Ochiai E. Chemicals for Life and Living

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192

16 Environmental Issues: Organic Pollutants

PCDD (polychlorinated dibenzo-p-dioxin) TCDD (2,3,7,8-tetrachloro dibengo-diacin)

Fig. 16.2 Dioxins

Dieldrin

Aldrin

Heptachlor

Benzene hexachloride

(HCB)

Chlordane

Endrin

CCl

p,p-DDT o,p-DDT

Fig. 16.1 DDT and other similar chlorohydrocarbon pesticides (dirty seven)

16.2 Endocrine Disruptors

A book titled “Our Stolen Future” appeared in 1996. The authors Theo Colborn,

Dianne Dumanoski, and John Peterson Myers argued that some chemical substances

dispersed into the environment have gotten into human bodies and disrupted the

endocrine (hormonal) system of the humans (and other animals). They built their

thesis based on a number of scattered data.

For example, a Danish reproductive scientist, Niels Skakkebaek started to

observe sperm abnormalities as well as a drop in the sperm count (the number of

sperms in a unit volume). He also noticed that the number of patients with testicular

cancer tripled in Denmark between 1940s and 1980s. He and his coworkers checked

literatures available at the time and found to their surprise that the average human

19316.2 Endocrine Disruptors

male sperm counts dropped by 50% between 1938 and 1990 everywhere including

US, European countries, India, Nigeria, Brazil, Libya, Thailand, etc. This rapid

change, the authors contended, cannot be due to changes in the genetic composition

but must be due to some environmental factors.

Another such symptom is the decreased survival of alligators in Lake Apopka in

Florida. An accident at a chemical factory along the lake wiped out about 90% of

the alligator population. Yet, long after the lake water seemed to have turned nor-

mally clean, the remaining female alligators had a lot of reproductive problems.

Only about 18% of their eggs hatched, and many of the hatchlings died early, while

the normal hatching percentage is considered to be about 90%.

This second example suggests that even a very small quantity of an environmen-

tal contaminant might be effective in disrupting the reproductive system. This (and

of course, a lot other reports) led to a thesis that such an effect is very likely due to

the effect on endocrine systems, as they are based on low level of speciﬁc chemi-

cals, i.e., hormones.

In 1970s, many young women developed a special kind of vaginal cancer in the

United States. It turned out that their mothers had taken a medicine called DES,

diethyl stilbestrol, during their pregnancy. Many other DES daughters developed

malformed organs such as uterus. Apparently, an exposure to DES during the prena-

tal and neonatal stage of human development, particularly at the earlier stages, has

a profound effect on the later development in the affected person, both man and

woman. The effects of DES seem to be very widespread, on the reproductive sys-

tem, immune system, and possibly on the brain functions as well.

DES was not an accidental, environmental pollutant, but it was developed by a

drug company, approved by FDA, and touted as a wonder drug, and prescribed

widely for preventing miscarriage, morning sickness, etc. in the United States and

other countries starting in 1950s. It was supposed to mimic the indigenous hormone,

estrogen. Let us take a look at the chemical structures of the two compounds, estradiol

and DES, as shown in Fig. 16.3. The overall similarity of their structures is obvious,

Fig. 16.3 Estradiol

(upper) and DES

194

16 Environmental Issues: Organic Pollutants

and that makes DES a good substitute for estrogen as far as their interaction with the

receptor site is concerned. In other words, the receptor site may not be able to distin-

guish the two compounds. This is chemistry. However, the manifestations of that

interaction with the receptor are physiological issues, and whether it causes good or

bad effects depends on many factors including timing of the drug-taking and dosage.

The physiological effects, however, are eventually caused by chemical interactions

between the chemical compound and the cells/tissues/organs, but this aspect is not

very well understood yet, and besides, it is beyond the scope of this book.

Today, an endocrine disruptor is deﬁned as an exogenous substance or mixture

that alters function(s) of the endocrine system and consequently causes adverse

health effects in an organism or its progeny or (sub)populations. This deﬁnition

does not say anything about the mechanism of disruption. There are several ways

of disruption of the endocrine system by an exogenous substance. Some of them

are: (a) a substance interacts with the receptor of an endogenous hormone as in the

case of DES mentioned above and disrupts the interaction of proper hormone

molecules with the receptor; (b) a substance disrupts storage, secretion, and

transport of a hormone; and (c) a substance disrupts the proper processing of pro-

duction and metabolism of a hormone. The last mechanism can be more general,

including such things as inhibition of the enzymes involved in the metabolism of

a hormone.

