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Sexual Dimorphism in
Environmental Exposures and Behavior
Bernard Weiss, Ph.D.
Department of Environmental Medicine and
Environmental Health Sciences Center
University of Rochester School of
Medicine and Dentistry
Rochester, New York
Gonadal Development and Testosterone
 The Y chromosome determines testicular development
 The SRY gene on Y chromosome encodes testis-determinating


factor (TDF)
The fetal testes secrete testosterone, which promotes growth of
internal and external sex organs
Ovaries do not make steroids until after birth
Sexual Differentiation of the Brain
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The undifferentiated brain is basically female, the default structure
Fetal testosterone transforms it into the male structure via estradiol
The transformation is governed by aromatase (TE)
Alpha-fetoprotein prevents masculinization of females
Fetal testosterone
Masculine brain
aromatase
Estradiol
Undifferentiated
brain
Female brain
Sex Differences in Brain Structure
 Male brains are more asymmetrical (lateralized)
 Several structures show differences in size
 The sexually dimorphic nucleus of the preoptic area is larger in males
 The anteroventral periventricular nucleus is larger in females
 Male brains, corrected for height, are 2-3% larger in males
 Female brains have a higher percentage of gray matter, male
brains a higher percentage of white matter.
Sex Differences in Gray Matter,
White Matter, and Cerebrospinal Fluid
(Gur et al, 1999)
Male-Female Performance Differences
(Kimura, 1992)
Males better
Females better
Hormonal Determinants of Neurobehavioral
Development in Animals
 Sexual differentiation of the brain
 Sexual behavior
 Courtship, mating, motivation
 Maternal behavior
 Aggressive and attack behaviors
 Sensory-motor function
 Stress responses
 Cognitive function
 Learning and performance
 Play behavior
EXAMPLES OF
ENDOCRINE-DISRUPTING CHEMICALS
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Phthalates (plasticizers): testicular poisons
Alkylphenols (detergents): estrogenic properties
Bisphenol A (coatings): estrogenic properties
Organochlorine pesticides: estrogenic properties
PCBs: thyroid hormone dysfunction
PCDDs: anti-androgenic properties
Vinclozolin (fungicide): anti-androgen
Phytoestrogens (plants): estrogenic properties
Characteristics of Endocrine
Disrupters
• Structurally diverse group
• Resist degradation
• Tend to accumulate in fatty tissues
• Affect developing organisms at low doses
• Behavior is a sensitive endpoint
Dioxins and Related Compounds
2,3,7,8 TCDD: the Prototypical Disrupter
• Binds to the intracellular Ah receptor
• Impairs copulatory behavior in males
• Impairs genital development in females
• Modifies operant behavior
• Alters sex differences in other behaviors
Wheel running activity in the female rat
• Rodents run spontaneously in wheels
• Gross output correlated to stages of the estrous cycle
• Rising levels of circulating estrogen associated with
increased running
Reinforcing Value of Access to Running Wheels
(Motivation to Run)
Method:
• single maternal dose of 0, 20, 60, or 180 ng/kg TCDD
on Gestational Day 18
• mean human body burden of dioxins is 13.5 ng/kg
• female offspring began training at 5 months
• examined with a series of fixed-ratio schedules of
access to running wheels
Running Wheel Reinforcement
Earned Runs as Percent of Control
Earned Running Periods in Female Rats
Exposed to Dioxin on GD18 (Markowski et al , 2001)
100
Maternal
Dose:
90
20 ng/kg
80
60 ng/kg
180 ng/kg
70
60
50
40
30
FR1
FR2
FR5
FR10
20
FR20
FR30
10
0
0
1
2
3
4
5
6
7
8
9
10
11
Session
12
13
14
15
16
17
18
19
20
Benchmark Dose Plot
for Fixed-Ratio Access to Running Wheel
(Markowski et al, 2001)
Chamber for Schedule-Controlled
Operant Behavior
Schedules of Reinforcement,
Las Vegas Style
Sex Differences in Fixed-Ratio Performance in Rats Exposed
Prenatally to Dioxin (Hojo et al, 2002)
Male-Female Contrasts in Fixed Ratio Response Rate
in Rats Exposed to TCDD on GD8
Quadratic Fit and Benchmark Dose for Male-Female
Differences on Fixed Ratio Response Rates
in Rats Exposed to TCDD on GD8
Endocrine Modulation of
Cerebral Lateralization
• Male Rats
– Right cerebral cortex
thicker than left (48/49
areas)
– Cell counts are higher on
right
– More estrogen receptors
in left neonate cortex
– Testes removal on PND1
reverses laterality
• Female Rats
– Left cerebral cortex thicker
than right (45/63 areas)
– Cell counts higher on left
– More estrogen receptors
in right neonate cortex
– After ovariectomy at birth,
left thicker than right in
only 2/7 areas
Scheme for Measurement of Cortical
Thickness
Measurement of Cortical Thickness for
Lateralization Index
Cortical Lateralization (Right-Left) in Female Offspring
Exposed to 180 ng/kg TCDD on GD8
Exposed
Control
(%)
(%)
- 10
-8
-6
-4
-2
0
2
4
6
-6
-4
-2
0
2
3
3
2
17
2
17
18a
18a
39
39
17a
17a
17b
17b
18a
18a
4
6
8
10
Radial Maze Diagram
Radial Maze Errors in Dioxin-Exposed
Male and Female Offspring
(Seo et al, 2000)
Males
Females
Sample items on Pre-School Activity Inventory
(Vreugdenhil et al, 2002)
• Toy choices
– Guns
– Dolls
• Activities
– Playing house
– Sports and ball games
• Behavioral characteristics
– Likes pretty thing
– Enjoys rough and tumble play
Regression Coefficients for Play Behavior
versus PCBs in Cord Blood
(Vreugdenhill et al, 2002)
Boys
Girls
Composite
4.06
-1.45
Masculine
-3.85
2.09
Feminine
0.15
0.71
Implications of Dioxin’s
Neurobehavioral Effects
• Sexually dimorphic behaviors are sensitive to doses in
the range of current human levels
• Exposures in utero may produce global, permanent
alterations in behavior or transient, domain-specific
changes
• Behavioral changes reflect altered patterns of brain
development
Is Prenatal Dioxin a Risk Factor for Depression?
• Impaired serotonin function is the clearest neurochemical risk
– SSRIs are the major drug treatments for depression
• Serotonin is a prime modulator of brain development
• In adult rodents dioxin disrupts serotonin function
– Brain turnover of serotonin is increased
– Tryptophan, the amino acid precursor, is increased in brain, plasma
• Trytophan crosses the placenta, alters fetal brain serotonin
• Fetal dioxin exposure in mice reduces serotonin neuron numbers
A Rat Model of Depression
(Males Only)