions, but a single mid-
luteal sample suffices to document corpus
luteum formation.
Cortisol is also of interest, because
of its close relation to stress, which can
affect cyclicity, and therefore, fertil-
ity. However, extensive diurnal fluctua-
tions and response to activity and ambient
temperature contraindicate cortisol as
a useful general biologic marker of repro-
ductive function.
NERVOUS SYSTEM
A major issue in interpreting the
impact of chronic exposure to toxicants
on brain functions is the extent of under-
lying age changes. Rodents become more
sensitive to some agents with age, as
judged by greater depletion of dopamine
in 28- versus 4-month-old rats exposed
to the same dose of the neurotoxin 6-hy-
droxydopamine (Marshall et al., 1983~.
OCR for page 174
174
These age changes might be caused by al-
tered clearance or weakened detoxifica-
tion mechanisms, of which there is ample
evidence (Vessel and Dawson, 1985~. Some
rodent studies have shown age-related
decreases in extracellular space, which
might increase the efficacy of toxicants
(Bondareff, 1973~. The effects of age on
toxicant stability and metabolism in viva
need more study.
Alternatively, toxic effects might
be greater with age because of age-related
reductions in "neuronal reserve" (Fig.
13-2~. Particular support for that idea
is found in Huntington's chorea, an autoso-
mal dominant disease that has onset in
persons 30 to 60 years old and is associated
with the selective neuronal deteriora-
tion. Asymptomatic carriers have shown
necrologic abnormalities after drug chal-
lenge (Klawans et al., 1972), as though
their resistance to the drug is diminished
or their capacity to function under stress
has diminished (Finch, 1980~. Thus, pro-
gressive, age-related changes in the brain
might approach a dysfunction threshold
so that the margin of safety for a range
of insults is smaller, through either loss
of neurons or erosion of the dendritic
arbor (Finch, 1976; Calne et al., 1986~.
Those phenomena are suspected to occur
in the hypothalamus with advancing age,
but few data are available.
Dopaminergic losses do not produce neur-
-
a) 100
z
-
~:
o
~ 10-
c,~ O -
FEMALE REPRODUCTIVE TOXICOLOGY
ologic symptoms until critical threshold
is reached (cross-hatched region) leading
to parkinsonian symptoms (see Fig. 13-
2~. Ultimately, lesion summates with
normal age trend for loss of nigro-striatal
dopaminergic activity to exceed putative
threshold (Finch, 1976~. Greater induc-
tion of reversible parkinsonian symptoms
in older patients by antipsychotic dopa-
minergic antagonists (Ayd, 1961 ) is also
consistent with this model. Parkinson
disease thus could afford a "window" on
aging changes. Huntington's chorea
(Finch, 1980) and Alzheimer's disease
(Caine et al., 1986) are among other age-
related necrologic diseases with distinc-
tive ages of incidence that might be viewed
similarly (from Finch, 1981~.
The extent to which age-related manifes-
tations are time-dependent and cumulative
is also uncertain; for example, the inci-
dence of skin cancer in mice is related more
closely to duration of exposure to benzo-
pyrene than to age (Peso et al., 1975~.
A general representation of that concept
is the experience space of Figure 13-3,
which shows how duration of exposure and
strength of the stimulus (e.g., toxicant
or drug) could interact to determine dif-
ferent trajectories that approach the
hypothetical dysfunction threshold at
different rates.
DELAYED CONSEQUENCES OF VIRAL ENCEPHALITIS
OR GENETIC DEFICIENCIES
20 40 60 80 100
FIGURE 13-2 Late-midlife onset of some
types of parkinsonism might result from early
viral lesion (encephalitis lethargica) that causes
loss of substantial nigral dopaminergic neurons
\ NORMAL AGING TREND (Poskanzer and Schwab, 1961) or from genetic
, Viral V~%Loss/Yr) deficiency (Mjones, 1949; Mynanthopoulos et
g_ n e ales \ al., 1969) of nigral dopaminergic function.