Lists of suspected endocrine disruptors have been published and revised over and

over again. It is a rather difﬁcult task to establish the cause–effect relationship with

regard to an endocrine disruptor, as the level of presence of such a substance necessary

to cause an effect could be fairly low and the relationship could be indirect. We will

list several different types of suspected endocrine-disrupting compounds, as follows.

16.2.1 Those Binding to the Steroid Hormone Receptors

These substances bind to the steroid hormone receptors, and disrupt the hormone

systems concerned. Synthetic estrogens including DES and those mentioned in

Sect. 7.7 obviously belong to this type, because of their structural similarity.

However, some other compounds such as bisphenol A, and hydroxylated PCB

(polychlorobiphenyl) are also considered to bind to the receptors despite the fact

that there is no overall structural similarity (see Fig. 16.4). If they do indeed bind as

suggested, the receptor site could conceivably bind them through an OH group

along with an aromatic ring in its vicinity. This is a common feature of these differ-

ent types of compounds. In other words, the receptor site may recognize this feature

rather than the overall structural similarity. Many of the steroid hormone receptors

are “zinc ﬁnger” proteins as mentioned in Sections 6.4 and 7.7.

The system of male hormones, androgens, can also be subject to disruption by

some compounds. Such compounds include DDE (a DDT metabolite mentioned

earlier) and some esters of phthalic acid. However, whether the esters of phthalic

acid are indeed endocrine disruptors is still being investigated.

19516.2 Endocrine Disruptors

16.2.2 Those Affecting AH Receptor and Cytochrome-P450

Enzymatic Systems

Dioxin, PCB, DDT, and the like, i.e., chlorinated aromatic hydrocarbons are believed

to bind to a special receptor called “AH” receptor (AH stands for aryl hydrocarbon).

The AH receptor bound with dioxin (or PCB) enters into the nucleus of the cell, and

binds to a speciﬁc site of a DNA. One of the effects caused by such a binding seems

to be an induction of an enzyme dependent on cytochrome P-450. Cytochrome

P-450-dependent monooxygenase was talked about in Sect. 6.2.2, and is involved

in the metabolism of a wide variety of compounds including steroids and foreign

substances (drugs). Probably the P-450 enzymes induced by dioxin, PCB, and

others would then metabolize steroid hormones unnecessarily, and thus disrupt the

endocrine system. The details are still not very well understood. However, you see

that the processes are all chemical reactions at the deepest level.

PCDF (polychlorinated dibenzofuran)

Bisphenol-A

PCB’s

300-600

[O]

Fig. 16.4 PCB etc.

197

E. Ochiai, Chemicals for Life and Living,

DOI 10.1007/978-3-642-20273-5_17, © Springer-Verlag Berlin Heidelberg 2011

Chemicals surround us. We ourselves are made of chemicals, we need them, and we

are absolutely dependent on them. There is no escaping from this fact. Our lives are

a festival staged and performed by chemicals.

However, there are also chemicals we can do without. A living organism always

tries to enhance its own survival; it is the basic nature of living things. In that effort,

an organism may create a substance that is harmful to others; this is a natural defense

mechanism. Such a substance is a natural chemical weapon and can be harmful to

the human body (i.e., natural toxin), and we can do without it. People have used

throughout history a variety of chemicals with an intention to harm others; poisons

(of arsenic, cyanide, many poisons (alkaloids and others) obtained from plants and

others), explosives and chemical weapons (mostly neurotoxins). We are better off

without them. I must hasten to add, though, that some of these chemicals can be

used for useful purposes as well.

In addition, we humans have created a civilization in which a vast number of

goods that are made of chemicals are produced or synthesized and put into use for

enhancing our lives. Altogether about 20 million compounds have been registered

by the end of twentieth century. The intended use of most of these substances is

legitimate and is beneﬁcial, as we talked about on the pages of this book except for

a few chapters. But, after use, they are often discarded, left to deteriorate and decom-

pose and be dispersed into the surroundings. The environment may tolerate the pres-

ence of these chemicals to a certain extent, and can even get rid of them by

decomposing and converting them to less harmful forms. By the way, the self-

cleaning of the environment is done biologically and/or chemically. Most of these

processes involved are essentially chemical reactions even if done in the biological

systems, i.e., the so-called bioremediation. Some purely physical processes may

also be involved in certain cases. The catch is, though, that there is a limit to this

self-cleansing capacity of nature (the environments). Beyond this threshold, the

environment and the organisms in it may be adversely affected.

Use, Abuse, and Misuse of Chemicals

198

17 Use, Abuse, and Misuse of Chemicals

Some compounds synthesized artiﬁcially by mankind are difﬁcult to decompose.

They are made to last forever or at least for long. The reasons that they are difﬁcult

to decompose are (1) they are usually chemically very inert, and (2) Nature (mean-

ing organisms) does not know how to handle them because they have had no previ-

ous experience of handling them. Residual material from such chemicals can be an

environmental hazard because organisms that come in contact with them do not

have mechanisms to render them harmless. However, these incidents are not intended

results, and are simply results of bad management and neglect including disposal of

certain chemicals. Some aspects of this issue have been discussed in the last two

chapters. It is also to be noted that a lot of efforts are being made to produce the so-

called “bio-degradable” products, so that they can be decomposed and be rendered

harmless by the microorganisms in the environment.

Chemicals, useful or not, can also be misused because of lack of knowledge or

misunderstanding of how to handle them. Let us differentiate “misuse” (incorrect

use) from “abuse”; the former involves no intentional improper use whereas the

latter does.

Human beings tend to abuse chemicals for certain speciﬁc gains, including enter-

tainment. We do so, particularly when there is pressure from others. This is an

intentional improper use of a chemical compound other than its proper use. For

example, ammonium nitrate is a very good chemical fertilizer, but it happens to be

usable as a basic ingredient in an explosive, as exempliﬁed in the bombing of the

Oklahoma federal building (see also Chap. 8). (It has to be mentioned that overuse

of strictly inorganic fertilizers such as ammonium nitrate can degrade the soil, and

nitrate released into water systems pollute the water. Another more commonly used

fertilizer, ammonium sulfate is worse than the nitrate in degrading the soil, partly

because sulfate combines calcium to form calcium sulfate rendering calcium less

available to plants and others). Hormones that enhance muscle and blood formation

can be used for the purpose of gaining an advantage in athletic competitions.

A number of gold medalists at 2004 Athens summer Olympic Games were stripped

of their medals, when they were tested positive for such drugs. We will talk about a

few examples of chemicals abused often.

Many of abused chemicals and animal toxins interfere with the functions of brain

and its associated organs. Therefore, we will brieﬂy review here the chemistry/

physiology of the brain.

17.1 Chemistry of Brain Function: Basics

The nervous system consists of the central nervous system (brain and spinal cord),

the peripheral or autonomous (sympathetic and parasympathetic) nervous sys-

tems, and the sensory organs. The brain is where a huge number of signals are

brought in from the sense organs and others and processed and bodily functions are

effected accordingly. These signals and their interpretation by the brain represent

the consciousness; they manifest as “sensation”, ”emotion”, “memory”, “thought”, etc.

19917.1 Chemistry of Brain Function: Basics

They elicit some actions such as muscle movement. Hence, disruption of the brain

functions can lead to such a result as emotional/mood change or paralysis, etc.

The brain consists of cells called “neurons”; there are several hundreds of billions

of such cells in our brain. A neuron makes connections to a number (several thou-

sands) of other neurons. The signal travels within a neuron as an electric signal; the

electric impulse is created by ionic movement through ion channels across the cell

membrane such as sodium and potassium channel. When the signal comes to a junc-

tion called “synapse”, it has to be carried by a chemical compound across the narrow

gap (which is 5–20 nm wide) between the neurons. Such a chemical compound is

called “neurotransmitter”. A neurotransmitter molecule binds to the receptor site on

the surface of a post-synaptic neuron. The receptor is an ion channel, and the binding

of a neurotransmitter opens the channel, hence resulting in the creation of a new

electric signal on the postsynaptic cell.

Several different types of neurotransmitter compounds are known. One is acetyl-

choline, and its mechanism of action seems to be best understood and will be dis-

cussed shortly. The second group called “catecholamines” contains rather familiar

compounds such as adrenalin (epinephrine), noradrenalin (norepinephrine), and

dopamine (Fig. 17.1). The third group consists of several amino acids such as regu-

lar ones: glutamic acid and aspartic acid, and unusual ones such as g-aminobutyric

acid (GABA) and N-methyl-D-aspartate (NMDA). Another group contains several

small proteins (peptides). Examples are enkephalin, endorphin, gonadotropin,

oxytocin, and vassopressin.