Genetic ~-_ \^ Dopaminergic losses do not produce necrologic
Deficiencies? ~-_~, symptoms until critical threshold is reached
//// PARKINSON SYMPToMs if//// (cross-hatched region), leading to parkinsonian
symptoms. Ultimately, lesion summates with
420 (years) normal age trend for loss of nigro-striatal dopa-
minergic activity to exceed putative threshold
(Finch, 1976~. Greater induction of reversible
parkinsonian symptoms in older patients by an-
tipsychotic dopaminergic antagonists (Ayd, 1961)
is also consistent with this model. Par-
kinson's disease thus might afford a window on
aging changes. Huntington's chores (Finch,
1980) and Alzheimer's disease (Caine et al.,
1986) are among other age-related necrologic
diseases with distinctive ages of incidence that
might be viewed similarly. Source: Finch, 1981.
OCR for page 175
REPRODUCTIVE DEVELOPMENT AND AGING
functional ~
impairment T
100
a)
Threshold-- Q 50
LL
cryptic ~
damage ~' 10
o
175
-- ~ ~ ~ ~
l iN
dose
o
CHANGE (percent)
100
10
time- ~ lifespan
Change = f (dose, time)
FIGURE 1~3 Ag~related phenomena might be represented on a 3-d~mensional experience surface whose axes
are time, dose (strength of a cause of ag~related change, e.g., estradiol in ova~y-dependent neuroendocrine syn-
drome of rodents), and change (impairment as function of dose and timed. In many cases, change might be
cryptic functional consequence) until some threshold is reached (stippled background). Three trajectories at
different doses are shown (arrows). Source: Finch, 1987.
Behavior
Rodents have a robust repertoire of
sex-steroid-dependent behavior that can
be used to assess the effects of environ-
mental toxicants—such as lordosis and
open-field activity. Hormonal influences
on sexual behavior in women have been dif-
ficult to prove, and no markers have been
generally accepted. Increasing evidence
shows that sexual interest might be linked
to concentrations of plasma androgens
(Morriset al., 1987~.
Cell Populations
A few reports suggest age-related loss
of hypothalamic neurons in the human female
(Sheehan, 1968; Swaab and Fliers, 1985~.
The data are scarce, however, and do not
establish any change in neuron populations
as a suitable marker of reproductive neuro-
toxicity. However, studies in rodents
indicate that this may be a useful biologic
marker.
In rodents, at least three markers of
age-related neuron damage are available.
Glial hyperactivity in the arcuate nucleus
increases during female reproductive
senescence (Schipper et al., 1981 ~ and
can be induced in young rats by estrogen
exposure (Brewer et al., 1983~. N-Methyl-
d-aspartate causes premature cycle
lengthening and also kills 30% of arcuate
neurons (May and Kohama, 1986~. Binding
of lead-210 by the hypothalamic median
eminence in autoradiographic studies
(Stumpf et al., 1980) and the effect of lead
on neurotransmitters (Silbergeld, 1983)
are additional possible CNS markers of
toxicity in rodents. Postmortem human
brain tissue might be used for similar
analyses, but few studies have been
attempted.
In humans, research is needed to deter-
mine whether changes in hypothalamic
cell populations can be measured nonin-
vasively and whether these changes corre-
late with reproductive toxicity.
Important information must be obtained
by brain-imaging techniques, such as 2-
deoxyglucose uptake, which is sensitive
OCR for page 176
176
to neuronal degeneration in other brain
regions. Sex-related differences in size
of neuron population and in susceptibility
to damage from endogenous hormones or ex-
ogenous agents also are of interest.
Neuron damage often is viewed as an
all-or-none outcome, with cell death as
the only end point. However, a spectrum
of damage should be considered-from rever-
sible to irreversible. Neurotoxicants
and their interactions with hypoxia and
sugar in hippocampal neurons illustrate
the possibilities (Sapolsky, 1985, 1986~.
Molecular approaches should be applic-
able, e.g., by following changes of mRNA
that are induced by hypoxia (Pulsinelli,
1985) and corticosteroids (Nichols et al.,
1986~. Other molecular markers of inter-
mediate stages of neuron damage during
early and late responses to toxicants
should be sought.
Neuron loss from acute or chronic expo-
sures to toxicants cannot be evaluated
without a greatly extended data base on
possibly age-related neuron loss. Data
are available from postmortem material
that is meager for ages under 65 years.
Most studies have been conducted on fewer
than 5 brains from persons within any 20-
year age span. Consequently, the normative
range of neuronal numbers for different
brain regions and pathways in healthy young
adults is unknown. The absence of these
data severely limits future studies on
neurotoxicant-age interactions in the
hypothalamus. More information will
emerge slowly from studies of nerve cell
loss during Alzheimer disease, since a
range of control groups is being sought.