The mechanisms of all the neurotransmitters’ function have not been well under-

stood. One neurotransmitter, acetylcholine, has been studied intensely and will be

discussed brieﬂy here. The structure of acetylcholine is shown in Fig. 17.2, along with

those of nicotine, serotonin and muscarine. Acetylcholine is released from the syn-

apse and migrates to the next neuron surface nearby, and binds to a receptor. There are

two types of acetylcholine receptor; one is “nicotinic”, implying that it also binds

nicotine, and the other “muscarinic”. Nicotine and muscarine (as seen in Fig. 17.2)

have a common feature, i.e., a positively charged nitrogen such as acetylcholine. The

receptor itself is an ion channel. When acetylcholine binds with the receptor, the ion

channel opens up, and the inﬂow of Na

and outﬂow of K

ensues. The sudden change

of the cationic concentration inside and outside of the postsynaptic neuron creates an

DOPA

N(CH

Norepine phrine

Epinephrine

Dopamine

COOH

Fig. 17.1 Catecholamines

200

17 Use, Abuse, and Misuse of Chemicals

electric potential change; this is the electrical impulse that is then propagated along

the neuron. Acetylcholine released to the inter-synaptic space has to be decomposed

so that the impulse caused is stopped; otherwise the elicited effect continues and can

result in the disruption of the nerve impulse propagation. The decomposition of ace-

tylcholine is carried out by an enzyme called “acetylcholine esterase”. We will later

look into acetylcholine esterase in connection with chemical weapons.

The structure of a nicotinic acetylcholine receptor has been determined and is

shown schematically in Fig. 17.3. It has been demonstrated that acetylcholine binds

to a segment of the receptor, in which the binding center is an amino acid residue,

tryptophan (149-Trp). Tryptophan has the structure shown in Fig. 17.4, and has a

negatively charged portion in the center of the aromatic rings (hexagon and pentagon).

The positive charge on the end of acetylcholine binds to this negative charge

(Fig. 17.5). Nicotine, having a positively charged nitrogen such as acetylcholine,

does bind to the same general area containing the 149-Trp residue, but the major

interaction seems to be with different residues in the same area.

Fig. 17.3 A schematic

representation of (nico-

tinic) acetylcholine

receptor (from Dougherty

DA and Lester HA (2001)

Nature 411: 252–25)

muscarine

nicotine

serotonin

acetylcholine (ACh)

Fig. 17.2 Acetycholine, nicotine, serotonin and muscarine

20117.1 Chemistry of Brain Function: Basics

It has been demonstrated also that serotonin (another neurotransmitter,

alternatively called “5-HT (5-hydroxytryptamine), see Fig. 17.2) similarly binds to

a receptor through the interaction between a tryptophan residue and the positive

charge on serotonin.

Catecholamines as depicted in Fig. 17.1 are not electrically charged, but under

physiological conditions (pH), a nitrogen atom in each of these compounds gains a

proton (H

) and hence becomes positively charged. This is Lewis acid–base interac-

tion due to the presence of a lone pair on the nitrogen atom and was talked about in

Chaps. 1 and 19. It is possible, though it has not been veriﬁed, that the positively

charged nitrogen entity may be involved in binding to the respective receptor site as

in the case of acetylcholine and serotonin. It is further speculated that since alka-

loids such as morphine and poison frog’s batrachotoxin (see below) also have simi-

lar nitrogen atoms they can become positively charged under the physiological

condition and, perhaps, bind similarly to the receptors. Such a binding of a foreign

compound to the neurotransmitter receptor site obviously disrupts the brain

functions.

The workings of brain are very complicated. Hence, there is a complicated, yet

to be understood, often convoluted relationship between the basic chemical

interactions of a neurotransmitter or a drug with the receptor and the physio-

logical manifestation, e.g., psychic effects. Chemistry can suggest only the basic

mechanisms.

negatively charged

Tryptophan

COOH

Fig. 17.4 Tryptophan and its electric charge distribution

Fig. 17.5 Binding of

acetylcholine to the (149)

tryptophan residue (from

Zhang W et al. (1989) Proc

Nat Acad Sci (USA) 95:

12088–12093)