Feasibility studies are needed to deter-
mine which of the toxicant-sensitive neur-
on populations can be counted most
reliably by automated image analysis to
determine loss. Normative age-related
profiles could be established later from
postmortem specimens of neurologically
normal brain donors with known health sta-
tus enrolled in the Alzheimer's Disease
Research Centers. Such tissues would pro-
vide a basis for investigating groups
that might be at risk of toxicant-related
neuron damage, e.g., from occupational
exposure to metals or from dietary expo-
sure to phytoestrogens.
F~hL4LE REPRODUCTIVE TOO
OBSERVATIONS ON THE USE OF
THESE MARKERS
Need for Multiple Biologic Markers
Onset, changes, and loss of menstrual
cycles and their duration are major b~o-
logic markers of changes during maturation
and menopause. Fertility depends on other
functions as well; therefore, other mark-
ers of reproductive status are needed to
assess the impact of environmental toxi-
cants. Multiple assays of ovarian and
pituitary hormones are needed-especially
during transitional periods-to establish
the stability of basal values and charac-
terize the frequency and amplitude of epi-
sodic changes, such as preovulatory LH
surges and pulsatile LH release. The ef-
fects of lead in reducing progesterone
concentrations and lengthening luteal
phases and menstrual cycles of young adult
monkeys (Franks et al., 1986) illustrate
the value of these biologic markers and
the need for data on menstrual cycle length
and hormonal status. Accounts of irreg-
ular menstrual cyclicity in association
with phytoestrogens from tulip bulbs eaten
in the Netherlands during World War II
(Burroughs et al., 1985) cannot be evalu-
ated clearly without supporting data on
nutritional and endocrine status.
Differential Susceptibility of Individuals
and Populations
Biologic markers are needed to identify
individuals or populations whose repro-
ductive functions are particularly sus-
ceptible to toxic effects. Human indi-
viduality might arise from genotypic dif-
ferences or from a broad spectrum of en-
vironmental influences throughout life.
A wide range of examples of genotypic and
environmental influences on responses
to toxicants has been modeled in labora-
tory animal studies, genetic influences
on the cytochrome P-450 drug metabolizing
enzymes (Gonder et al., 1985; Koizumi et
al., 1986~. Human genetic polymorphisms
in responses to toxicants have not been
identified, but studies of twins and
drug clearance indicate greater concor-
dance between monozygotic twins than be-
OCR for page 177
REPRODUCTIVE DEVELOPMENT AND AGING
tween dizygotic twins (Vesell et al.,
1971~. The well-known prevalence of lac-
tase deficiency in adult Orientals (McKus-
ick, 1975) that causes intolerance to the
lactose in milk and unfermented milk prod-
ucts also supports the presence of genetic
polymorphisms that could influence re-
sponses to environmental toxicants.
Analysis of Menstrual Cycle Lengths
The frequency of menstrual cycles gener-
ally has been characterized in statistical
terms. The large longitudinal data bases
of cycle lengths from hundreds of women
collected by Treloar et al. ( 1970) and
others could be used to develop new statis-
tical descriptors of changes in cycle fre-
quency, for example, the frequency of con-
secutive cycles of particular lengths.
Many sophisticated approaches might de-
tect structured or random toxic effects
on cycle length and on lengths of consecu-
tive cycles. That information also might
bear on the increase in birth defects
with maternal age. Pilot studies are
needed to evaluate the applicability of
existing approaches and needs for further
177
development. Primate and rodent responses
to toxicants that influence cycle frequen-
cy could be used to evaluate the sensitiv-
ity of these approaches.
Long-Term Necrologic Consequences of
Toxicant Exposure
In view of the many examples of cryptic
neuron damage that results in necrologic
disorders years after toxicant exposure,
pilot studies should be established to
track subjects exposed to neurotoxicants
early in life. The recently established
followup studies of MPTP exposure (Caine
et al., 1985) are a precedent for this ap-
proach that might be extended to long-
term effects from occupational exposures
to lead, manganese, and other neurotoxic
agents.
Longitudinal necrologic and psychiatric
studies at the Alzheimer Disease Research
Centers compare various normal and dis-
ease-afflicted groups with dementia pa-
tients and might be helpful in determining
long-term effects. Additional groups for
antemortem or postmortem studies could
be added easily.
OCR for page 178
Representative terms from entire chapter:
biologic markers
